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Sample records for parent-metabolite pharmacokinetic model

  1. Population pharmacokinetics of telapristone (CDB-4124) and its active monodemethylated metabolite CDB-4453, with a mixture model for total clearance.

    Science.gov (United States)

    Morris, Denise; Podolski, Joseph; Kirsch, Alan; Wiehle, Ronald; Fleckenstein, Lawrence

    2011-12-01

    Telapristone is a selective progesterone antagonist that is being developed for the long-term treatment of symptoms associated with endometriosis and uterine fibroids. The population pharmacokinetics of telapristone (CDB-4124) and CDB-4453 was investigated using nonlinear mixed-effects modeling. Data from two clinical studies (n = 32) were included in the analysis. A two-compartment (parent) one compartment (metabolite) mixture model (with two populations for apparent clearance) with first-order absorption and elimination adequately described the pharmacokinetics of telapristone and CDB-4453. Telapristone was rapidly absorbed with an absorption rate constant (Ka) of 1.26 h(-1). Moderate renal impairment resulted in a 74% decrease in Ka. The population estimates for oral clearance (CL/F) for the two populations were 11.6 and 3.34 L/h, respectively, with 25% of the subjects being allocated to the high-clearance group. Apparent volume of distribution for the central compartment (V2/F) was 37.4 L, apparent inter-compartmental clearance (Q/F) was 21.9 L/h, and apparent peripheral volume of distribution for the parent (V4/F) was 120 L. The ratio of the fraction of telapristone converted to CDB-4453 to the distribution volume of CDB-4453 (Fmet(est)) was 0.20/L. Apparent volume of distribution of the metabolite compartment (V3/F) was fixed to 1 L and apparent clearance of the metabolite (CLM/F) was 2.43 L/h. A two-compartment parent-metabolite model adequately described the pharmacokinetics of telapristone and CDB-4453. The clearance of telapristone was separated into two populations and could be the result of metabolism via polymorphic CYP3A5.

  2. Model-based meta-analysis for comparing Vitamin D2 and D3 parent-metabolite pharmacokinetics.

    Science.gov (United States)

    Ocampo-Pelland, Alanna S; Gastonguay, Marc R; Riggs, Matthew M

    2017-08-01

    Association of Vitamin D (D3 & D2) and its 25OHD metabolite (25OHD3 & 25OHD2) exposures with various diseases is an active research area. D3 and D2 dose-equivalency and each form's ability to raise 25OHD concentrations are not well-defined. The current work describes a population pharmacokinetic (PK) model for D2 and 25OHD2 and the use of a previously developed D3-25OHD3 PK model [1] for comparing D3 and D2-related exposures. Public-source D2 and 25OHD2 PK data in healthy or osteoporotic populations, including 17 studies representing 278 individuals (15 individual-level and 18 arm-level units), were selected using search criteria in PUBMED. Data included oral, single and multiple D2 doses (400-100,000 IU/d). Nonlinear mixed effects models were developed simultaneously for D2 and 25OHD2 PK (NONMEM v7.2) by considering 1- and 2-compartment models with linear or nonlinear clearance. Unit-level random effects and residual errors were weighted by arm sample size. Model simulations compared 25OHD exposures, following repeated D2 and D3 oral administration across typical dosing and baseline ranges. D2 parent and metabolite were each described by 2-compartment models with numerous parameter estimates shared with the D3-25OHD3 model [1]. Notably, parent D2 was eliminated (converted to 25OHD) through a first-order clearance whereas the previously published D3 model [1] included a saturable non-linear clearance. Similar to 25OHD3 PK model results [1], 25OHD2 was eliminated by a first-order clearance, which was almost twice as fast as the former. Simulations at lower baselines, following lower equivalent doses, indicated that D3 was more effective than D2 at raising 25OHD concentrations. Due to saturation of D3 clearance, however, at higher doses or baselines, the probability of D2 surpassing D3's ability to raise 25OHD concentrations increased substantially. Since 25OHD concentrations generally surpassed 75 nmol/L at these higher baselines by 3 months, there would be no

  3. Comparative Pharmacokinetics of Chlorpyrifos versus its Major Metabolites Following Oral Administration in the Rat

    Energy Technology Data Exchange (ETDEWEB)

    Busby-Hjerpe, Andrea L.; Campbell, James A.; Smith, Jordan N.; Lee, Sookwang; Poet, Torka S.; Barr, Dana; Timchalk, Charles

    2010-01-31

    Chlorpyrifos (CPF) is a commonly used diethylphosphorothionate organophosphorus (OP) insecticide. Diethylphosphate (DEP), diethylthiophosphate (DETP) and 3,5,6-trichloro-2-pyridinol (TCPy) are products of in vivo metabolism and environmental degradation of CPF and are routinely measured in urine as biomarkers of exposure. Hence, urinary biomonitoring of TCPy, DEP and DETP may be reflective of an individual’s contact with both the parent pesticide and exposure to these metabolites. In the current study, simultaneous dosing of 13C- or 2H- isotopically labeled CPF (13Clabeled CPF, 5 13C on the TCPy ring; or 2H-labeled CPF, diethyl-D10 (deuterium labeled) on the side chain) were exploited to directly compare the pharmacokinetics and metabolism of CPF with TCPy, and DETP. Individual metabolites were co-administered (oral gavage) with the parent compound at equal molar doses (14 μmol/kg; ~5mg/kg CPF). The key objective in the current study was to quantitatively evaluate the pharmacokinetics of the individual metabolites relative to their formation following a dose of CPF. Major differences in the pharmacokinetics between CPF and metabolites doses were observed within the first 3 h of exposure, due to the required metabolism of CPF to initially form TCPy and DETP. Nonetheless, once a substantial amount of CPF has been metabolized (≥ 3 h post-dosing) pharmacokinetics for both treatment groups and metabolites were very comparable. Urinary excretion rates for orally administered TCPy and DETP relative to 13C-CPF or 2H-CPF derived 13C-TCPy and 2H-DETP were consistent with blood pharmacokinetics, and the urinary clearance of metabolite dosed groups were comparable with the results for the 13C- and 2H-CPF groups. Since the pharmacokinetics of the individual metabolites were not modified by co-exposure to 3 CPF; it suggests that environmental exposure to low dose mixtures of pesticides and metabolites will not impact the pharmacokinetics of either.

  4. Population Pharmacokinetics of Telapristone (CDB-4124) and its Active Monodemethylated Metabolite CDB-4453, with a Mixture Model for Total Clearance

    OpenAIRE

    Morris, Denise; Podolski, Joseph; Kirsch, Alan; Wiehle, Ronald; Fleckenstein, Lawrence

    2011-01-01

    Telapristone is a selective progesterone antagonist that is being developed for the long-term treatment of symptoms associated with endometriosis and uterine fibroids. The population pharmacokinetics of telapristone (CDB-4124) and CDB-4453 was investigated using nonlinear mixed-effects modeling. Data from two clinical studies (n?=?32) were included in the analysis. A two-compartment (parent) one compartment (metabolite) mixture model (with two populations for apparent clearance) with first-or...

  5. Neonatal Maturation of Paracetamol (Acetaminophen) Glucuronidation, Sulfation, and Oxidation Based on a Parent-Metabolite Population Pharmacokinetic Model.

    Science.gov (United States)

    Cook, Sarah F; Stockmann, Chris; Samiee-Zafarghandy, Samira; King, Amber D; Deutsch, Nina; Williams, Elaine F; Wilkins, Diana G; Sherwin, Catherine M T; van den Anker, John N

    2016-11-01

    This study aimed to model the population pharmacokinetics of intravenous paracetamol and its major metabolites in neonates and to identify influential patient characteristics, especially those affecting the formation clearance (CL formation ) of oxidative pathway metabolites. Neonates with a clinical indication for intravenous analgesia received five 15-mg/kg doses of paracetamol at 12-h intervals (paracetamol, paracetamol-glucuronide, paracetamol-sulfate, and the combined oxidative pathway metabolites (paracetamol-cysteine and paracetamol-N-acetylcysteine) were simultaneously modeled in NONMEM 7.2. The model incorporated 259 plasma and 350 urine samples from 35 neonates with a mean gestational age of 33.6 weeks (standard deviation 6.6). CL formation for all metabolites increased with weight; CL formation for glucuronidation and oxidation also increased with postnatal age. At the mean weight (2.3 kg) and postnatal age (7.5 days), CL formation estimates (bootstrap 95% confidence interval; between-subject variability) were 0.049 L/h (0.038-0.062; 62 %) for glucuronidation, 0.21 L/h (0.17-0.24; 33 %) for sulfation, and 0.058 L/h (0.044-0.078; 72 %) for oxidation. Expression of individual oxidation CL formation as a fraction of total individual paracetamol clearance showed that, on average, fractional oxidation CL formation increased paracetamol and its metabolites in neonates. Maturational changes in the fraction of paracetamol undergoing oxidation were small relative to between-subject variability.

  6. New Photosafety Assessment Strategy Based on the Photochemical and Pharmacokinetic Properties of Both Parent Chemicals and Metabolites.

    Science.gov (United States)

    Kato, Masashi; Suzuki, Gen; Ohtake, Hiroto; Seto, Yoshiki; Onoue, Satomi

    2015-11-01

    Photoreactivity and dermal/ocular deposition of compounds have been recognized as key considerations for evaluating the phototoxic risk of compounds. Because some drugs are known to cause phototoxic reactions via generation of potent phototoxic metabolites, photosafety assessments on parent drugs alone may lead to false predictions about their photosafety. This study aimed to establish a new photosafety assessment strategy for evaluating the in vivo phototoxic potential of both a parent substance and its metabolites. The in vivo phototoxic risk of fenofibrate (FF) and its metabolites, fenofibric acid (FA) and reduced fenofibric acid, were evaluated based on photochemical and pharmacokinetic analyses. FF and FA exhibited intensive UV absorption, with molar extinction coefficient values of 17,000 (290 nm) and 14,000 M(-1)cm(-1) (295 nm), respectively. Superoxide generation from FA was significantly higher than from FF, and a marked increase in superoxide generation from FF was observed after incubation with rat hepatic S9 fractions, suggesting enhanced photoreactivity of FF after metabolism. FA showed high dermal/ocular deposition after oral administration (5 mg/kg, p.o.) although the concentration of FF was negligible, suggesting high exposure risk from FA. On the basis of these findings, FA was deduced to be a major contributor to phototoxicity induced by FF taken orally, and this prediction was in accordance with the results from in vitro/in vivo phototoxicity tests. Results from this study suggest that this new screening strategy for parent substances and their metabolites provides reliable photosafety information on drug candidates and would be useful for drug development with wide safety margins. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

  7. Population pharmacokinetic model of transdermal nicotine delivered from a matrix-type patch.

    Science.gov (United States)

    Linakis, Matthew W; Rower, Joseph E; Roberts, Jessica K; Miller, Eleanor I; Wilkins, Diana G; Sherwin, Catherine M T

    2017-12-01

    Nicotine addiction is an issue faced by millions of individuals worldwide. As a result, nicotine replacement therapies, such as transdermal nicotine patches, have become widely distributed and used. While the pharmacokinetics of transdermal nicotine have been extensively described using noncompartmental methods, there are few data available describing the between-subject variability in transdermal nicotine pharmacokinetics. The aim of this investigation was to use population pharmacokinetic techniques to describe this variability, particularly as it pertains to the absorption of nicotine from the transdermal patch. A population pharmacokinetic parent-metabolite model was developed using plasma concentrations from 25 participants treated with transdermal nicotine. Covariates tested in this model included: body weight, body mass index, body surface area (calculated using the Mosteller equation) and sex. Nicotine pharmacokinetics were best described with a one-compartment model with absorption based on a Weibull distribution and first-order elimination and a single compartment for the major metabolite, cotinine. Body weight was a significant covariate on apparent volume of distribution of nicotine (exponential scaling factor 1.42). After the inclusion of body weight in the model, no other covariates were significant. This is the first population pharmacokinetic model to describe the absorption and disposition of transdermal nicotine and its metabolism to cotinine and the pharmacokinetic variability between individuals who were administered the patch. © 2017 The British Pharmacological Society.

  8. Pharmacokinetic models of morphine and its metabolites in neonates: Systematic comparisons of models from the literature, and development of a new meta-model

    NARCIS (Netherlands)

    K.R. Knøsgaard (Katrine Rørbæk); D.J.R. Foster (David John Richard); M. Kreilgaard (Mads); E. Sverrisdóttir (Eva); R.N. Upton (Richard Neil); J.N. van den Anker (John)

    2016-01-01

    textabstractMorphine is commonly used for pain management in preterm neonates. The aims of this study were to compare published models of neonatal pharmacokinetics of morphine and its metabolites with a new dataset, and to combine the characteristics of the best predictive models to design a

  9. Pharmacokinetics of ifosfamide and some metabolites in children

    NARCIS (Netherlands)

    Kaijser, G. P.; de Kraker, J.; Bult, A.; Underberg, W. J.; Beijnen, J. H.

    1998-01-01

    The pharmacokinetics of ifosfamide and some metabolites in children was investigated. The patients received various doses of ifosfamide, mostly by continuous infusion, over several days. The penetration of ifosfamide and its metabolites into the cerebrospinal fluid was also studied in four cases.

  10. Prediction of Drug-Drug Interactions with Bupropion and Its Metabolites as CYP2D6 Inhibitors Using a Physiologically-Based Pharmacokinetic Model.

    Science.gov (United States)

    Xue, Caifu; Zhang, Xunjie; Cai, Weimin

    2017-12-21

    The potential of inhibitory metabolites of perpetrator drugs to contribute to drug-drug interactions (DDIs) is uncommon and underestimated. However, the occurrence of unexpected DDI suggests the potential contribution of metabolites to the observed DDI. The aim of this study was to develop a physiologically-based pharmacokinetic (PBPK) model for bupropion and its three primary metabolites-hydroxybupropion, threohydrobupropion and erythrohydrobupropion-based on a mixed "bottom-up" and "top-down" approach and to contribute to the understanding of the involvement and impact of inhibitory metabolites for DDIs observed in the clinic. PK profiles from clinical researches of different dosages were used to verify the bupropion model. Reasonable PK profiles of bupropion and its metabolites were captured in the PBPK model. Confidence in the DDI prediction involving bupropion and co-administered CYP2D6 substrates could be maximized. The predicted maximum concentration (C max ) area under the concentration-time curve (AUC) values and C max and AUC ratios were consistent with clinically observed data. The addition of the inhibitory metabolites into the PBPK model resulted in a more accurate prediction of DDIs (AUC and C max ratio) than that which only considered parent drug (bupropion) P450 inhibition. The simulation suggests that bupropion and its metabolites contribute to the DDI between bupropion and CYP2D6 substrates. The inhibitory potency from strong to weak is hydroxybupropion, threohydrobupropion, erythrohydrobupropion, and bupropion, respectively. The present bupropion PBPK model can be useful for predicting inhibition from bupropion in other clinical studies. This study highlights the need for caution and dosage adjustment when combining bupropion with medications metabolized by CYP2D6. It also demonstrates the feasibility of applying the PBPK approach to predict the DDI potential of drugs undergoing complex metabolism, especially in the DDI involving inhibitory

  11. Sandwich-Cultured Hepatocytes for Mechanistic Understanding of Hepatic Disposition of Parent Drugs and Metabolites by Transporter-Enzyme Interplay.

    Science.gov (United States)

    Matsunaga, Norikazu; Fukuchi, Yukina; Imawaka, Haruo; Tamai, Ikumi

    2018-05-01

    Functional interplay between transporters and drug-metabolizing enzymes is currently one of the hottest topics in the field of drug metabolism and pharmacokinetics. Uptake transporter-enzyme interplay is important to determine intrinsic hepatic clearance based on the extended clearance concept. Enzyme and efflux transporter interplay, which includes both sinusoidal (basolateral) and canalicular efflux transporters, determines the fate of metabolites formed in the liver. As sandwich-cultured hepatocytes (SCHs) maintain metabolic activities and form a canalicular network, the whole interplay between uptake and efflux transporters and drug-metabolizing enzymes can be investigated simultaneously. In this article, we review the utility and applicability of SCHs for mechanistic understanding of hepatic disposition of both parent drugs and metabolites. In addition, the utility of SCHs for mimicking species-specific disposition of parent drugs and metabolites in vivo is described. We also review application of SCHs for clinically relevant prediction of drug-drug interactions caused by drugs and metabolites. The usefulness of mathematical modeling of hepatic disposition of parent drugs and metabolites in SCHs is described to allow a quantitative understanding of an event in vitro and to develop a more advanced model to predict in vivo disposition. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

  12. Population pharmacokinetics of caffeine and its metabolites theobromine, paraxanthine and theophylline after inhalation in combination with diacetylmorphine.

    Science.gov (United States)

    Zandvliet, Anthe S; Huitema, Alwin D R; de Jonge, Milly E; den Hoed, Rob; Sparidans, Rolf W; Hendriks, Vincent M; van den Brink, Wim; van Ree, Jan M; Beijnen, Jos H

    2005-01-01

    The stimulant effect of caffeine, as an additive in diacetylmorphine preparations for study purposes, may interfere with the pharmacodynamic effects of diacetylmorphine. In order to obtain insight into the pharmacology of caffeine after inhalation in heroin users, the pharmacokinetics of caffeine and its dimethylxanthine metabolites were studied. The objectives were to establish the population pharmacokinetics under these exceptional circumstances and to compare the results to published data regarding intravenous and oral administration in healthy volunteers. Diacetylmorphine preparations containing 100 mg of caffeine were used by 10 persons by inhalation. Plasma concentrations of caffeine, theobromine, paraxanthine and theophylline were measured by high performance liquid chromatography. Non-linear mixed effects modelling was used to estimate population pharmacokinetic parameters. The model was evaluated by the jack-knife procedure. Caffeine was rapidly and effectively absorbed after inhalation. Population pharmacokinetics of caffeine and its dimethylxanthine metabolites could adequately and simultaneously be described by a linear multi-compartment model. The volume of distribution for the central compartment was estimated to be 45.7 l and the apparent elimination rate constant of caffeine at 8 hr after inhalation was 0.150 hr(-1) for a typical individual. The bioavailability was approximately 60%. The presented model adequately describes the population pharmacokinetics of caffeine and its dimethylxanthine metabolites after inhalation of the caffeine sublimate of a 100 mg tablet. Validation proved the stability of the model. Pharmacokinetics of caffeine after inhalation and intravenous administration are to a large extent similar. The bioavailability of inhaled caffeine is approximately 60% in experienced smokers.

  13. Human pharmacokinetics of proguanil and its metabolites

    DEFF Research Database (Denmark)

    Bygbjerg, Ib Christian; Ravn, P; Rønn, A

    1987-01-01

    The pharmacokinetics of proguanil and its metabolites cycloguanil and p-chlorophenylbiguanide were studied in five healthy volunteers taking 200 mg orally for 14 days. A highly sensitive and specific high-performance liquid chromatographic assay was applied, clearly identifying all three compounds...

  14. Estimation of placental and lactational transfer and tissue distribution of atrazine and its main metabolites in rodent dams, fetuses, and neonates with physiologically based pharmacokinetic modeling

    International Nuclear Information System (INIS)

    Lin, Zhoumeng; Fisher, Jeffrey W.; Wang, Ran; Ross, Matthew K.; Filipov, Nikolay M.

    2013-01-01

    Atrazine (ATR) is a widely used chlorotriazine herbicide, a ubiquitous environmental contaminant, and a potential developmental toxicant. To quantitatively evaluate placental/lactational transfer and fetal/neonatal tissue dosimetry of ATR and its major metabolites, physiologically based pharmacokinetic models were developed for rat dams, fetuses and neonates. These models were calibrated using pharmacokinetic data from rat dams repeatedly exposed (oral gavage; 5 mg/kg) to ATR followed by model evaluation against other available rat data. Model simulations corresponded well to the majority of available experimental data and suggest that: (1) the fetus is exposed to both ATR and its major metabolite didealkylatrazine (DACT) at levels similar to maternal plasma levels, (2) the neonate is exposed mostly to DACT at levels two-thirds lower than maternal plasma or fetal levels, while lactational exposure to ATR is minimal, and (3) gestational carryover of DACT greatly affects its neonatal dosimetry up until mid-lactation. To test the model's cross-species extrapolation capability, a pharmacokinetic study was conducted with pregnant C57BL/6 mice exposed (oral gavage; 5 mg/kg) to ATR from gestational day 12 to 18. By using mouse-specific parameters, the model predictions fitted well with the measured data, including placental ATR/DACT levels. However, fetal concentrations of DACT were overestimated by the model (10-fold). This overestimation suggests that only around 10% of the DACT that reaches the fetus is tissue-bound. These rodent models could be used in fetal/neonatal tissue dosimetry predictions to help design/interpret early life toxicity/pharmacokinetic studies with ATR and as a foundation for scaling to humans. - Highlights: • We developed PBPK models for atrazine in rat dams, fetuses, and neonates. • We conducted pharmacokinetic (PK) study with atrazine in pregnant mice. • Model predictions were in good agreement with experimental rat and mouse PK data.

  15. Estimation of placental and lactational transfer and tissue distribution of atrazine and its main metabolites in rodent dams, fetuses, and neonates with physiologically based pharmacokinetic modeling

    Energy Technology Data Exchange (ETDEWEB)

    Lin, Zhoumeng [Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602 (United States); Interdisciplinary Toxicology Program, University of Georgia, Athens, GA 30602 (United States); Fisher, Jeffrey W. [Division of Biochemical Toxicology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR 72079 (United States); Wang, Ran [Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS 39762 (United States); Institute of Food Safety, Jiangsu Academy of Agricultural Sciences, Nanjing 210014 (China); Ross, Matthew K. [Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS 39762 (United States); Filipov, Nikolay M., E-mail: filipov@uga.edu [Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602 (United States); Interdisciplinary Toxicology Program, University of Georgia, Athens, GA 30602 (United States)

    2013-11-15

    Atrazine (ATR) is a widely used chlorotriazine herbicide, a ubiquitous environmental contaminant, and a potential developmental toxicant. To quantitatively evaluate placental/lactational transfer and fetal/neonatal tissue dosimetry of ATR and its major metabolites, physiologically based pharmacokinetic models were developed for rat dams, fetuses and neonates. These models were calibrated using pharmacokinetic data from rat dams repeatedly exposed (oral gavage; 5 mg/kg) to ATR followed by model evaluation against other available rat data. Model simulations corresponded well to the majority of available experimental data and suggest that: (1) the fetus is exposed to both ATR and its major metabolite didealkylatrazine (DACT) at levels similar to maternal plasma levels, (2) the neonate is exposed mostly to DACT at levels two-thirds lower than maternal plasma or fetal levels, while lactational exposure to ATR is minimal, and (3) gestational carryover of DACT greatly affects its neonatal dosimetry up until mid-lactation. To test the model's cross-species extrapolation capability, a pharmacokinetic study was conducted with pregnant C57BL/6 mice exposed (oral gavage; 5 mg/kg) to ATR from gestational day 12 to 18. By using mouse-specific parameters, the model predictions fitted well with the measured data, including placental ATR/DACT levels. However, fetal concentrations of DACT were overestimated by the model (10-fold). This overestimation suggests that only around 10% of the DACT that reaches the fetus is tissue-bound. These rodent models could be used in fetal/neonatal tissue dosimetry predictions to help design/interpret early life toxicity/pharmacokinetic studies with ATR and as a foundation for scaling to humans. - Highlights: • We developed PBPK models for atrazine in rat dams, fetuses, and neonates. • We conducted pharmacokinetic (PK) study with atrazine in pregnant mice. • Model predictions were in good agreement with experimental rat and mouse PK data

  16. Pharmacokinetics of ketamine and its metabolite norketamine administered at a sub-anesthetic dose together with xylazine to calves prior to castration.

    Science.gov (United States)

    Gehring, R; Coetzee, J F; Tarus-Sang, J; Apley, M D

    2009-04-01

    The objective of this study was to evaluate the plasma pharmacokinetics of ketamine and its active metabolite norketamine administered intravenously at a dose of 0.1 mg/kg together with xylazine (0.05 mg/kg) to control the pain associated with castration in calves. A two-compartment model with an additional metabolite compartment linked to the central compartment was used to simultaneously describe the time-concentration profiles of both ketamine and its major metabolite norketamine. Parameter values estimated from the time-concentration profiles observed in this study were volume of the central compartment (V(c) = 132.82 +/- 68.23 mL/kg), distribution clearance (CL(D) = 15.49 +/- 2.56 mL/min/kg), volume of the peripheral compartment (V(T) = 257.05 +/- 41.65 mL/kg), ketamine clearance by the formation of the norketamine metabolite (CL(2M) = 8.56 +/- 7.37 mL/kg/min) and ketamine clearance by other routes (CL(o) = 16.41 +/- 3.42 mL/kg/min). Previously published data from rats suggest that the metabolite norketamine contributes to the analgesic effect of ketamine, with a potency that is one-third of the parent drug. An understanding of the time-concentration relationships and the disposition of the parent drug and its metabolite is therefore important for a better understanding of the analgesic potential of ketamine in cattle.

  17. Human Microdosing with Carcinogenic Polycyclic Aromatic Hydrocarbons: In Vivo Pharmacokinetics of Dibenzo[ def,p ]chrysene and Metabolites by UPLC Accelerator Mass Spectrometry

    Energy Technology Data Exchange (ETDEWEB)

    Madeen, Erin P.; Ognibene, Ted J.; Corley, Richard A.; McQuistan, Tammie J.; Henderson, Marilyn C.; Baird, William M.; Bench, Graham; Turteltaub, Ken W.; Williams, David E.

    2016-10-17

    Metabolism is a key health risk factor following exposures to pro-carcinogenic polycyclic aromatic hydrocarbons (PAHs) such as dibenzo[def,p]chrysene (DBC), an IARC classified 2A probable human carcinogen. Human exposure to PAHs occurs primarily from the diet in non-smokers. However, little data is available on the metabolism and pharmacokinetics in humans of high molecular weight PAHs (≥4 aromatic rings), including DBC. We previously determined the pharmacokinetics of DBC in human volunteers orally administered a micro-dose (29 ng; 5 nCi) of [14C]-DBC by accelerator mass spectrometry (AMS) analysis of total [14C] in plasma and urine. In the current study, we utilized a novel “moving wire” interface between ultra-performance liquid chromatography (UPLC) and AMS to detect and quantify parent DBC and its major metabolites. The major [14C] product identified in plasma was unmetabolized [14C]-DBC itself, (Cmax= 18.5 ± 15.9 fg/mL, Tmax= 2.1 ± 1.0 h), whereas the major metabolite was identified as [14C]-(+/-)-DBC-11,12-diol (Cmax= 2.5 ± 1.3 fg/mL, Tmax= 1.8 h). Several minor species of [14C]-DBC metabolites were also detected for which no reference standards were available. Free and conjugated metabolites were detected in urine with [14C]-(+/-)-DBC-11,12,13,14-tetraol isomers identified as the major metabolites, 56.3% of which were conjugated (Cmax= 35.8 ± 23.0 pg/pool, Tmax= 6-12 h pool). [14C]-DBC-11,12-diol, of which 97.5% was conjugated, was also identified in urine (Cmax= 29.4 ± 11.6 pg/pool, Tmax= 6-12 h pool). Parent [14C]-DBC was not detected in urine. This is the first dataset to assess metabolite profiles and associated pharmacokinetics of a carcinogenic PAH in human volunteers at an environmentally relevant dose, providing the data necessary for translation of high dose animal models to humans for translation of environmental health risk assessment.

  18. Population pharmacokinetics of imatinib mesylate and its metabolite in children and young adults.

    Science.gov (United States)

    Menon-Andersen, Divya; Mondick, John T; Jayaraman, Bhuvana; Thompson, Patrick A; Blaney, Susan M; Bernstein, Mark; Bond, Mason; Champagne, Martin; Fossler, Michael J; Barrett, Jeffrey S

    2009-01-01

    Imatinib mesylate (Gleevec) is a small molecule tyrosine kinase inhibitor approved for use in the management of chronic myeloid leukemia in adults and children and in gastrointestinal stromal tumors in adults. Population pharmacokinetic (PPK) studies evaluating the effect of population covariates on the pharmacokinetics of imatinib and its active metabolite have been developed in adults with chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST). However, this still remains to be described in children. The objectives of the analysis were to develop a PPK model of imatinib and its active metabolite, CGP74588, to describe exposure in children and young adults and to identify covariates that are predictors of variability in disposition. Plasma concentrations from 26 subjects with Philadelphia (Ph+) leukemia (Phase I study) and 15 subjects with refractory solid tumors (Phase II study), who received oral imatinib at doses ranging from 260 to 570 mg/m(2), were available for the PPK analysis in NONMEM. Blood samples were drawn prior to dosing and over 24-48 h on days 1 and 8 of the studies. Covariates studied included weight, age, albumin, alanine aminotransferase and the study population. The pharmacokinetics of imatinib and CGP 74588 were well described by one and two compartment models, respectively. Total body weight was the only covariate found to significantly affect Cl/F and V/F. The final imatinib-CGP 74588 model is summarized as follows: CL/F (imatinib) (L/h) = 10.8 x (WT/70)(0.75), V/F (imatinib) (L) = 284 x (WT/70) and D1(duration of zero order absorption,imatinib) (h) = 1.67 and CL/F (CGP 74588) (L/h) = 9.65 x (WT/70)(0.75), V1/F (CGP 74588) (L) = 11.6 x (WT/70), Q (CGP 74588) (L/h) = 2.9 x (WT/70)(0.75) and V2/F (CGP 74588) (L) = 256*(WT/70). Model evaluation indicated that the final model was robust and satisfactory. Current imatinib dosing guidelines in pediatrics is based on the achievement of exposures consistent with doses known to be

  19. Pharmacokinetics and pharmacokinetic-dynamic relationship between rapacuronium (Org 9487) and its 3-desacetyl metabolite (Org 9488)

    NARCIS (Netherlands)

    Schiere, S; Proost, Hans; Schuringa, M; Wierda, J.MKH

    Rapacuronium (Org 9487) is a rapid-onset and short- to intermediate-acting muscle relaxant. Its 3-desacetyl metabolite, Org 9488, also exerts neuromuscular-blocking activity that. may became apparent after prolonged maintenance of relaxation with rapacuronium. In this study, the pharmacokinetic

  20. The influence of paroxetine on the pharmacokinetics of atomoxetine and its main metabolite.

    Science.gov (United States)

    Todor, Ioana; Popa, Adina; Neag, Maria; Muntean, Dana; Bocsan, Corina; Buzoianu, Anca; Vlase, Laurian; Gheldiu, Ana-Maria; Chira, Ruxandra; Briciu, Corina

    2015-01-01

    To evaluate the effects of paroxetine on the pharmacokinetics of atomoxetine and its main metabolite, 4-hydroxyatomoxetine-O-glucuronide, after coadministration of atomoxetine and paroxetine in healthy volunteers. 22 healthy volunteers, extensive metabolizers, took part in this open-label, non-randomized, clinical trial. The study consisted of two periods: Reference, when a single oral dose of 25 mg atomoxetine was administrated to each subject and Test, when 25 mg atomoxetine and 20 mg paroxetine were coadministered. Between the two periods, the volunteers received an oral daily dose of 20-40 mg paroxetine, for 6 days. Atomoxetine and 4-hydroxyatomoxetine-O-glucuronide plasma concentrations were determined within the first 48 hours following drug administration. The pharmacokinetic parameters of both compounds were assessed using a non-compartmental method and the analysis of variance aimed at identifying any statistical significant differences between the pharmacokinetic parameters of atomoxetine and its main metabolite, corresponding to each study period. Paroxetine modified the pharmacokinetic parameters of atomoxetine. Cmax increased from 221.26±94.93 to 372.53±128.28 ng/mL, while AUC0-t and AUC0-∞ also increased from 1151.19±686.52 to 6452.37±3388.76 ng*h/mL, and from 1229.15±751.04 to 7111.74±4195.17 ng*h/mL respectively. The main metabolite pharmacokinetics was also influenced by paroxetine intake, namely Cmax, AUC0-t and AUC0-∞ decreased from 688.76±270.27 to 131.01±100.43 ng*h/mL, and from 4810.93±845.06 to 2606.04±923.88 and from 4928.55±853.25 to 3029.82 ±941.84 respectively. Multiple-dose paroxetine intake significantly influenced atomoxetine and its active metabolite pharmacokinetics, causing a 5.8-fold increased exposure to atomoxetine and 1.6-fold reduced exposure to 4-hydroxyatomoxetine-O-glucuronide.

  1. Population pharmacokinetics of oxcarbazepine and its metabolite 10-hydroxycarbazepine in healthy subjects.

    Science.gov (United States)

    Antunes, Natalicia de Jesus; van Dijkman, Sven C; Lanchote, Vera Lucia; Wichert-Ana, Lauro; Coelho, Eduardo Barbosa; Alexandre Junior, Veriano; Takayanagui, Osvaldo Massaiti; Tozatto, Eduardo; van Hasselt, J G Coen; Della Pasqua, Oscar

    2017-11-15

    Oxcarbazepine is indicated for the treatment of partial or generalised tonic-clonic seizures. Most of the absorbed oxcarbazepine is converted into its active metabolite, 10-hydroxycarbazepine (MHD), which can exist as R-(-)- and S-(+)-MHD enantiomers. Here we describe the influence of the P-glycoprotein (P-gp) inhibitor verapamil, on the disposition of oxcarbazepine and MHD enantiomers, both of which are P-gp substrates. Healthy subjects (n=12) were randomised to oxcarbazepine or oxcarbazepine combined with verapamil at doses of 300mg b.i.d. and 80mg t.i.d., respectively. Blood samples (n=185) were collected over a period of 12h post oxcarbazepine dose. An integrated PK model was developed using nonlinear mixed effects modelling using a meta-analytical approach. The pharmacokinetics of oxcarbazepine was described by a two-compartment model with absorption transit compartments and first-order elimination. The concentration-time profiles of both MHD enantiomers were characterised by a one-compartment distribution model. Clearance estimates (95% CI) were 84.9L/h (69.5-100.3) for oxcarbazepine and 2.0L/h (1.9-2.1) for both MHD enantiomers. The volume of distribution was much larger for oxcarbazepine (131L (97-165)) as compared to R-(-)- and S-(+)-MHD (23.6L (14.4-32.8) vs. 31.7L (22.5-40.9), respectively). Co-administration of verapamil resulted in a modest increase of the apparent bioavailability of oxcarbazepine by 12% (10-28), but did not affect parent or metabolite clearances. Despite the evidence of comparable systemic levels of OXC and MHD following administration of verapamil, differences in brain exposure to both moieties cannot be excluded after P-glycoprotein inhibition. Copyright © 2017. Published by Elsevier B.V.

  2. Chiral Plasma Pharmacokinetics of 3,4-Methylenedioxymethamphetamine and its Phase I and II Metabolites following Controlled Administration to Humans.

    OpenAIRE

    Steuer Andrea E; Schmidhauser Corina; Schmid Yasmin; Rickli Anna; Liechti Matthias E; Kraemer Thomas

    2015-01-01

    Generally, pharmacokinetic studies on 3,4-methylenedioxymethamphetamine (MDMA) in blood have been performed after conjugate cleavage, without taking into account that phase II metabolites represent distinct chemical entities with their own effects and stereoselective pharmacokinetics. The aim of the present study was to stereoselectively investigate the pharmacokinetics of intact glucuronide and sulfate metabolites of MDMA in blood plasma after a controlled single MDMA dose. Plasma samples fr...

  3. Effect of Smoking on Pharmacokinetics of Clopidogrel, an ...

    African Journals Online (AJOL)

    ... in patients undergoing PCI. Keywords: Antiplatelet, Clopidogrel, Pharmacokinetics, Smoking, Cigarette ..... regimen of choice to prevent thrombotic complications. [2,16]. ... either the parent drug [19] or the carboxylic acid metabolite as an ...

  4. Enhancement of curcumin oral absorption and pharmacokinetics of curcuminoids and curcumin metabolites in mice

    Science.gov (United States)

    Zhongfa, Liu; Chiu, Ming; Wang, Jiang; Chen, Wei; Yen, Winston; Fan-Havard, Patty; Yee, Lisa D.; Chan, Kenneth K.

    2012-01-01

    Purpose Curcumin has shown a variety of biological activity for various human diseases including cancer in preclinical setting. Its poor oral bioavailability poses significant pharmacological barriers to its clinical application. Here, we established a practical nano-emulsion curcumin (NEC) containing up to 20% curcumin (w/w) and conducted the pharmacokinetics of curcuminoids and curcumin metabolites in mice. Methods This high loading NEC was formulated based on the high solubility of curcumin in polyethylene glycols (PEGs) and the synergistic enhancement of curcumin absorption by PEGs and Cremophor EL. The pharmacokinetics of curcuminoids and curcumin metabolites was characterized in mice using a LC–MS/MS method, and the pharmacokinetic parameters were determined using WinNonlin computer software. Results A tenfold increase in the AUC0→24h and more than 40-fold increase in the Cmax in mice were observed after an oral dose of NEC compared with suspension curcumin in 1% methylcellulose. The plasma pharmacokinetics of its two natural congeners, demethoxycurcumin and bisdemethoxycurcumin, and three metabolites, tetrahydrocurcumin (THC), curcumin-O-glucuronide, and curcumin-O-sulfate, was characterized for the first time in mice after an oral dose of NEC. Conclusion This oral absorption enhanced NEC may provide a practical formulation to conduct the correlative study of the PK of curcuminoids and their pharmacodynamics, e.g., hypomethylation activity in vivo. PMID:21968952

  5. Effects of Body Size and Gender on the Population Pharmacokinetics of Artesunate and Its Active Metabolite Dihydroartemisinin in Pediatric Malaria Patients

    OpenAIRE

    Morris, Carrie A.; Tan, Beesan; Duparc, Stephan; Borghini-Fuhrer, Isabelle; Jung, Donald; Shin, Chang-Sik; Fleckenstein, Lawrence

    2013-01-01

    Despite the important role of the antimalarial artesunate and its active metabolite dihydroartemisinin (DHA) in malaria treatment efforts, there are limited data on the pharmacokinetics of these agents in pediatric patients. This study evaluated the effects of body size and gender on the pharmacokinetics of artesunate-DHA using data from pediatric and adult malaria patients. Nonlinear mixed-effects modeling was used to obtain a base model consisting of first-order artesunate absorption and on...

  6. Development of a Physiologically Based Pharmacokinetic and Pharmacodynamic Model to Determine Dosimetry and Cholinesterase Inhibition for a Binary Mixture of Chlorpyrifos and Diazinon in the Rat

    Energy Technology Data Exchange (ETDEWEB)

    Timchalk, Chuck; Poet, Torka S.

    2008-05-01

    Physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) models have been developed and validated for the organophosphorus (OP) insecticides chlorpyrifos (CPF) and diazinon (DZN). Based on similar pharmacokinetic and mode of action properties it is anticipated that these OPs could interact at a number of important metabolic steps including: CYP450 mediated activation/detoxification, and blood/tissue cholinesterase (ChE) binding/inhibition. We developed a binary PBPK/PD model for CPF, DZN and their metabolites based on previously published models for the individual insecticides. The metabolic interactions (CYP450) between CPF and DZN were evaluated in vitro and suggests that CPF is more substantially metabolized to its oxon metabolite than is DZN. These data are consistent with their observed in vivo relative potency (CPF>DZN). Each insecticide inhibited the other’s in vitro metabolism in a concentration-dependent manner. The PBPK model code used to described the metabolism of CPF and DZN was modified to reflect the type of inhibition kinetics (i.e. competitive vs. non-competitive). The binary model was then evaluated against previously published rodent dosimetry and ChE inhibition data for the mixture. The PBPK/PD model simulations of the acute oral exposure to single- (15 mg/kg) vs. binary-mixtures (15+15 mg/kg) of CFP and DZN at this lower dose resulted in no differences in the predicted pharmacokinetics of either the parent OPs or their respective metabolites; whereas, a binary oral dose of CPF+DZN at 60+60 mg/kg did result in observable changes in the DZN pharmacokinetics. Cmax was more reasonably fit by modifying the absorption parameters. It is anticipated that at low environmentally relevant binary doses, most likely to be encountered in occupational or environmental related exposures, that the pharmacokinetics are expected to be linear, and ChE inhibition dose-additive.

  7. Pharmacologic activity and pharmacokinetics of metabolites of regorafenib in preclinical models

    OpenAIRE

    Zopf, Dieter; Fichtner, Iduna; Bhargava, Ajay; Steinke, Wolfram; Thierauch, Karl?Heinz; Diefenbach, Konstanze; Wilhelm, Scott; Hafner, Frank?Thorsten; Gerisch, Michael

    2016-01-01

    Abstract Regorafenib is an orally administered inhibitor of protein kinases involved in tumor angiogenesis, oncogenesis, and maintenance of the tumor microenvironment. Phase III studies showed that regorafenib has efficacy in patients with advanced gastrointestinal stromal tumors or treatment?refractory metastatic colorectal cancer. In clinical studies, steady?state exposure to the M?2 and M?5 metabolites of regorafenib was similar to that of the parent drug; however, the contribution of thes...

  8. Pharmacokinetics of dextromethorphan and its metabolites in horses following a single oral administration.

    Science.gov (United States)

    Corado, Carley R; McKemie, Daniel S; Knych, Heather K

    2017-06-01

    Dextromethorphan is an N-methyl-D-aspartate (NMDA) non-competitive antagonist commonly used in human medicine as an antitussive. Dextromethorphan is metabolized in humans by cytochrome P450 2D6 into dextrorphan, which is reported to be more potent than the parent compound. The goal of this study is to describe the metabolism of and determine the pharmacokinetics of dextromethorphan and its major metabolites following oral administration to horses. A total of 23 horses received a single oral dose of 2 mg/kg. Blood samples were collected at time 0 and at various times up to 96 h post drug administration. Urine samples were collected from 12 horses up to 120 h post administration. Plasma and urine samples were analyzed using liquid chromatography-mass spectrometry, and the resulting data analyzed using non-compartmental analysis. The C max , T max , and the t 1/2 of dextromethorphan were 519.4 ng/mL, 0.55 h, and 12.4 h respectively. The area under the curve of dextromethorphan, free dextrorphan, and conjugated dextrorphan were 563.8, 2.19, and 6,691 h*ng/mL respectively. In addition to free and glucuronidated dextrorphan, several additional glucuronide metabolites were identified in plasma, including hydroxyl-desmethyl dextrorphan, desmethyl dextrorphan, and three forms of hydroxylated dextrorphan. Dextromethorphan was found to be eliminated from the urine predominately as the O-demethylated metabolite, dextrorphan. Several additional metabolites including several novel hydroxy-dextrorphan metabolites were also detected in the urine in both free and glucuronidated forms. No significant undesirable behavioural effects were noted throughout the duration of the study. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  9. Stereoselective pharmacokinetics of moguisteine metabolites in healthy subjects.

    Science.gov (United States)

    Bernareggi, A; Crema, A; Carlesi, R M; Castoldi, D; Ratti, E; Renoldi, M I; Ratti, D; Ceserani, R; Tognella, S

    1995-01-01

    We studied the pharmacokinetics of moguisteine, a racemic non-narcotic peripheral antitussive drug, in 12 healthy male subjects after a single oral administration of 200 mg. The unchanged drug was absent in plasma and urine of all subjects. Moguisteine was immediately and completely hydrolyzed to its main active metabolite, the free carboxylic acid M1. Therefore, we evaluated the kinetic profiles of M1, of its enantiomers R(+)-M1 and S(-)-M1, and of M1 sulfoxide optical isomers M2/I and M2/II by conventional and stereospecific HPLC. Maximum plasma concentrations for M1 (2.83 mg/l), M2/I (0.26 mg/l) and M2/II (0.40 mg/l), were respectively reached at 1.3, 1.6 and 1.5 h after moguisteine administration. Plasma concentrations declined after the peak with mean apparent terminal half-lives of 0.65 h (M1), 0.88 h (M2/I) and 0.84 h (M2/II). Most of the administered dose was recovered in urine within 6 h from moguisteine treatment. The systemic and renal clearance values indicated high renal extraction ratio for all moguisteine metabolites, and particularly for M1 sulfoxide optical isomers. Plasma concentration-time profiles and urinary excretion patterns for M1 enantiomers R(+)-M1 and S(-)-M1 were quite similar. Thus, for later moguisteine pharmacokinetic evaluations the investigation of the plasma concentration-time curve and the urinary excretion of the sole racemic M1 through non-stereospecific analytical methods may suffice in most cases.

  10. Bioavailability and Pharmacokinetics of Oral Cocaine in Humans.

    Science.gov (United States)

    Coe, Marion A; Jufer Phipps, Rebecca A; Cone, Edward J; Walsh, Sharon L

    2018-06-01

    The pharmacokinetic profile of oral cocaine has not been fully characterized and prospective data on oral bioavailability are limited. A within-subject study was performed to characterize the bioavailability and pharmacokinetics of oral cocaine. Fourteen healthy inpatient participants (six males) with current histories of cocaine use were administered two oral doses (100 and 200 mg) and one intravenous (IV) dose (40 mg) of cocaine during three separate dosing sessions. Plasma samples were collected for up to 24 h after dosing and analyzed for cocaine and metabolites by gas chromatography-mass spectrometry. Pharmacokinetic parameters were calculated by non-compartmental analysis, and a two-factor model was used to assess for dose and sex differences. The mean ± SEM oral cocaine bioavailability was 0.32 ± 0.04 after 100 and 0.45 ± 0.06 after 200 mg oral cocaine. Volume of distribution (Vd) and clearance (CL) were both greatest after 100 mg oral (Vd = 4.2 L/kg; CL = 116.2 mL/[min kg]) compared to 200 mg oral (Vd = 2.9 L/kg; CL = 87.5 mL/[min kg]) and 40 mg IV (Vd = 1.3 L/kg; CL = 32.7 mL/[min kg]). Oral cocaine area-under-thecurve (AUC) and peak concentration increased in a dose-related manner. AUC metabolite-to-parent ratios of benzoylecgonine and ecgonine methyl ester were significantly higher after oral compared to IV administration and highest after the lower oral dose. In addition, minor metabolites were detected in higher concentrations after oral compared to IV cocaine. Oral cocaine produced a pharmacokinetic profile different from IV cocaine, which appears as a rightward and downward shift in the concentration-time profile. Cocaine bioavailability values were similar to previous estimates. Oral cocaine also produced a unique metabolic profile, with greater concentrations of major and minor metabolites.

  11. Pharmacokinetics of dietary kaempferol and its metabolite 4-hydroxyphenylacetic acid in rats.

    Science.gov (United States)

    Zabela, Volha; Sampath, Chethan; Oufir, Mouhssin; Moradi-Afrapoli, Fahimeh; Butterweck, Veronika; Hamburger, Matthias

    2016-12-01

    Kaempferol is a major flavonoid in the human diet and in medicinal plants. The compound exerts anxiolytic activity when administered orally in mice, while no behavioural changes were observed upon intraperitoneal administration, or upon oral administration in gut sterilized animals. 4-Hydroxyphenylacetic acid (4-HPAA), which possesses anxiolytic effects when administered intraperitoneally, is a major intestinal metabolite of kaempferol. Pharmacokinetic properties of the compounds are currently not clear. UHPLC-MS/MS methods were validated to support pharmacokinetic studies of kaempferol and 4-HPAA in rats. Non-compartmental and compartmental analyses were performed. After intravenous administration, kaempferol followed a one-compartment model, with a rapid clearance (4.40-6.44l/h/kg) and an extremely short half-life of 2.93-3.79min. After oral gavage it was not possible to obtain full plasma concentration-time profiles of kaempferol. Pharmacokinetics of 4-HPAA was characterized by a two-compartment model, consisting of a quick distribution phase (half-life 3.04-6.20min) followed by a fast elimination phase (half-life 19.3-21.1min). Plasma exposure of kaempferol is limited by poor oral bioavailability and extensive metabolism. Both compounds are rapidly eliminated, so that effective concentrations at the site of action do not appear to be reached. At present, it is not clear how the anxiolytic-like effects reported for the compounds can be explained. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Influence of Cremophor EL and genetic polymorphisms on the pharmacokinetics of paclitaxel and its metabolites using a mechanism-based model.

    Science.gov (United States)

    Fransson, Martin N; Gréen, Henrik; Litton, Jan-Eric; Friberg, Lena E

    2011-02-01

    The formulation vehicle Cremophor EL has previously been shown to affect paclitaxel kinetics, but it is not known whether it also affects the kinetics of paclitaxel metabolites. This information may be important for understanding paclitaxel metabolism in vivo and in the investigation of the role of genetic polymorphisms in the metabolizing enzymes CYP2C8 and CYP3A4/CYP3A5 and the ABCB1 transporter. In this study we used the population pharmacokinetic approach to explore the influence of predicted Cremophor EL concentrations on paclitaxel (Taxol) metabolites. In addition, correlations between genetic polymorphisms and enzyme activity with clearance of paclitaxel, its two primary metabolites, 6α-hydroxypaclitaxel and p-3'-hydroxypaclitaxel, and its secondary metabolite, 6α-p-3'-dihydroxypaclitaxel were investigated. Model building was based on 1156 samples from a study with 33 women undergoing paclitaxel treatment for gynecological cancer. Total concentrations of paclitaxel were fitted to a model described previously. One-compartment models characterized unbound metabolite concentrations. Total concentrations of 6α-hydroxypaclitaxel and p-3'-hydroxypaclitaxel were strongly dependent on predicted Cremophor EL concentrations, but this association was not found for 6α-p-3'-dihydroxypaclitaxel. Clearance of 6α-hydroxypaclitaxel (fraction metabolized) was significantly correlated (p < 0.05) to the ABCB1 allele G2677T/A. Individuals carrying the polymorphisms G/A (n = 3) or G/G (n = 5) showed a 30% increase, whereas individuals with polymorphism T/T (n = 8) showed a 27% decrease relative to those with the polymorphism G/T (n = 17). The correlation of G2677T/A with 6α-hydroxypaclitaxel has not been described previously but supports other findings of the ABCB1 transporter playing a part in paclitaxel metabolism.

  13. Pregnancy-Induced Changes in the Pharmacokinetics of Caffeine and Its Metabolites

    Science.gov (United States)

    Yu, Tian; Campbell, Sarah C.; Stockmann, Chris; Tak, Casey; Schoen, Katherine; Clark, Erin A. S.; Varner, Michael W.; Spigarelli, Michael G.; Sherwin, Catherine M. T.

    2017-01-01

    This study sought to assess the pharmacokinetic (PK) changes of caffeine and its CYP1A2 metabolites across the 3 trimesters of pregnancy. A prospective, multicenter PK study was conducted among 59 pregnant women (93.2% white) who were studied once during a trimester. One beverage with 30–95 mg caffeine was consumed, and a blood/urine sample was collected within 1 hour postingestion. Concentrations of caffeine and its primary metabolites were quantified from serum and urine by LC-MS/MS. There was a significant increase in dose-normalized caffeine serum and urine concentrations between the first and third trimesters (Ptheobromine concentrations. This study identified decreased caffeine metabolism and an increase in the active metabolite theophylline concentrations during pregnancy, especially in the third trimester, revealing evidence of the large role that pregnancy plays in influencing caffeine metabolism. PMID:26358647

  14. Effects of CYP2C19 polymorphism on the pharmacokinetics of lansoprazole and its main metabolites in healthy Chinese subjects.

    Science.gov (United States)

    Zhang, Dan; Wang, Xiaolin; Yang, Man; Wang, Guocai; Liu, Huichen

    2011-06-01

    The aim of the study was to determine the pharmacokinetics of lansoprazole and its main metabolites (5'-hydroxy lansoprazole and lansoprazole sulphone) after administration of enteric-coated tablet in healthy Chinese subjects classified by CYP2C19 genotypes, and evaluate the effects of CYP2C19 genotypes on the pharmacokinetics of the three compounds. A single oral dose of 30 mg lansoprazole was administrated to 24 healthy Chinese male volunteers in different CYP2C19 genotype groups. Blood samples were collected from pre-dose up to 14-h post-dose. Plasma concentration of lansoprazole and its main metabolites were quantified by liquid chromatography-tandem mass spectrometry. CYP2C19 polymorphism had significant effects on the pharmacokinetics of lansoprazole and its main metabolites. The differences in the pharmacokinetics between CYP2C19 extensive metabolizers (Ems) (homo-EMs and hete-EMs) and PMs were more significant for lansoprazole sulphone than for 5'-hydroxy lansoprazole. The results indicate that the monitoring of lansoprazole and its main metabolites in plasma at the time-points in the elimination phase for lansoprazole could reflect the activity of CYP2C19. Simultaneously monitored with lansoprazole sulphone, lansoprazole might be a useful probe drug for CYP2C19.

  15. Preliminary physiologically based pharmacokinetic models for benzo[a]pyrene and dibenzo[def,p]chrysene in rodents

    International Nuclear Information System (INIS)

    Crowell, Susan Ritger; Amin, Shantu G.; Anderson, Kim A.; Krishnegowda, Gowdahalli; Sharma, Arun K.; Soelberg, Jolen J.; Williams, David E.; Corley, Richard A.

    2011-01-01

    Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants generated as byproducts of natural and anthropogenic combustion processes. Despite significant public health concern, physiologically based pharmacokinetic (PBPK) modeling efforts for PAHs have so far been limited to naphthalene, plus simpler PK models for pyrene, nitropyrene, and benzo[a]pyrene (B[a]P). The dearth of published models is due in part to the high lipophilicity, low volatility, and myriad metabolic pathways for PAHs, all of which present analytical and experimental challenges. Our research efforts have focused upon experimental approaches and initial development of PBPK models for the prototypic PAH, B[a]P, and the more potent, albeit less studied transplacental carcinogen, dibenzo[def,p]chrysene (DBC). For both compounds, model compartments included arterial and venous blood, flow limited lung, liver, richly perfused and poorly perfused tissues, diffusion limited fat, and a two compartment theoretical gut (for oral exposures). Hepatic and pulmonary metabolism was described for both compounds, as were fractional binding in blood and fecal clearance. Partition coefficients for parent PAH along with their diol and tetraol metabolites were estimated using published algorithms and verified experimentally for the hydroxylated metabolites. The preliminary PBPK models were able to describe many, but not all, of the available data sets, comprising multiple routes of exposure (oral, intravenous) and nominal doses spanning several orders of magnitude. Supported by Award Number P42 ES016465 from the National Institute of Environmental Health Sciences. -- Highlights: ► We present PBPK models for benzo[a]pyrene (B[a]P) and dibenzo[def,p]chrysene (DBC). ► B[a]P model accurately predicts data from multiple sources over a wide dose range. ► DBC model was based on the B[a]P model as less chemical specific data is available. ► DBC model accurately predicted preliminary

  16. Sex- and dose-dependency in the pharmacokinetics and pharmacodynamics of (+)-methamphetamine and its metabolite (+)-amphetamine in rats

    International Nuclear Information System (INIS)

    Milesi-Halle, Alessandra; Hendrickson, Howard P.; Laurenzana, Elizabeth M.; Gentry, W. Brooks; Owens, S. Michael

    2005-01-01

    These studies investigated how (+)-methamphetamine (METH) dose and rat sex affect the pharmacological response to METH in Sprague-Dawley rats. The first set of experiments determined the pharmacokinetics of METH and its pharmacologically active metabolite (+)-amphetamine (AMP) in male and female Sprague-Dawley rats after 1.0 and 3.0 mg/kg METH doses. The results showed significant sex-dependent changes in METH pharmacokinetics, and females formed significantly lower amounts of AMP. While the area under the serum concentration-time curve in males increased proportionately with the METH dose, the females showed a disproportional increase. The sex differences in systemic clearance, renal clearance, volume of distribution, and percentage of unchanged METH eliminated in the urine suggested dose-dependent pharmacokinetics in female rats. The second set of studies sought to determine the behavioral implications of these pharmacokinetic differences by quantifying locomotor activity in male and female rats after saline, 1.0, and 3.0 mg/kg METH. The results showed sex- and dose-dependent differences in METH-induced locomotion, including profound differences in the temporal profile of effects at higher dose. These findings show that the pharmacokinetic and metabolic profile of METH (slower METH clearance and lower AMP metabolite formation) plays a significant role in the differential pharmacological response to METH in male and female rats

  17. The Influence of CYP2D6 Phenotype on the Pharmacokinetic Profile of Atomoxetine in Caucasian Healthy Subjects

    Directory of Open Access Journals (Sweden)

    Todor Ioana

    2017-06-01

    Full Text Available Objective: To analyze a potential phenotypic variation within the studied group based on the pharmacokinetic profile of atomoxetine and its active metabolite, and to further investigate the impact of CYP2D6 phenotype on atomoxetine pharmacokinetics. Methods: The study was conducted as an open-label, non-randomized clinical trial which included 43 Caucasian healthy volunteers. Each subject received a single oral dose of atomoxetine 25 mg. Subsequently, atomoxetine and 4-hydroxyatomoxetine-O-glucuronide (glucuronidated active metabolite plasma concentrations were determined and a noncompartmental method was used to calculate the pharmacokinetic parameters of both compounds. Further on, the CYP2D6 metabolic phenotype was assessed using the area under the curve (AUC metabolic ratio (atomoxetine/ 4-hydroxyatomoxetine-O-glucuronide and specific statistical tests (Lilliefors (Kolgomorov-Smirnov and Anderson-Darling test. The phenotypic differences in atomoxetine disposition were identified based on the pharmacokinetic profile of the parent drug and its metabolite. Results: The statistical analysis revealed that the AUC metabolic ratio data set did not follow a normal distribution. As a result, two different phenotypes were identified, respectively the poor metabolizer (PM group which included 3 individuals and the extensive metabolizer (EM group which comprised the remaining 40 subjects. Also, it was demonstrated that the metabolic phenotype significantly influenced atomoxetine pharmacokinetics, as PMs presented a 4.5-fold higher exposure to the parent drug and a 3.2-fold lower exposure to its metabolite in comparison to EMs. Conclusions: The pharmacokinetic and statistical analysis emphasized the existence of 2 metabolic phenotypes: EMs and PMs. Furthermore, it was proved that the interphenotype variability had a marked influence on atomoxetine pharmacokinetic profile.

  18. POPULATION PHARMACOKINETICS OF ENROFLOXACIN AND ITS METABOLITE CIPROFLOXACIN IN THE GREEN SEA URCHIN (STRONGYLOCENTROTUS DROEBACHIENSIS) FOLLOWING INTRACOELOMIC AND IMMERSION ADMINISTRATION.

    Science.gov (United States)

    Phillips, Brianne E; Harms, Craig A; Lewbart, Gregory A; Lahner, Lesanna L; Haulena, Martin; Rosenberg, Justin F; Papich, Mark G

    2016-03-01

    Sea urchin mass mortality events have been attributed to both infectious and noninfectious etiologies. Bacteria, including Vibrio spp. and Pseudoalteromonas spp., have been isolated during specific mortality events. Aquarium collection sea urchins are also subject to bacterial infections and could benefit from antimicrobial treatment, but pharmacokinetic studies have been lacking for this invertebrate group until recently. This study evaluated the pharmacokinetics of enrofloxacin and its active metabolite ciprofloxacin in the green sea urchin (Strongylocentrotus droebachiensis) after intracoelomic injection and medicated bath immersion administration. The utility of a population pharmacokinetic method using nonlinear mixed effects modeling (NLME) was also evaluated. Thirty sea urchins were assigned to either the injection or immersion group. Twelve study animals and three untreated controls were utilized for each administration method: enrofloxacin 10 mg/kg intracoelomic injection or a 6-hr enrofloxacin 10 mg/L immersion. Each animal was sampled four times from 0 to 120 hr. Water samples were collected during immersion treatment and posttreatment time points in both groups. Hemolymph and water sample drug concentrations were analyzed using high-performance liquid chromatography, and pharmacokinetic parameters were determined using an NLME population pharmacokinetic method. Enrofloxacin concentrations were fit to a two-compartment model with first-order input for the intracoelomic injection group. The enrofloxacin elimination half-life (t½), peak hemolymph concentration (CMAX), and area under the curve (AUC) were 38.82 hr, 90.92 μg/ml, and 1,199 hr·μg/ml, respectively. Enrofloxacin was modeled to a one-compartment model with first-order input for the immersion treatment. The enrofloxacin t½, CMAX, and AUC were 33.46 hr, 0.48 μg/ml, and 32.88 hr·μg/ml, respectively. Ciprofloxacin was detected in trace concentrations in all hemolymph samples, indicating

  19. The metabolism and pharmacokinetics of isotretinoin in patients with acne and rosacea are not influenced by ethanol

    DEFF Research Database (Denmark)

    Grønhøj Larsen, F; Jakobsen, P; Grønhøj Larsen, C

    2009-01-01

    BACKGROUND: Isotretinoin is effective in the treatment of severe acne and rosacea. Both parent drug and its main metabolite 4-oxo-isotretinoin are potentially teratogenic compounds and contain a carboxylic acid moiety. In the presence of ethanol, naturally occurring as well as synthetic retinoids......-RA), and other possible metabolites in the presence or absence of ethanol are converted to their corresponding ethyl derivatives in patients with severe acne or rosacea after multiple isotretinoin dosing. In addition, pharmacokinetic parameters of the parent drug and its 4-oxo metabolite were determined....... PATIENTS/METHODS: Eleven patients with severe acne or rosacea were treated with isotretinoin daily for 3 months and investigated pharmacokinetically during 24 h after 1 month of treatment and for up to 28 days after discontinuation of therapy. A possible influence of ethanol was evaluated using a simple...

  20. Pharmacokinetic study of harmane and its 10 metabolites in rat after intravenous and oral administration by UPLC-ESI-MS/MS.

    Science.gov (United States)

    Li, Shuping; Teng, Liang; Liu, Wei; Cheng, Xuemei; Jiang, Bo; Wang, Zhengtao; Wang, Chang-Hong

    2016-09-01

    Context The β-carboline alkaloid harmane is widely distributed in common foods, beverages and hallucinogenic plants. Harmane exerts potential in therapies for Alzheimer's and depression diseases. However, little information on its dynamic metabolic profiles and pharmacokinetics in vivo is currently available. Objective This study investigates the dynamic metabolic profiles and pharmacokinetic properties of harmane and its metabolites in rats in vivo. Materials and methods A highly selective, sensitive and rapid ultra-performance liquid chromatography combined with electrospray ionization tandem mass spectrometry (UPLC-ESI-MS/MS) method was developed and well-validated for simultaneous quantitative determination of harmane and its uncertain endogenous metabolite harmine, as well as for semiquantitative determination of 10 harmane metabolites in rats after intravenous injection and oral administration of harmane at 1.0 and 30.0 mg/kg, respectively. Results The calibration curves of harmane and harmine showed excellent linearity within the concentration range of 1-2000 ng/mL with acceptable accuracy, precision, selectivity, recovery, matrix effect and stability. Ten metabolites, including harmane but not harmine, were detected and identified after intravenous and oral administration of harmane. The absolute bioavailability of harmane following an oral dose was 19.41 ± 3.97%. According to the AUC0-t values of all the metabolites, the metabolic levels of phase II metabolites were higher than those of phase I metabolites, and the sulphation pathways were the dominant metabolic routes for harmane in both routes of administration. Discussion and conclusion The pharmacokinetic properties of harmane and its 10 metabolites in rats were determined. Sulphate conjugation was the predominant metabolic process of harmane in rats.

  1. Gut Microbiota-Regulated Pharmacokinetics of Berberine and Active Metabolites in Beagle Dogs After Oral Administration.

    Science.gov (United States)

    Feng, Ru; Zhao, Zhen-Xiong; Ma, Shu-Rong; Guo, Fang; Wang, Yan; Jiang, Jian-Dong

    2018-01-01

    Berberine (BBR) is considered a multi-target drug that has significant advantages. In contrast to its significant pharmacological effects in clinic, the plasma level of BBR is very low. Our previous work revealed that dihydroberberine (dhBBR) could be an absorbable form of BBR in the intestine, and butyrate is an active metabolite that is generated by gut bacteria in rats. In this study, for the first time we describe gut microbiota-regulated pharmacokinetics in beagle dogs after oral administration of BBR by single (50 mg/kg) or multiple doses (50 mg/kg/d) for 7 days. GC-MS, GC, LC-MS/MS, and LC/MS n -IT-TOF were used to detect dhBBR, butyrate and BBR as well as its Phase I and II metabolites, respectively. The results showed that dhBBR was not detected in dog plasma but was excreted in small amounts in the feces of dogs examined on days 3 and 7. Butyrate was generated by gut bacteria and increased by 1.3- and 1.2-fold in plasma or feces, respectively, after 7 days of BBR treatment compared to the levels before treatment. Changes of intestinal bacterial composition were analyzed by 16S rRNA genes analysis. The results presented that dogs treated with BBR for 7 days increased both the abundance of the butyrate- and the nitroreductases- producing bacteria. We also identified chemical structures of the Phase I and II metabolites and analyzed their contents in beagle dogs. Eleven metabolites were detected in plasma and feces after BBR oral administration (50 mg/kg) to dogs, including 8 metabolites of Phase I and III metabolites of Phase II. The pharmacokinetic profile indicated that the concentration of BBR in plasma was low, with a C max value of 36.88 ± 23.45 ng/mL. The relative content of glucuronic acid conjugates (M11) was higher than those of other metabolites (M1, M2, M12, and M14) in plasma. BBR was detected in feces, with high excreted amounts on day 3 (2625.04 ± 1726.94 μg/g) and day 7 (2793.43 ± 488.10 μg/g). In summary, this is the first study to

  2. Comparative pharmacokinetics of acetyl salicylic acid and its metabolites in children suffering from autoimmune diseases.

    Science.gov (United States)

    Juárez Olguín, Hugo; Flores Pérez, Janett; Lares Asseff, Ismael; Loredo Abdalá, Arturo; Carbajal Rodríguez, Luis

    2004-01-01

    The aim of the present study was to compare the effect produced by juvenile rheumatoid arthritis (JRA) or rheumatic fever (RF) on the pharmacokinetics of acetyl salicylic acid (ASA) and its metabolites in children with autoimmune diseases (AD). A prospective, open labelled study was performed in 17 children with JRA and 17 with RF who received a single dose of 25 mg ASA/kg orally. The pharmacokinetics of ASA and its metabolites were determined. The blood and urine levels of each salicylate collected during 24 h were measured by HPLC. A group of 15 healthy teenage volunteers was included as a control group. The maximum plasma concentration, half-life time, area under the curve and the amount of salicylates excreted were statistically different between the JRA and the RF groups, as well as between the RF group and the controls, however, there were no significant differences between the JRA group and the controls. Dosage schemes must be adjusted for JRA patients, since the half life in these patients is longer than in RF patients. However, due to ample variability of pharmacokinetic parameters it is recommended that dose schemes are individualized on the type of autoimmune disease considered. Copyright 2004 John Wiley & Sons, Ltd.

  3. Modelling delays in pharmacokinetics

    International Nuclear Information System (INIS)

    Farooqi, Z.H.; Lambrecht, R.M.

    1990-01-01

    Linear system analysis has come to form the backbone of pharmacokinetics. Natural systems usually involve time delays, thus models incorporating them would be an order closer approximation to the real world compared to those that do not. Delays may be modelled in several ways. The approach considered in this study is to have a discrete-time delay dependent rate with the delay respresenting the duration between the entry of a drug into a compartment and its release in some form (may be as a metabolite) from the compartment. Such a delay may be because of one or more of several physiological reasons, like, formation of a reservoir, slow metabolism, or receptor binding. The mathematical structure this gives rise to is a system of delay-differential equations. Examples are given of simple one and two compartment systems with drugs like bumetanide, carbamazepine, and quinolone-caffeine interaction. In these examples generally a good fit is obtained and the suggested models form a good approximation. 21 refs., 6 figs

  4. Pharmacokinetic interplay of phase II metabolism and transport: a theoretical study.

    Science.gov (United States)

    Wu, Baojian

    2012-01-01

    Understanding of the interdependence of cytochrome P450 enzymes and P-glycoprotein in disposition of drugs (also termed "transport-metabolism interplay") has been significantly advanced in recent years. However, whether such "interplay" exists between phase II metabolic enzymes and efflux transporters remains largely unknown. The objective of this article is to explore the role of efflux transporters (acting on the phase II metabolites) in disposition of the parent drug in Caco-2 cells, liver, and intestine via simulations utilizing a catenary model (for Caco-2 system) and physiologically based pharmacokinetic (PBPK) models (for the liver and intestine). In all three models, "transport-metabolism interplay" (i.e., inhibition of metabolite efflux decreases the metabolism) can be observed only when futile recycling (or deconjugation) occurred. Futile recycling appeared to bridge the two processes (i.e., metabolite formation and excretion) and enable the interplay thereof. Without futile recycling, metabolite formation was independent on its downstream process excretion, thus impact of metabolite excretion on its formation was impossible. Moreover, in liver PBPK model with futile recycling, impact of biliary metabolite excretion on the exposure of parent drug [(systemic (reservoir) area under the concentration-time curve (AUC(R1))] was limited; a complete inhibition of efflux resulted in AUC(R1) increases of less than 1-fold only. In intestine PBPK model with futile recycling, even though a complete inhibition of efflux could result in large elevations (e.g., 3.5-6.0-fold) in AUC(R1), an incomplete inhibition of efflux (e.g., with a residual activity of ≥ 20% metabolic clearance) saw negligible increases (interplay between phase II enzymes and efflux transporters. Those studying such "interplay" are encouraged to adequately consider potential consequences of inhibition of efflux transporters in humans. Copyright © 2011 Wiley-Liss, Inc.

  5. Comparative Pharmacokinetics of the Organophosphorus Insecticide Chlorpyrifos and its Major Metabolites Diethylphosphate, Diethylthiophosphate and 3,5,6-Trichloro-2-pyridinol in the Rat

    Energy Technology Data Exchange (ETDEWEB)

    Timchalk, Chuck; Busby, Andrea L; Campbell, James A; Needham, Larry L; Barr, Dana

    2007-07-31

    Abstract Chlorpyrifos (CPF) is a commonly used diethylphosphorothionate organophosphorus (OP) insecticide. Diethylphosphate (DEP), diethylthiophosphate (DETP) and 3,5,6-trichloro-2-pyridinol (TCPy) are products of metabolism and of environmental degradation of CPF and are routinely measured in urine as biomarkers of exposure. However, because these same chemicals can result from metabolism or by biodegradation, monitoring total urinary metabolite levels may be reflective of not only an individual’s contact with the parent pesticide, but also exposure with the metabolites, which are present in the environment. The objective of the current study was to compare the pharmacokinetics of orally administered DEP, DETP and TCPy with their kinetics following oral dosing with the parent insecticide CPF in the rat. Groups of rats were orally administered CPF, DEP, TCPy or DETP at doses of 140 μmol/kg body weight, and the time-courses of the metabolites were evaluated in blood and urine. Following oral administration, all three metabolites were well absorbed with peak blood concentrations being attained between 1-3 h post-dosing. In the case of DEP and TCPy virtually all the administered dose was recovered in the urine by 72 h post-dosing, suggesting negligible, if any, metabolism; whereas with DETP, ~50% of the orally administered dose was recovered in the urine. The CPF oral dose was likewise rapidly absorbed and metabolized to DEP, TCPy and DETP, with the distribution of metabolites in the urine followed the order: TCPy (22 ± 3 μmol) > DETP (14 ± 2 μmol) > DEP (1.4 ± 0.7 μmol). Based upon the total amount of TCPy detected in the urine a minimum of 63% of the oral CPF dose was absorbed. These studies support the hypotheses that DEP, DETP and TCPy present in the environment can be readily absorbed and eliminated in the urine of rats and potentially humans.

  6. Population pharmacokinetics of artesunate and dihydroartemisinin following single- and multiple-dosing of oral artesunate in healthy subjects

    Directory of Open Access Journals (Sweden)

    Kirsch Lee E

    2009-12-01

    Full Text Available Abstract Background The population pharmacokinetics of artesunate (AS and its active metabolite dihydroartemisinin (DHA were studied in healthy subjects receiving single- or multiple-dosing of AS orally either in combination with pyronaridine (PYR or as a monotherapy with or without food. Methods Data from 118 concentration-time profiles arising from 91 healthy Korean subjects were pooled from four Phase I clinical studies. Subjects received 2-5 mg/kg of single- and multiple-dosing of oral AS either in combination with PYR or as a monotherapy with or without food. Plasma AS and DHA were measured simultaneously using a validated liquid chromatography- mass spectrometric method with a lower limit of quantification of 1 ng/mL for both AS and DHA. Nonlinear mixed-effect modelling was used to obtain the pharmacokinetic and variability (inter-individual and residual variability parameter estimates. Results A novel parent-metabolite pharmacokinetic model consisting of a dosing compartment, a central compartment for AS, a central compartment and a peripheral compartment for DHA was developed. AS and DHA data were modelled simultaneously assuming stoichiometric conversion to DHA. AS was rapidly absorbed with a population estimate of absorption rate constant (Ka of 3.85 h-1. The population estimates of apparent clearance (CL/F and volume of distribution (V2/F for AS were 1190 L/h with 36.2% inter-individual variability (IIV and 1210 L with 57.4% IIV, respectively. For DHA, the population estimates of apparent clearance (CLM/F and central volume of distribution (V3/F were 93.7 L/h with 28% IIV and 97.1 L with 30% IIV, respectively. The population estimates of apparent inter-compartmental clearance (Q/F and peripheral volume of distribution (V4/F for DHA were 5.74 L/h and 18.5 L, respectively. Intake of high-fat and high-caloric meal prior to the drug administration resulted in 84% reduction in Ka. Body weight impacted CLM/F, such that a unit change in

  7. Effects of caffeine, tea polyphenol and daidzein on the pharmacokinetics of lansoprazole and its metabolites in rats

    Directory of Open Access Journals (Sweden)

    Tao Wu

    2015-12-01

    Full Text Available abstract The aim of this study was to evaluate the effects of caffeine, tea polyphenol and daidzein on the pharmacokinetics of lansoprazole and its metabolites. Rats were intragastrically administered caffeine (30 mg·kg-1, once per day, tea polyphenol (400 mg·kg-1, once per day or daidzein (13.5 mg·kg-1, once per day for 14 days, followed by an intragastric administration of lansoprazole (8 mg·kg-1 on the 15th day. The plasma concentrations of lansoprazole and its two primary metabolites, 5-hydroxylansoprazole and lansoprazole sulfone, were determined by high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS. Tea polyphenol significantly elevated the Area Under the Curve (AUC of lansoprazole from 680.29 ± 285.99 to 949.76 ± 155.18 μg/L.h and reduced that of lansoprazole sulfone from 268.82 ± 82.37 to 177.72 ± 29.73 μg/L.h. Daidzein increased the AUC of lansoprazole from 680.29 ± 285.99 to 1130.44 ± 97.6 μg/L.h and decreased that of lansoprazole sulfone from 268.82 ± 82.37 to 116.23 ± 40.14 μg/L.h. The pharmacokinetics of 5-hydroxylansoprazole remained intact in the presence of tea polyphenol or daidzein. Caffeine did not affect the pharmacokinetics of lansoprazole and its metabolites. The results imply that tea polyphenol and daidzein may inhibit the in vivo metabolism of lansoprazole by suppressing CYP3A.

  8. Pharmacokinetics of Cannabinoids

    Directory of Open Access Journals (Sweden)

    Iain J McGilveray

    2005-01-01

    Full Text Available Delta-9-tetrahydrocannabinol (Δ-9-THC is the main psychoactive ingredient of cannabis (marijuana. The present review focuses on the pharmacokinetics of THC, but also includes known information for cannabinol and cannabidiol, as well as the synthetic marketed cannabinoids, dronabinol (synthetic THC and nabilone. The variability of THC in plant material (0.3% to 30% leads to variability in tissue THC levels from smoking, which is, in itself, a highly individual process. THC bioavailability averages 30%. With a 3.55% THC cigarette, a peak plasma level of 152±86.3 ng/mL occured approximately 10 min after inhalation. Oral THC, on the other hand, is only 4% to 12% bioavailable and absorption is highly variable. THC is eliminated from plasma in a multiphasic manner, with low amounts detectable for over one week after dosing. A major active 11-hydroxy metabolite is formed after both inhalation and oral dosing (20% and 100% of parent, respectively. THC is widely distributed, particularly to fatty tissues, but less than 1% of an administered dose reaches the brain, while the spleen and body fat are long-term storage sites. The elimination of THC and its many metabolites (from all routes occurs via the feces and urine. Metabolites persist in the urine and feces for severalweeks. Nabilone is well absorbed and the pharmacokinetics, although variable, appear to be linear from oral doses of 1 mg to 4 mg (these doses show a plasma elimination half-life of approximately 2 h. As with THC, there is a high first-pass effect, and the feces to urine ratio of excretion is similar to other cannabinoids. Pharmacokineticpharmacodynamic modelling with plasma THC versus cardiac and psychotropic effects show that after equilibrium is reached, the intensity of effect is proportional to the plasma THC profile. Clinical trials have found that nabilone produces less tachycardia and less euphoria than THC for a similar antiemetic response.

  9. Effects of caffeine, tea polyphenol and daidzein on the pharmacokinetics of lansoprazole and its metabolites in rats

    OpenAIRE

    Wu, Tao; Wu, Ji; Gao, Ping; Xiang, Daochun; Liu, Dong; Song, Hongping

    2015-01-01

    abstract The aim of this study was to evaluate the effects of caffeine, tea polyphenol and daidzein on the pharmacokinetics of lansoprazole and its metabolites. Rats were intragastrically administered caffeine (30 mg·kg-1, once per day), tea polyphenol (400 mg·kg-1, once per day) or daidzein (13.5 mg·kg-1, once per day) for 14 days, followed by an intragastric administration of lansoprazole (8 mg·kg-1) on the 15th day. The plasma concentrations of lansoprazole and its two primary metabolites,...

  10. Pharmacokinetics of tramadol hydrochloride and its metabolite O-desmethyltramadol in peafowl (Pavo cristatus).

    Science.gov (United States)

    Black, Peter A; Cox, Sherry K; Macek, Michael; Tieber, Anne; Junge, Randall E

    2010-12-01

    Tramadol is a centrally acting opiate analgesic that has not been well studied in avian species. Tramadol and its metabolites exert their effects at multiple sites, including opiate (mu, kappa, and delta), adrenergic (alpha-2), and serotonin (5HT) receptors. This multi-receptor mode of action is advantageous for avian patients because the mechanisms for analgesia have not been fully elucidated in all species. The objective of this study was to document the pharmacokinetics of tramadol and its active metabolite O-desmethyltramadol (M1) in common peafowl (Pavo cristatus). Based on results from a pilot animal, six adult peafowl (three male, three female) judged to be clinically healthy based on physical exam and routine bloodwork were selected for this study. Each bird was anesthetized for placement of a jugular catheter, and 7.5 mg/kg tramadol was administered orally via gavage tube. Blood samples were collected just prior to drug administration; at 30 min; and at 1, 2, 3, 4, 6, 8, 10, 12, 24, and 34 hr. Plasma levels of tramadol and M1 were measured and the pharmacokinetics for each drug was calculated. Although tramadol was quickly metabolized, plasma levels of M1 remained at or near human analgesic levels for 12-24 hr. Based on these data, tramadol may be a practical option as an orally administered analgesic agent in avian patients. Further studies, including antinociceptive studies, are needed.

  11. The Role of Drug Metabolites in the Inhibition of Cytochrome P450 Enzymes.

    Science.gov (United States)

    Mikov, Momir; Đanić, Maja; Pavlović, Nebojša; Stanimirov, Bojan; Goločorbin-Kon, Svetlana; Stankov, Karmen; Al-Salami, Hani

    2017-12-01

    Following the drug administration, patients are exposed not only to the parent drug itself, but also to the metabolites generated by drug-metabolizing enzymes. The role of drug metabolites in cytochrome P450 (CYP) inhibition and subsequent drug-drug interactions (DDIs) have recently become a topic of considerable interest and scientific debate. The list of metabolites that were found to significantly contribute to clinically relevant DDIs is constantly being expanded and reported in the literature. New strategies have been developed for better understanding how different metabolites of a drug candidate contribute to its pharmacokinetic properties and pharmacological as well as its toxicological effects. However, the testing of the role of metabolites in CYP inhibition is still not routinely performed during the process of drug development, although the evaluation of time-dependent CYP inhibition during the clinical candidate selection process may provide information on possible effects of metabolites in CYP inhibition. Due to large number of compounds to be tested in the early stages of drug discovery, the experimental approaches for assessment of CYP-mediated metabolic profiles are particularly resource demanding. Consequently, a large number of in silico or computational tools have been developed as useful complement to experimental approaches. In summary, circulating metabolites may be recognized as significant CYP inhibitors. Current data may suggest the need for an optimized effort to characterize the inhibitory potential of parent drugs metabolites on CYP, as well as the necessity to develop the advanced in vitro models that would allow a better quantitative predictive value of in vivo studies.

  12. A NOVEL PNYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODEL FOR DIMETHYLARSINIC ACID (DMA): THE LUNG AS A STORAGE COMPARTMENT

    Science.gov (United States)

    A NOVEL PHYSIOLOGICALLY-BASED PHARMACOKINETIC (PBPK) MODEL FOR DIMETHYLARSINIC ACID (DMA): THE LUNG AS A STORAGE COMPARTMENT. Evans, M.V., Hughes, M.F., and Kenyon, E.M. USEPA, ORD, NHEERL, RTP, NC 27711DMA is the major methylated metabolite of inorganic arsenic, a kno...

  13. New Modified UPLC/Tandem Mass Spectrometry Method for Determination of Risperidone and Its Active Metabolite 9-Hydroxyrisperidone in Plasma: Application to Dose-Dependent Pharmacokinetic Study in Sprague-Dawley Rats

    Directory of Open Access Journals (Sweden)

    Essam Ezzeldin

    2017-01-01

    Full Text Available Sensitive and specific liquid-chromatography tandem mass spectrometry (UPLC-MS/MS assay has been developed and validated for simultaneous quantification of risperidone (RIS and its active metabolite 9-hydroxyrisperidone (9-OH-RIS in rat plasma using olanzapine (OLA as internal standard (IS. Pharmacokinetics of risperidone and its active metabolite 9-hydroxyrisperidone was compared across different doses (0.3, 1.0, and 6.0 mg/kg. Serial blood sample was collected over a time of 48 hours and analyzed for risperidone and its active metabolite 9-hydroxyrisperidone. The pharmacokinetics parameters including Cmax, tmax, and AUC were determined for risperidone and its active ingredient. The method was linear in the concentration range of 0.2–500 ng/mL for risperidone and 9-OH-risperidone, with coefficients of determination greater than 0.998 and lower limit of quantitation of 0.2 ng/mL. Blood levels of risperidone and its active metabolite were roughly dose-proportional. The method developed herein is simple and rapid and was successfully applied for dose-dependent pharmacokinetic study.

  14. Development of an updated PBPK model for trichloroethylene and metabolites in mice, and its application to discern the role of oxidative metabolism in TCE-induced hepatomegaly

    International Nuclear Information System (INIS)

    Evans, M.V.; Chiu, W.A.; Okino, M.S.; Caldwell, J.C.

    2009-01-01

    Trichloroethylene (TCE) is a lipophilic solvent rapidly absorbed and metabolized via oxidation and conjugation to a variety of metabolites that cause toxicity to several internal targets. Increases in liver weight (hepatomegaly) have been reported to occur quickly in rodents after TCE exposure, with liver tumor induction reported in mice after long-term exposure. An integrated dataset for gavage and inhalation TCE exposure and oral data for exposure to two of its oxidative metabolites (TCA and DCA) was used, in combination with an updated and more accurate physiologically-based pharmacokinetic (PBPK) model, to examine the question as to whether the presence of TCA in the liver is responsible for TCE-induced hepatomegaly in mice. The updated PBPK model was used to help discern the quantitative contribution of metabolites to this effect. The update of the model was based on a detailed evaluation of predictions from previously published models and additional preliminary analyses based on gas uptake inhalation data in mice. The parameters of the updated model were calibrated using Bayesian methods with an expanded pharmacokinetic database consisting of oral, inhalation, and iv studies of TCE administration as well as studies of TCE metabolites in mice. The dose-response relationships for hepatomegaly derived from the multi-study database showed that the proportionality of dose to response for TCE- and DCA-induced hepatomegaly is not observed for administered doses of TCA in the studied range. The updated PBPK model was used to make a quantitative comparison of internal dose of metabolized and administered TCA. While the internal dose of TCA predicted by modeling of TCE exposure (i.e., mg TCA/kg-d) showed a linear relationship with hepatomegaly, the slope of the relationship was much greater than that for directly administered TCA. Thus, the degree of hepatomegaly induced per unit of TCA produced through TCE oxidation is greater than that expected per unit of TCA

  15. Development of an updated PBPK model for trichloroethylene and metabolites in mice, and its application to discern the role of oxidative metabolism in TCE-induced hepatomegaly.

    Science.gov (United States)

    Evans, M V; Chiu, W A; Okino, M S; Caldwell, J C

    2009-05-01

    Trichloroethylene (TCE) is a lipophilic solvent rapidly absorbed and metabolized via oxidation and conjugation to a variety of metabolites that cause toxicity to several internal targets. Increases in liver weight (hepatomegaly) have been reported to occur quickly in rodents after TCE exposure, with liver tumor induction reported in mice after long-term exposure. An integrated dataset for gavage and inhalation TCE exposure and oral data for exposure to two of its oxidative metabolites (TCA and DCA) was used, in combination with an updated and more accurate physiologically-based pharmacokinetic (PBPK) model, to examine the question as to whether the presence of TCA in the liver is responsible for TCE-induced hepatomegaly in mice. The updated PBPK model was used to help discern the quantitative contribution of metabolites to this effect. The update of the model was based on a detailed evaluation of predictions from previously published models and additional preliminary analyses based on gas uptake inhalation data in mice. The parameters of the updated model were calibrated using Bayesian methods with an expanded pharmacokinetic database consisting of oral, inhalation, and iv studies of TCE administration as well as studies of TCE metabolites in mice. The dose-response relationships for hepatomegaly derived from the multi-study database showed that the proportionality of dose to response for TCE- and DCA-induced hepatomegaly is not observed for administered doses of TCA in the studied range. The updated PBPK model was used to make a quantitative comparison of internal dose of metabolized and administered TCA. While the internal dose of TCA predicted by modeling of TCE exposure (i.e., mg TCA/kg-d) showed a linear relationship with hepatomegaly, the slope of the relationship was much greater than that for directly administered TCA. Thus, the degree of hepatomegaly induced per unit of TCA produced through TCE oxidation is greater than that expected per unit of TCA

  16. Incorporating pharmacokinetic differences between children and adults in assessing children's risks to environmental toxicants

    International Nuclear Information System (INIS)

    Ginsberg, Gary; Hattis, Dale; Sonawane, Babasaheb

    2004-01-01

    Children's risks from environmental toxicant exposure can be affected by pharmacokinetic factors that affect the internal dose of parent chemical or active metabolite. There are numerous physiologic differences between neonates and adults that affect pharmacokinetics including size of lipid, and tissue compartments, organ blood flows, protein binding capacity, and immature function of renal and hepatic systems. These factors combine to decrease the clearance of many therapeutic drugs, which can also be expected to occur with environmental toxicants in neonates. The net effect may be greater or lesser internal dose of active toxicant depending upon how the agent is distributed, metabolized, and eliminated. Child/adult pharmacokinetic differences decrease with increasing postnatal age, but these factors should still be considered in any children's age group, birth through adolescence, for which there is toxicant exposure. Physiologically based pharmacokinetic (PBPK) models can simulate the absorption, distribution, metabolism, and excretion of xenobiotics in both children and adults, allowing for a direct comparison of internal dose and risk across age groups. This review provides special focus on the development of hepatic cytochrome P-450 enzymes (CYPs) in early life and how this information, along with many factors unique to children, can be applied to PBPK models for this receptor population. This review describes a case study involving the development of neonatal PBPK models for the CYP1A2 substrates caffeine and theophylline. These models were calibrated with pharmacokinetic data in neonates and used to help understand key metabolic differences between neonates and adults across these two drugs

  17. Pharmacokinetics, tissue distribution, and metabolites of a polyvinylpyrrolidone-coated norcantharidin chitosan nanoparticle formulation in rats and mice, using LC-MS/MS

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    Ding XY

    2012-04-01

    rat feces and urine samples, collected after oral administration. A prototype drug and two metabolites were found in the feces, and seven metabolites in the urine. The primary elimination route of NCTD was via the urine. The quantity of the parent drug eliminated in the feces of the PVP–NCTD–NP group, was 32 times greater than that of the NCTD group, indicating that the NPs dramatically increased the reduction quantity from liver to bile. We conclude that PVP–NCTD–NPs are an adequate formulation for enhancing the absorption of NCTD, and significantly improving therapeutic effects targeting the hepatic system. Decarboxylation and hydroxylation were the dominant metabolic pathways for NCTD. Metabolites were mainly excreted into rat kidney and finally into urine.Keywords: pharmacokinetics, metabolites, NCTD, PVP, LC-MS/MS

  18. Effects of body size and gender on the population pharmacokinetics of artesunate and its active metabolite dihydroartemisinin in pediatric malaria patients.

    Science.gov (United States)

    Morris, Carrie A; Tan, Beesan; Duparc, Stephan; Borghini-Fuhrer, Isabelle; Jung, Donald; Shin, Chang-Sik; Fleckenstein, Lawrence

    2013-12-01

    Despite the important role of the antimalarial artesunate and its active metabolite dihydroartemisinin (DHA) in malaria treatment efforts, there are limited data on the pharmacokinetics of these agents in pediatric patients. This study evaluated the effects of body size and gender on the pharmacokinetics of artesunate-DHA using data from pediatric and adult malaria patients. Nonlinear mixed-effects modeling was used to obtain a base model consisting of first-order artesunate absorption and one-compartment models for artesunate and for DHA. Various methods of incorporating effects of body size descriptors on clearance and volume parameters were tested. An allometric scaling model for weight and a linear body surface area (BSA) model were deemed optimal. The apparent clearance and volume of distribution of DHA obtained with the allometric scaling model, normalized to a 38-kg patient, were 63.5 liters/h and 65.1 liters, respectively. Estimates for the linear BSA model were similar. The 95% confidence intervals for the estimated gender effects on clearance and volume parameters for artesunate fell outside the predefined no-relevant-clinical-effect interval of 0.75 to 1.25. However, the effect of gender on apparent DHA clearance was almost entirely contained within this interval, suggesting a lack of an influence of gender on this parameter. Overall, the pharmacokinetics of artesunate and DHA following oral artesunate administration can be described for pediatric patients using either an allometric scaling or linear BSA model. Both models predict that, for a given artesunate dose in mg/kg of body weight, younger children are expected to have lower DHA exposure than older children or adults.

  19. Disposition of 1,2,3-trichloropropane in the Fischer 344 rat: conventional and physiological pharmacokinetics

    International Nuclear Information System (INIS)

    Volp, R.F.; Sipes, I.G.; Falcoz, C.; Carter, D.E.; Gross, J.F.

    1984-01-01

    To investigate the disposition of 1,2,3-trichloropropane (TCP), [14C]-TCP was administered iv to male Fischer 344 rats. Unchanged TCP and total radiolabel were determined in tissues and excreta at varying intervals after administration. The compound was distributed and eliminated rapidly. Initial and terminal half-lives of unchanged TCP in the blood were 0.29 and 23 hr. Adipose tissue accumulated 37% of the dose within 15 min and retained more of the dose than any other tissue until 4 hr; most (69%) of the radiolabel in adipose tissue through 4 hr was unchanged TCP. After 4 hr, the liver contained the largest fraction of the dose, primarily as metabolites. Thus TCP disappeared from adipose tissue while metabolites appeared in liver and other tissues. Excretion was nearly complete (90% of the dose) in 24 hr and was predominantly via the urine (47% of the dose). Expiration was the only route by which unchanged TCP (5% of the dose) was excreted. In addition, 25% of the dose was expired as carbon dioxide. There were numerous other metabolites, none accounting for more than 10% of the dose. Nonvolatile metabolites were longer lived than the parent compound. On the basis of high water solubility, reaction with 2,4-dinitrofluorobenzene, and diminished radiolabel in bile of glycidol-treated rats, glutathione conjugation is suggested as an important metabolic route for TCP. A physiological pharmacokinetic model was developed to describe the time course of trichloropropane concentration in tissues. The model demonstrates the possibility of using physiological and pharmacokinetic data to predict concentration-time relations for toxic compounds

  20. Pharmacokinetics and metabolic rates of acetyl salicylic acid and its metabolites in an Otomi ethnic group of Mexico.

    Science.gov (United States)

    Lares-Asseff, Ismael; Juárez-Olguín, Hugo; Flores-Pérez, Janett; Guillé-Pérez, Adrian; Vargas, Arturo

    2004-05-01

    The objective of this study was to determine pharmacokinetic differences of acetyl salicylic acid (ASA) and its metabolites: gentisic acid (GA), salicylic acid (SA) and salicyluric acid (SUA) between Otomies and Mesticians healthy subjects. Design. Ten Otomies and 10 Mesticians were included. After a single dose of aspirin given orally (15 mg/kg), blood and urine samples were collected at different times. Results. Pharmacokinetic parameters of salicylates showed significant differences, except distribution volume of SA, and elimination half-life of SUA. Metabolic rates of ASA showed significant differences for all rates between both groups. On the other hand, percentages of dose excreted were more reduced for SA and SUA for the Otomies than for the Mesticians. Conclusion. Results reflect differences in the hydrolysis way i.e. from ASA to SA and aromatic hydroxylation i.e. from SA to GA, which were slower in Otomies subjects, showing a possible pharmacokinetic differences about the capabilities of ASA biotransformation as a consequence of ethnic differences.

  1. Pharmacokinetic study of isocorynoxeine metabolites mediated by cytochrome P450 enzymes in rat and human liver microsomes.

    Science.gov (United States)

    Zhao, Lizhu; Zang, Bin; Qi, Wen; Chen, Fangfang; Wang, Haibo; Kano, Yoshihiro; Yuan, Dan

    2016-06-01

    Isocorynoxeine (ICN) is one of the major bioactive tetracyclic oxindole alkaloids found in Uncaria rhynchophylla (Miq.) Jacks. that is widely used for the treatment of hypertension, vascular dementia, and stroke. The present study was undertaken to assess the plasma pharmacokinetic characteristics of major ICN metabolites, and the role of simulated gastric and intestinal fluid (SGF and SIF), human and rat liver microsomes (HLMs and RLMs), and seven recombinant human CYP enzymes in the major metabolic pathway of ICN. A rapid, sensitive and accurate UHPLC/Q-TOF MS method was validated for the simultaneous determination of ICN and its seven metabolites in rat plasma after oral administration of ICN at 40mg/kg. It was found that 18.19-dehydrocorynoxinic acid (DCA) and 5-oxoisocorynoxeinic acid (5-O-ICA) were both key and predominant metabolites, rather than ICN itself, due to the rapid and extensive metabolism of ICN in vivo. The further study indicated that ICN was mainly metabolized in human or rat liver, and CYPs 2C19, 3A4 and 2D6 were the major enzymes responsible for the biotransformation of ICN to DCA and 5-O-ICA in human. These findings are of significance in understanding of the pharmacokinetic nature of tetracyclic oxindole alkaloids, and provide helpful information for the clinical co-administration of the herbal preparations containing U. rhynchophylla with antihypertensive drugs that are mainly metabolized by CYP3A4 and CYP2C19. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. Pharmacokinetics and pharmacodynamics of mivacurium in young adult and elderly patients

    DEFF Research Database (Denmark)

    Østergaard, Doris; Viby-Mogensen, Jørgen; Pedersen, N.A.

    2002-01-01

    age factors; butyrylcholinesterase; cholinesterase; dose-response curves; enzymes; metabolites; mivacurium; neuromuscular relaxants; pharmacodynamics; pharmacokinetics; pharmacology; pseudocholinesterase; stereoisomers......age factors; butyrylcholinesterase; cholinesterase; dose-response curves; enzymes; metabolites; mivacurium; neuromuscular relaxants; pharmacodynamics; pharmacokinetics; pharmacology; pseudocholinesterase; stereoisomers...

  3. The In Vivo Quantitation of Diazinon, chlorpyrifos, and Their Major Metabolites in Rat Blood for the Refinement of a Physiologically-Based Pharmacokinetic/Pharmacodynamic Models

    Energy Technology Data Exchange (ETDEWEB)

    Busby, A.; Kousba, A.; Timchalk, C.

    2004-01-01

    Chlorpyrifos (CPF)(O,O-diethyl-O-[3,5,6-trichloro-2-pyridyl]-phosphorothioate, CAS 2921-88-2), and diazinon (DZN)(O,O-diethyl-O-2-isopropyl-4-methyl-6-pyrimidyl thiophosphate, CAS 333-41-5) are commonly encountered organophosphorus insecticides whose oxon metabolites (CPF-oxon and DZN-oxon) have the ability to strongly inhibit acetylcholinesterase, an enzyme responsible for the breakdown of acetylcholine at nerve synapses. Chlorpyrifos-oxon and DZN-oxon are highly unstable compounds that degrade via hepatic, peripheral blood, and intestinal metabolism to the more stable metabolites, TCP (3,5,6-trichloro-2-pyridinol, CAS not assigned) and IMHP (2-isopropyl-6-methyl-4-pyrimidinol, CAS 2814-20-2), respectively. Studies have been performed to understand and model the chronic and acute toxic effects of CPF and DZN individually but little is known about their combined effects. The purpose of this study was to improve physiologically based pharmacokinetic/ pharmacodynamic (PBPK/PD) computational models by quantifying concentrations of CPF and DZN and their metabolites TCP and IMHP in whole rat blood, following exposure to the chemicals individually or as a mixture. Male Sprague-Dawley rats were orally dosed with 60 mg/kg of CPF, DZN, or a mixture of these two pesticides. When administered individually DZN and CPF were seen to reach their maximum concentration at ~3 hours post-dosing. When given as a mixture, both DZN and CPF peak blood concentrations were not achieved until ~6 hours post-dosing and the calculated blood area under the curve (AUC) for both chemicals exceeded those calculated following the single dose. Blood concentrations of IMHP and TCP correlated with these findings. It is proposed that the higher AUC obtained for both CPF and DZN as a mixture resulted from competition for the same metabolic enzyme systems.

  4. Population pharmacokinetics of artesunate and dihydroartemisinin in pregnant and non-pregnant women with malaria

    Directory of Open Access Journals (Sweden)

    Bose Carl

    2011-05-01

    Full Text Available Abstract Background The World Health Organization endorses the use of artemisinin-based combination therapy for treatment of acute uncomplicated falciparum malaria in the second and third trimesters of pregnancy. However, the effects of pregnancy on the pharmacokinetics of artemisinin derivatives, such as artesunate (AS, are poorly understood. In this analysis, the population pharmacokinetics of oral AS, and its active metabolite dihydroartemisinin (DHA, were studied in pregnant and non-pregnant women at the Kingasani Maternity Clinic in the DRC. Methods Data were obtained from 26 pregnant women in the second (22 - 26 weeks or the third (32 - 36 weeks trimester of pregnancy and from 25 non-pregnant female controls. All subjects received 200 mg AS. Plasma AS and DHA were measured using a validated LC-MS method. Estimates for pharmacokinetic and variability parameters were obtained through nonlinear mixed effects modelling. Results A simultaneous parent-metabolite model was developed consisting of mixed zero-order, lagged first-order absorption of AS, a one-compartment model for AS, and a one-compartment model for DHA. Complete conversion of AS to DHA was assumed. The model displayed satisfactory goodness-of-fit, stability, and predictive ability. Apparent clearance (CL/F and volume of distribution (V/F estimates, with 95% bootstrap confidence intervals, were as follows: 195 L (139-285 L for AS V/F, 895 L/h (788-1045 L/h for AS CL/F, 91.4 L (78.5-109 L for DHA V/F, and 64.0 L/h (55.1-75.2 L/h for DHA CL/F. The effect of pregnancy on DHA CL/F was determined to be significant, with a pregnancy-associated increase in DHA CL/F of 42.3% (19.7 - 72.3%. Conclusions In this analysis, pharmacokinetic modelling suggests that pregnant women have accelerated DHA clearance compared to non-pregnant women receiving orally administered AS. These findings, in conjunction with a previous non-compartmental analysis of the modelled data, provide further evidence that

  5. Physiologically based pharmacokinetic modeling of dibromoacetic acid in F344 rats

    International Nuclear Information System (INIS)

    Matthews, Jessica L.; Schultz, Irvin R.; Easterling, Michael R.; Melnick, Ronald L.

    2010-01-01

    A novel physiologically based pharmacokinetic (PBPK) model structure, which includes submodels for the common metabolites (glyoxylate (GXA) and oxalate (OXA)) that may be involved in the toxicity or carcinogenicity of dibromoacetic acid (DBA), has been developed. Particular attention is paid to the representation of hepatic metabolism, which is the primary elimination mechanism. DBA-induced suicide inhibition is modeled by irreversible covalent binding of the intermediate metabolite α-halocarboxymethylglutathione (αH1) to the glutathione-S-transferase zeta (GSTzeta) enzyme. We also present data illustrating the presence of a secondary non-GSTzeta metabolic pathway for DBA, but not dichloroacetic acid (DCA), that produces GXA. The model is calibrated with plasma and urine concentration data from DBA exposures in female F344 rats through intravenous (IV), oral gavage, and drinking water routes. Sensitivity analysis is performed to confirm identifiability of estimated parameters. Finally, model validation is performed with data sets not used during calibration. Given the structural similarity of dihaloacetates (DHAs), we hypothesize that the PBPK model presented here has the capacity to describe the kinetics of any member or mixture of members of this class in any species with the alteration of chemical-and species-specific parameters.

  6. Enantioselective pharmacokinetics of sibutramine in rat.

    Science.gov (United States)

    Noh, Keumhan; Bae, Kyoungjin; Min, Bokyoung; Kim, Eunyoung; Kwon, Kwang-il; Jeong, Taecheon; Kang, Wonku

    2010-02-01

    Racemic sibutramine is widely used to treat obesity owing to its inhibition of serotonin and noradrenaline reuptake in synapses. Although the enantioselective effects of sibutramine and its two active desmethyl-metabolites, monodesmethylsibutramine (MDS) and didesmethylsibutramine (DDS), on anorexia and energy expenditure have been elucidated, the enantioselective pharmacokinetics of sibutramine are still unclear. Therefore, we aimed to characterize the enantioselective pharmacokinetics of sibutramine and its metabolites in plasma and urine following an intravenous and a single oral administration of sibutramine in rats. The absolute bioavailability of sibutramine was only about 7%. The pharmacologically less effective S-isomer of DDS was predominant in the plasma: the C ( max ) and the AUC ( inf ) were 28 and 30 times higher than those of the R-isomer, respectively (psibutramine metabolites MDS and DDS were present at lower concentrations, owing to their rapid biotransformation to hydroxylated and/or carbamoylglucuronized forms and their faster excretion in the urine. The present study is the first to elucidate the enantioselective pharmacokinetics of sibutramine in rats.

  7. Quantitative Rationalization of Gemfibrozil Drug Interactions: Consideration of Transporters-Enzyme Interplay and the Role of Circulating Metabolite Gemfibrozil 1-O-β-Glucuronide.

    Science.gov (United States)

    Varma, Manthena V S; Lin, Jian; Bi, Yi-an; Kimoto, Emi; Rodrigues, A David

    2015-07-01

    Gemfibrozil has been suggested as a sensitive cytochrome P450 2C8 (CYP2C8) inhibitor for clinical investigation by the U.S. Food and Drug Administration and the European Medicines Agency. However, gemfibrozil drug-drug interactions (DDIs) are complex; its major circulating metabolite, gemfibrozil 1-O-β-glucuronide (Gem-Glu), exhibits time-dependent inhibition of CYP2C8, and both parent and metabolite also behave as moderate inhibitors of organic anion transporting polypeptide 1B1 (OATP1B1) in vitro. Additionally, parent and metabolite also inhibit renal transport mediated by OAT3. Here, in vitro inhibition data for gemfibrozil and Gem-Glu were used to assess their impact on the pharmacokinetics of several victim drugs (including rosiglitazone, pioglitazone, cerivastatin, and repaglinide) by employing both static mechanistic and dynamic physiologically based pharmacokinetic (PBPK) models. Of the 48 cases evaluated using the static models, about 75% and 98% of the DDIs were predicted within 1.5- and 2-fold of the observed values, respectively, when incorporating the interaction potential of both gemfibrozil and its 1-O-β-glucuronide. Moreover, the PBPK model was able to recover the plasma profiles of rosiglitazone, pioglitazone, cerivastatin, and repaglinide under control and gemfibrozil treatment conditions. Analyses suggest that Gem-Glu is the major contributor to the DDIs, and its exposure needed to bring about complete inactivation of CYP2C8 is only a fraction of that achieved in the clinic after a therapeutic gemfibrozil dose. Overall, the complex interactions of gemfibrozil can be quantitatively rationalized, and the learnings from this analysis can be applied in support of future predictions of gemfibrozil DDIs. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

  8. Pharmacokinetics of lansoprazole and its main metabolites after single and multiple intravenous doses in healthy Chinese subjects.

    Science.gov (United States)

    Zhang, Dan; Zhang, Yanan; Liu, Man; Wang, Xiaolin; Yang, Man; Han, Jing; Liu, Huichen

    2013-09-01

    The aim of the study was to evaluate and compare the pharmacokinetics of lansoprazole (LPZ) and its main metabolites, 5'-hydroxy lansoprazole (HLPZ) and lansoprazole sulfone (LPZS), after single and multiple intravenous (i.v.) doses of LPZ in healthy Chinese subjects. Twelve subjects (six males and six females) were given a single dose of LPZ by i.v. infusion on day 1, and multiple doses from day 2 to day 6. Blood samples were collected at designated time points for analysis of plasma concentrations of LPZ, HLPZ and LPZS by an LC-MS/MS method. LPZ was generally well tolerated in healthy Chinese subjects. After single and multiple i.v. doses of 30 mg LPZ, the C max values of LPZ, HLPZ and LPZS were 1490 ± 290 and 1450 ± 280, 175 ± 71 and 154 ± 56, and 51.3 ± 82.9 and 74.1 ± 158.7 ng/mL, with the AUC0-t values 3280 ± 2550 and 4260 ± 3880, 381 ± 128 and 389 ± 111, and 389 ± 1204 and 700 ± 2255 ng h/mL, respectively. The t 1/2 and CL values of LPZ after single and multiple i.v. doses were 1.48 ± 1.03 and 2.19 ± 1.03 h, and 11.67 ± 4.49 and 9.56 ± 4.08 L/h, respectively. Compared with the pharmacokinetics of LPZ after a single dose, t 1/2 increased markedly, CL decreased significantly and AUC increased by over 20 % after multiple doses. The results indicated that there was drug accumulation of LPZ after multiple i.v. doses, and there was no gender-related difference in pharmacokinetics of LPZ and its two metabolites.

  9. Population pharmacokinetics of Artemether and dihydroartemisinin in pregnant women with uncomplicated Plasmodium falciparum malaria in Uganda

    Directory of Open Access Journals (Sweden)

    Tarning Joel

    2012-08-01

    Full Text Available Abstract Background Malaria in pregnancy increases the risk of maternal anemia, abortion and low birth weight. Approximately 85.3 million pregnancies occur annually in areas with Plasmodium falciparum transmission. Pregnancy has been reported to alter the pharmacokinetic properties of many anti-malarial drugs. Reduced drug exposure increases the risk of treatment failure. The objective of this study was to evaluate the population pharmacokinetic properties of artemether and its active metabolite dihydroartemisinin in pregnant women with uncomplicated P. falciparum malaria in Uganda. Methods Twenty-one women with uncomplicated P. falciparum malaria in the second and third trimesters of pregnancy received the fixed oral combination of 80 mg artemether and 480 mg lumefantrine twice daily for three days. Artemether and dihydroartemisinin plasma concentrations after the last dose administration were quantified using liquid chromatography coupled to tandem mass-spectroscopy. A simultaneous drug-metabolite population pharmacokinetic model for artemether and dihydroartemisinin was developed taking into account different disposition, absorption, error and covariate models. A separate modeling approach and a non-compartmental analysis (NCA were also performed to enable a comparison with literature values and different modeling strategies. Results The treatment was well tolerated and there were no cases of recurrent malaria. A flexible absorption model with sequential zero-order and transit-compartment absorption followed by a simultaneous one-compartment disposition model for both artemether and dihydroartemisinin provided the best fit to the data. Artemether and dihydroartemisinin exposure was lower than that reported in non-pregnant populations. An approximately four-fold higher apparent volume of distribution for dihydroartemisinin was obtained by non-compartmental analysis and separate modeling compared to that from simultaneous modeling of the drug

  10. Pharmacokinetics of detomidine and its metabolites following intravenous and intramuscular administration in horses.

    Science.gov (United States)

    Grimsrud, K N; Mama, K R; Thomasy, S M; Stanley, S D

    2009-04-01

    Detomidine is commonly used i.v. for sedation and analgesia in horses, but the pharmacokinetics and metabolism of this drug have not been well described. To describe the pharmacokinetics of detomidine and its metabolites, 3-hydroxy-detomidine (OH-detomidine) and detomidine 3-carboxylic acid (COOH-detomidine), after i.v. and i.m. administration of a single dose to horses. Eight horses were used in a balanced crossover design study. In Phase 1, 4 horses received a single dose of i.v. detomidine, administered 30 microg/kg bwt and 4 a single dose i.m. 30 microg/kg bwt. In Phase 2, treatments were reversed. Plasma detomidine, OH-detomidine and COOH-detomidine were measured at predetermined time points using liquid chromatography-mass spectrometry. Following i.v. administration, detomidine was distributed rapidly and eliminated with a half-life (t1/2(el)) of approximately 30 min. Following i.m. administration, detomidine was distributed and eliminated with t1/2(el) of approximately one hour. Following, i.v. administration, detomidine clearance had a mean, median and range of 12.41, 11.66 and 10.10-18.37 ml/min/kg bwt, respectively. Detomidine had a volume of distribution with the mean, median and range for i.v. administration of 470, 478 and 215-687 ml/kg bwt, respectively. OH-detomidine was detected sooner than COOH-detomidine; however, COOH-detomidine had a much greater area under the curve. These pharmacokinetic parameters provide information necessary for determination of peak plasma concentrations and clearance of detomidine in mature horses. The results suggest that, when a longer duration of plasma concentration is warranted, the i.m. route should be considered.

  11. Evaluation of the Potential Pharmacokinetic Interaction between Atomoxetine and Fluvoxamine in Healthy Volunteers.

    Science.gov (United States)

    Todor, Ioana; Popa, Adina; Neag, Maria; Muntean, Dana; Bocsan, Corina; Buzoianu, Anca; Vlase, Laurian; Gheldiu, Ana-Maria; Briciu, Corina

    2017-01-01

    Attention deficit hyperactivity disorder (ADHD) is frequently associated with other psychiatric pathologies. Therefore, the present study investigated a possible pharmacokinetic interaction between atomoxetine (ATX), a treatment option for ADHD, and an antidepressant, namely, fluvoxamine (FVX). Designed as an open-label, non-randomized clinical trial, the study included 2 periods. In period 1 (reference), each subject received ATX 25 mg (single-dose), whereas in period 2 (test), all subjects were given a combination of ATX 25 mg + FVX 100 mg, following a 6-day pretreatment regimen with the enzymatic inhibitor. Non-compartmental methods were employed to determine the pharmacokinetic parameters of ATX and its main active metabolite (glucuronidated form), 4-hydroxyatomoxetine-O-glucuronide. The results revealed significant differences between the study periods for Cmax, AUC0-t and AUC0-∞ values corresponding to ATX and its metabolite. Small, but statistically significant increases in AUC values were reported for both parent drug (1,583.05 ± 1,040.29 vs. 2,111.55 ± 1,411.59 ng*h/ml) and 4-hydroxyatomoxetine-O-glucuronide (5,754.71 ± 1,235.5 vs. 6,293.17 ± 1,219.34 ng*h/ml) after combined treatment of ATX and the enzymatic inhibitor. FVX had a modest effect on the pharmacokinetics of ATX and 4-hydroxyatomoxetine-O-glucuronide. The presence or absence of any clinical consequences associated with this pharmacokinetic drug-drug interaction needs to be established in future studies. © 2016 S. Karger AG, Basel.

  12. Effects of clopidogrel on the pharmacokinetics of sibutramine and its active metabolites.

    Science.gov (United States)

    Bae, Jung-Woo; Jang, Choon-Gon; Lee, Seok-Young

    2011-12-01

    Sibutramine is metabolized by the enzymes CYP2B6 and CYP2C19 into 2 active metabolites, M1 (mono-desmethyl sibutramine) and M2 (di-desmethyl sibutramine). Clopidogrel is a mechanism-based inhibitor of CYP2B6 and CYP2C19. In this study, 13 extensive metabolizers of CYP2B6 and CYP2C19 were evaluated to clarify whether clopidogrel inhibits the formation of the active metabolites of sibutramine. In the control phase, each subject received a 15-mg oral dose of sibutramine. After a washout period of 2 weeks, in the clopidogrel phase, the subjects received 300 mg of clopidogrel on the first day and then 75-mg once daily for 6 days. One hour after the last dosing of clopidogrel, all subjects received 15-mg of sibutramine. Compared with the control phase, the mean sibutramine and M1 plasma concentrations were higher after clopidogrel treatment. Clopidogrel significantly increased the half-life (242% of control phase) and area under the plasma concentration-time curve from 0 to infinity (AUC(inf)) (227% of control phase) of sibutramine and decreased the apparent oral clearance (31% of control phase) of sibutramine. Pharmacokinetic analysis showed significant increases in the AUC(inf) (162% of control phase) of M1. The CYP2B6 and CYP2C19 inhibitor clopidogrel significantly inhibited the formations of M1 from sibutramine and M2 from sibutramine by 37% and 64%, respectively. Therefore, CYP2B6 and CYP2C19 are in vivo catalysts for the formation of the 2 active metabolites of sibutramine.

  13. Requirements for pharmacokinetic evaluation of antibiotics in phase I studies.

    Science.gov (United States)

    Bergan, T

    1986-01-01

    Initial pharmacokinetic studies usually include healthy volunteers to minimize variation generated by diseases. Ethical aspects of initial studies are paramount. The guidelines of the Helsinki Declaration should be followed or even extended. Thorough toxicologic screening in animals is a prerequisite. The use of radioisotopes for pharmacokinetic studies should be limited. The basic design of studies includes cross-over administration of intravenous and oral doses of several sizes. Bioavailability, total area under the serum concentration curve, serum half-life, amount eliminated in urine as active drug, and metabolism are the most important data. The fate of the parent compound and of its possible metabolites in both healthy persons and ill individuals (including those with renal or hepatic dysfunction) should be monitored. Diet may have consequences with regard to recommended dosage schedules. When possible, tissue penetration of antibiotics should be assessed, preferably through the analysis of peripheral human lymph and of suction-blister and peritoneal fluids. Theoretical dosage schedules based on pharmacokinetic assessments in healthy persons should be tested in patients with infectious disease, particularly in those with reduced renal and/or hepatic function.

  14. Population pharmacokinetic modelling of the enterohepatic recirculation of diclofenac and rofecoxib in rats

    Science.gov (United States)

    Huntjens, D R H; Strougo, A; Chain, A; Metcalf, A; Summerfield, S; Spalding, D J M; Danhof, M; Della Pasqua, O

    2008-01-01

    Background and purpose: Enterohepatic recirculation (EHC) is a common pharmacokinetic phenomenon that has been poorly modelled in animals. The presence of EHC leads to the appearance of multiple peaks in the concentration-time profile and increased exposure, which may have implications for drug effect and extrapolation across species. The aim of this investigation was to develop a population pharmacokinetic model for diclofenac and rofecoxib that describes EHC and to assess its consequence for the pharmacodynamics of both drugs. Experimental approach: The pharmacokinetics of diclofenac and rofecoxib was characterized in male rats following intravenous, intraperitoneal and oral administration. Blood samples were collected at pre-defined time points after dosing to determine plasma concentrations over time. A parametric approach using nonlinear mixed effects modelling was applied to describe EHC, whilst simulations were used to evaluate its impact on PGE2 inhibition. Key results: For diclofenac, EHC was described by a compartmental model with periodic transfer rate and metabolite formation rate. For rofecoxib, EHC modelling required a conversion compartment with first-order recycling rate and lag time. Based on model predictions, EHC causes an increase of 95% in the systemic exposure to diclofenac and of 15% in the exposure to rofecoxib. In addition, EHC prolongs the inhibition of PGE2 and increases the duration of the anti-inflammatory effect (24 h for rofecoxib 10 mg kg−1) without affecting maximum inhibition. Conclusions and implications: Our findings show the relevance of exploring EHC in a quantitative manner to accurately interpret pharmacodynamic findings in vivo, in particular when scaling across species. PMID:18193075

  15. Effect of CYP2B6 genotype on the pharmacokinetics of sibutramine and active metabolites in healthy subjects.

    Science.gov (United States)

    Chung, Jae Yong; Jang, Seong Bok; Lee, Yoon Jung; Park, Min Soo; Park, Kyungsoo

    2011-01-01

    Sibutramine is a pharmacologic intervention for the treatment of obesity. The effect of CYP2B6 genotypes on the pharmacokinetics of sibutramine and its active metabolites (desmethylsibutramine [M1] and didesmethylsibutramine [M2]) was evaluated in 57 healthy subjects. Each subject received a single oral dose of 10 or 15 mg sibutramine, and blood samples were collected up to 72 hours after dosing. The relationship between the genotypes and the pharmacokinetics of sibutramine, M1, and M2 was examined. A statistically significant difference in the elimination half-life (t(1/2)) of sibutramine M1 was found among the 3 genotype groups (P = .0006), between the *1/*1 and *1/*6 groups (P = .0001), and between the *1/*4 and *1/*6 groups (P = .012). The mean value of M1 t(1/2) in *1/*6 (33.3 ± 10.5 hours) was about 58% and 61% greater than that of the *1/*1 group (21.0 ± 7.4 hours) and the *1/*4 group (20.7 ± 9.8 hours), respectively. No significant differences in area under the concentration-time curve or maximum plasma drug concentration were observed between the groups. The CYP2B6*6 allele may be associated with a lower metabolic clearance of the M1 metabolite of sibutramine in human subjects.

  16. PHARMACOKINETICS OF TRAMADOL HYDROCHLORIDE AND ITS METABOLITE O-DESMETHYLTRAMADOL FOLLOWING A SINGLE, ORALLY ADMINISTERED DOSE IN CALIFORNIA SEA LIONS (ZALOPHUS CALIFORNIANUS).

    Science.gov (United States)

    Boonstra, Jennifer L; Barbosa, Lorraine; Van Bonn, William G; Johnson, Shawn P; Gulland, Frances M D; Cox, Sherry K; Martin-Jimenez, Tomas

    2015-09-01

    Tramadol is a synthetic, centrally acting, opiate-like analgesic that is structurally related to codeine and morphine. The objective of this study was to determine the pharmacokinetics of tramadol hydrochloride and its major active metabolite O-desmethyltramadol (M1) in the California sea lion (Zalophus californianus). A single dose of tramadol was administered orally in fish at 2 mg/kg to a total of 15 wild California sea lions admitted for rehabilitation. Twenty-four total blood samples were collected post drug administration at 10, 20, 30, and 45 min and at 1, 3, 5, 6, 8, 12, and 24 hr. Blood plasma was separated and stored at -80°C until analysis with high-performance liquid chromatography was performed to determine levels of tramadol and M1, the major active metabolite. The results indicate that the plasma levels of parent tramadol are low or negligible during the first 30-45 min and then reach the predicted mean maximum plasma concentration of 358 ng/ml at 1.52 hr. The M1 metabolite was not detectable in 21 of 24 plasma samples, below the level of quantification of 5 ng/ml in one sample, and detectable at 11 and 17 ng/ml in two of the samples. This study suggests that a 2 mg/kg dose would need to be administered every 6-8 hr to maintain concentrations of tramadol above the minimum human analgesic level for mild to moderate pain. Based on dosing simulations, a dose of 4 mg/kg q8 hr or q12 hr, on average, may represent an adequate compromise, but further studies are needed using a larger sample size. Pharmacodynamic studies are warranted to determine if tramadol provides analgesic effects in this species. The potential for tramadol toxicosis at any dose also has not been determined in this species.

  17. CYP2C19*17 increases clopidogrel-mediated platelet inhibition but does not alter the pharmacokinetics of the active metabolite of clopidogrel

    DEFF Research Database (Denmark)

    Pedersen, Rasmus Steen; Nielsen, Flemming; Stage, Tore Bjerregaard

    2014-01-01

    *1/*1, 11 CYP2C19*1/*17 and nine CYP2C19*17/*17). In Phase A, the pharmacokinetics of the derivatized active metabolite of clopidogrel (CAMD) and platelet function were determined after administration of a single oral dose of 600 mg clopidogrel (Plavix; Sanofi-Avensis, Horsholm, Denmark). In Phase B...

  18. PCPF-M model for simulating the fate and transport of pesticides and their metabolites in rice paddy field.

    Science.gov (United States)

    Boulange, Julien; Malhat, Farag; Thuyet, Dang Quoc; Watanabe, Hirozumi

    2017-12-01

    The PCPF-1 model was improved for forecasting the fate and transport of metabolites in addition to parent compounds in rice paddies. In the new PCPF-M model, metabolites are generated from the dissipation of pesticide applied in rice paddies through hydrolysis, photolysis and biological degradations. The methodology to parameterize the model was illustrated using two scenarios for which uncertainty and sensitivity analyses were also conducted. In a batch degradation experiment, the hourly forecasted concentrations of fipronil and its metabolites in paddy water were very accurate. In a field-scale experiment, the hourly forecasted concentrations of fipronil in paddy water and paddy soil were accurate while the corresponding daily forecasted concentrations of metabolites were adequate. The major contributors to the variation of the forecasted metabolite concentrations in paddy water and paddy soil were the formation fractions of the metabolites. The influence of uncertainty included in input parameters on the forecasted metabolite concentration was high during the peak concentration of metabolite in paddy water. In contrast, in paddy soil, the metabolite concentrations forecasted several days after the initial pesticide application were sensitive to the uncertainty incorporated in the input parameters. The PCPF-M model simultaneously forecasts the concentrations of a parent pesticide and up to three metabolites. The model was validated using fipronil and two of its metabolites in paddy water and paddy soil. The model can be used in the early stage of the pesticide registration process and in risk assessment analysis for the evaluation of pesticide exposure. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

  19. Dexamethasone decreases plasma levels of the prochiral fenbendazole and its chiral and achiral metabolites in sheep.

    Science.gov (United States)

    Sánchez, S; Small, J; Jones, D G; McKellar, Q A

    2003-07-01

    1. The effect of co-administration of either short- or long-acting formulations of DXM on hepatic function and the plasma pharmacokinetic behaviour of prochiral fenbendazole (FBZ) and its metabolites was evaluated in sheep. 2. Neither DXM treatment markedly affected any of the biochemical markers of hepatic function tested. In contrast, both formulations significantly modified the plasma pharmacokinetic behaviour of FBZ and its metabolites. 3. Plasma FBZ concentrations and the associated area under the time-concentration curves were significantly lower, although the plasma detection period was longer (72 versus 48 h) in the DXM pretreated animals compared with those given FBZ alone. 4. DXM also appeared to alter the pattern of FBZ absorption, possibly through effects on abomasal pH. The shape of the plasma concentration-time curves for oxfendazole (OFZ) and fenbendazole sulphone (FBZSO(2)) were similar to FBZ, raising the possibility that DXM treatment may have altered the liver biotransformation of the parent drug. 5. The concentrations of the (+) chiral metabolite of OFZ were significantly lower in DXM pretreated animals compared with those given FBZ alone. The trend was similar for the (-) antipode, although the differences between DXM pretreated and non-pretreated animals were not statistically significant.

  20. Plasma pharmacokinetics of catechin metabolite 4'-O-Me-EGC in healthy humans.

    Science.gov (United States)

    Renouf, Mathieu; Redeuil, Karine; Longet, Karin; Marmet, Cynthia; Dionisi, Fabiola; Kussmann, Martin; Williamson, Gary; Nagy, Kornél

    2011-10-01

    Tea is an infusion of the leaves of the Camellia sinensis plant and is the most widely consumed beverage in the world after water. Green tea contains significant amounts of polyphenol catechins and represents a promising dietary component to maintain health and well-being. Epidemiological studies indicate that polyphenol intake may have potential health benefits, such as, reducing the incidence of coronary heart disease, diabetes and cancer. While bioavailability of green tea bioactives is fairly well understood, some gaps still remain to be filled, especially the identification and quantification of conjugated metabolites in plasma, such as, sulphated, glucuronidated or methylated compounds. In the present study, we aimed to quantify the appearance of green tea catechins in plasma with particular emphasis on their methylated forms. After feeding 400 mL of green tea, 1.25% infusion to 9 healthy subjects, we found significant amounts of EC, EGC and EGCg in plasma as expected. EGC was the most bioavailable catechin, and its methylated form (4'-O-Me-EGC) was also present in quantifiable amounts. Its kinetics followed that of its parent compound. However, the relative amount of the methylated form of EGC was lower than that of the parent compound, an important aspect which, in the literature, has been controversial so far. The quantitative results presented in our study were confirmed by co-chromatography and accurate mass analysis of the respective standards. We show that the relative abundance of 4'-O-Me-EGC is ~40% compared to the parent EGC. 4'-O-Me-EGC is an important metabolite derived from catechin metabolism. Its presence in significant amounts should not be overlooked when assessing human bioavailability of green tea.

  1. The in vivo disposition and in vitro transmembrane transport of two model radiometabolites of DOTA-conjugated receptor-specific peptides labelled with (177) Lu.

    Science.gov (United States)

    Volková, Marie; Mandíková, Jana; Bárta, Pavel; Navrátilová, Lucie; Lázníčková, Alice; Trejtnar, František

    2015-01-01

    In vivo metabolism of the radiolabelled receptor-specific peptides has been described; however, information regarding the pharmacokinetic behaviour of the degradation products within the body is very scarce. The present study was designed to obtain new knowledge on the disposition and elimination of low-molecular radiometabolites of receptor-specific peptides in the organism and to reveal the potential involvement of selected membrane transport mechanisms in the cellular uptake of radiometabolites, especially in the kidney. The study compared pharmacokinetics of two radiometabolites: a final metabolite of somatostatin analogues, (177)Lu-DOTA-DPhe, and a tripeptide metabolite of (177)Lu-DOTA-minigastrin 11, (177)Lu-DOTA-DGlu-Ala-Tyr. Their pharmacokinetics was compared with that of respective parent (177)Lu-radiopeptide. Both radiometabolites exhibited relative rapid clearing from most body tissues in rats in vivo along with predominant renal excretion. The long-term renal retention of the smaller radiometabolite (177)Lu-DOTA-DPhe was lower than that of (177)Lu-DOTA-DGlu-Ala-Tyr. An uptake of (177)Lu-DOTA-DPhe by human renal influx transporter organic cation transporter 2 was found in vitro in a cellular model. The study brings the first experimental data on the in vivo pharmacokinetics of radiometabolites of receptor-specific somatostatin and gastrin analogues. The found results may indicate a negative correlation between the degree of decomposition of the parent peptide chain and the renal retention of the metabolite. Copyright © 2015 John Wiley & Sons, Ltd.

  2. Development of a Pharmacokinetic Model to Describe the Complex Pharmacokinetics of Pazopanib in Cancer Patients

    NARCIS (Netherlands)

    Yu, Huixin; van Erp, Nielka; Bins, Sander; Mathijssen, Ron H J; Schellens, Jan H M; Beijnen, Jos H.; Steeghs, Neeltje; Huitema, Alwin D R

    Background and Objective: Pazopanib is a multi-targeted anticancer tyrosine kinase inhibitor. This study was conducted to develop a population pharmacokinetic (popPK) model describing the complex pharmacokinetics of pazopanib in cancer patients. Methods: Pharmacokinetic data were available from 96

  3. Development of a Pharmacokinetic Model to Describe the Complex Pharmacokinetics of Pazopanib in Cancer Patients

    NARCIS (Netherlands)

    Yu, H.; Erp, N. van; Bins, S.; Mathijssen, R.H.; Schellens, J.H.; Beijnen, J.H.; Steeghs, N.; Huitema, A.D.

    2017-01-01

    BACKGROUND AND OBJECTIVE: Pazopanib is a multi-targeted anticancer tyrosine kinase inhibitor. This study was conducted to develop a population pharmacokinetic (popPK) model describing the complex pharmacokinetics of pazopanib in cancer patients. METHODS: Pharmacokinetic data were available from 96

  4. A Comparative Oncology Study of Iniparib Defines Its Pharmacokinetic Profile and Biological Activity in a Naturally-Occurring Canine Cancer Model.

    Directory of Open Access Journals (Sweden)

    Corey Saba

    Full Text Available Development of iniparib as an anti-cancer agent was hindered in part by lingering questions regarding its mechanism of action, the activity of its metabolites, and their potential accumulation in tumors. Due to strong similarities in metabolism of iniparib between humans and dogs, a veterinary clinical trial in pet dogs with spontaneous cancers was designed to answer specific questions pertaining to pharmacokinetic exposures and tolerability of iniparib. Dogs were treated with iniparib alone and in combination with carboplatin chemotherapy. Iniparib doses ranged between 10-70 mg/kg intravenously (IV. Plasma, tumor and normal tissue samples were collected before and at various time points scheduled after exposure for pharmacokinetic and biologic analysis. The primary endpoints included characterization of dose-limiting toxicities (DLT and determination of the drug exposures that could be achieved in both normal and tumor tissues. Nineteen dogs were treated. DLT included fever, anorexia, diarrhea, neutropenia, and thrombocytopenia; most effects were attributable to carboplatin based on the timing of adverse event onset. The maximum tolerated dose (MTD of iniparib was not identified. Moderate to high variability in plasma exposure was noted for iniparib and all metabolites between animals. When quantifiable, iniparib and metabolite plasma:tumor ratios were < 0.088 and <1.7, respectively. In this study, iniparib was well tolerated as a single agent and in combination with carboplatin over a range of doses. However, clinically relevant concentrations of the parent drug and selected metabolites were not detectable in canine tumor tissues at any studied dose, thus eliminating expectations for clinical responses in dogs or humans. Negative clinical trials in humans, and the uncertainties of its mechanism of action, ultimately led to the decision to stop clinical development of the drug. Nevertheless, the questions that can be asked and answered within

  5. Population PK modelling and simulation based on fluoxetine and norfluoxetine concentrations in milk: a milk concentration-based prediction model.

    Science.gov (United States)

    Tanoshima, Reo; Bournissen, Facundo Garcia; Tanigawara, Yusuke; Kristensen, Judith H; Taddio, Anna; Ilett, Kenneth F; Begg, Evan J; Wallach, Izhar; Ito, Shinya

    2014-10-01

    Population pharmacokinetic (pop PK) modelling can be used for PK assessment of drugs in breast milk. However, complex mechanistic modelling of a parent and an active metabolite using both blood and milk samples is challenging. We aimed to develop a simple predictive pop PK model for milk concentration-time profiles of a parent and a metabolite, using data on fluoxetine (FX) and its active metabolite, norfluoxetine (NFX), in milk. Using a previously published data set of drug concentrations in milk from 25 women treated with FX, a pop PK model predictive of milk concentration-time profiles of FX and NFX was developed. Simulation was performed with the model to generate FX and NFX concentration-time profiles in milk of 1000 mothers. This milk concentration-based pop PK model was compared with the previously validated plasma/milk concentration-based pop PK model of FX. Milk FX and NFX concentration-time profiles were described reasonably well by a one compartment model with a FX-to-NFX conversion coefficient. Median values of the simulated relative infant dose on a weight basis (sRID: weight-adjusted daily doses of FX and NFX through breastmilk to the infant, expressed as a fraction of therapeutic FX daily dose per body weight) were 0.028 for FX and 0.029 for NFX. The FX sRID estimates were consistent with those of the plasma/milk-based pop PK model. A predictive pop PK model based on only milk concentrations can be developed for simultaneous estimation of milk concentration-time profiles of a parent (FX) and an active metabolite (NFX). © 2014 The British Pharmacological Society.

  6. Pharmacokinetic modeling: Prediction and evaluation of route dependent dosimetry of bisphenol A in monkeys with extrapolation to humans

    International Nuclear Information System (INIS)

    Fisher, Jeffrey W.; Twaddle, Nathan C.; Vanlandingham, Michelle; Doerge, Daniel R.

    2011-01-01

    A physiologically based pharmacokinetic (PBPK) model was developed for bisphenol A (BPA) in adult rhesus monkeys using intravenous (iv) and oral bolus doses of 100 μg d6-BPA/kg (). This calibrated PBPK adult monkey model for BPA was then evaluated against published monkey kinetic studies with BPA. Using two versions of the adult monkey model based on monkey BPA kinetic data from and , the aglycone BPA pharmacokinetics were simulated for human oral ingestion of 5 mg d16-BPA per person (Völkel et al., 2002). Völkel et al. were unable to detect the aglycone BPA in plasma, but were able to detect BPA metabolites. These human model predictions of the aglycone BPA in plasma were then compared to previously published PBPK model predictions obtained by simulating the Völkel et al. kinetic study. Our BPA human model, using two parameter sets reflecting two adult monkey studies, both predicted lower aglycone levels in human serum than the previous human BPA PBPK model predictions. BPA was metabolized at all ages of monkey (PND 5 to adult) by the gut wall and liver. However, the hepatic metabolism of BPA and systemic clearance of its phase II metabolites appear to be slower in younger monkeys than adults. The use of the current non-human primate BPA model parameters provides more confidence in predicting the aglycone BPA in serum levels in humans after oral ingestion of BPA. -- Highlights: ► A bisphenol A (BPA) PBPK model for the infant and adult monkey was constructed. ► The hepatic metabolic rate of BPA increased with age of the monkey. ► The systemic clearance rate of metabolites increased with age of the monkey. ► Gut wall metabolism of orally administered BPA was substantial across all ages of monkeys. ► Aglycone BPA plasma concentrations were predicted in humans orally given oral doses of deuterated BPA.

  7. Significance of metabolites in the environmental risk assessment of pharmaceuticals consumed by human.

    Science.gov (United States)

    Han, Eun Jeong; Lee, Dong Soo

    2017-08-15

    The purpose of this study is to demonstrate the significance of metabolites to the ERA of human pharmaceuticals. The predicted exposure concentrations (PECs) in surface water were estimated for a total of 24 selected active pharmaceutical ingredients (APIs) and their metabolites using a life cycle based emission estimation model combined with a multimedia fate model with Monte-Carlo calculations. With the eco-toxicity data, the hazard quotients (HQs) of the metabolites were compared with those of individual parents alone. The results showed that PEC or toxicity or both of the metabolites was predicted to be higher than that of their parent APIs, which resulted in a total of 18 metabolites (from 12 parents) that have greater HQs than their parents. This result clearly demonstrated that some metabolites may potentially pose greater risk than their parent APIs in the water environment. Therefore, significance of metabolites should be carefully evaluated for monitoring strategy, priority setting, and scoping of the environmental risk assessment of APIs. The method used in the present work may serve as a pragmatic approach for the purpose of preliminary screening or priority setting of environmental risk posed by both APIs and their metabolites. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Semi-physiologic model validation and bioequivalence trials simulation to select the best analyte for acetylsalicylic acid.

    Science.gov (United States)

    Cuesta-Gragera, Ana; Navarro-Fontestad, Carmen; Mangas-Sanjuan, Victor; González-Álvarez, Isabel; García-Arieta, Alfredo; Trocóniz, Iñaki F; Casabó, Vicente G; Bermejo, Marival

    2015-07-10

    The objective of this paper is to apply a previously developed semi-physiologic pharmacokinetic model implemented in NONMEM to simulate bioequivalence trials (BE) of acetyl salicylic acid (ASA) in order to validate the model performance against ASA human experimental data. ASA is a drug with first-pass hepatic and intestinal metabolism following Michaelis-Menten kinetics that leads to the formation of two main metabolites in two generations (first and second generation metabolites). The first aim was to adapt the semi-physiological model for ASA in NOMMEN using ASA pharmacokinetic parameters from literature, showing its sequential metabolism. The second aim was to validate this model by comparing the results obtained in NONMEM simulations with published experimental data at a dose of 1000 mg. The validated model was used to simulate bioequivalence trials at 3 dose schemes (100, 1000 and 3000 mg) and with 6 test formulations with decreasing in vivo dissolution rate constants versus the reference formulation (kD 8-0.25 h (-1)). Finally, the third aim was to determine which analyte (parent drug, first generation or second generation metabolite) was more sensitive to changes in formulation performance. The validation results showed that the concentration-time curves obtained with the simulations reproduced closely the published experimental data, confirming model performance. The parent drug (ASA) was the analyte that showed to be more sensitive to the decrease in pharmaceutical quality, with the highest decrease in Cmax and AUC ratio between test and reference formulations. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. An Allometric Model of Remifentanil Pharmacokinetics and Pharmacodynamics

    NARCIS (Netherlands)

    Eleveld, Douglas J.; Proost, Johannes H.; Vereecke, Hugo; Absalom, Anthony R.; Olofsen, Erik; Vuyk, Jaap; Struys, Michel M. R. F.

    Background: Pharmacokinetic and pharmacodynamic models are used to predict and explore drug infusion schemes and their resulting concentration profiles for clinical application. Our aim was to develop a pharmacokinetic-pharmacodynamic model for remifentanil that is accurate in patients with a wide

  10. Monitoring MDMA metabolites in urban wastewater as novel biomarkers of consumption.

    Science.gov (United States)

    González-Mariño, Iria; Zuccato, Ettore; Santos, Miquel M; Castiglioni, Sara

    2017-05-15

    Consumption of 3,4-methylendioxymethamphetamine (MDMA) has been always estimated by measuring the parent substance through chemical analysis of wastewater. However, this may result in an overestimation of the use if the substance is directly disposed in sinks or toilets. Using specific urinary metabolites may overcome this limitation. This study investigated for the first time the suitability of a panel of MDMA metabolites as biomarkers of consumption, considering the specific criteria recently proposed, i.e. being detectable and stable in wastewater, being excreted in a known percentage in urine, and having human excretion as the sole source. A new analytical method was developed and validated for the extraction and analysis of MDMA and three of its main metabolites in wastewater. 24-h composite raw wastewater samples from three European cities were analysed and MDMA use was back-calculated. Results from single MDMA loads, 4-hydroxy-3-methoxymethamphetamine (HMMA) loads and from the sum of MDMA, HMMA and 4-hydroxy-3-methoxyamphetamine (HMA) loads were in line with the well-known recreational use of this drug: consumption was higher during the weekend in all cities. HMMA and HMA turned out to be suitable biomarkers of consumption; however, concentrations measured in wastewater did not resemble the expected pharmacokinetic profiles, quite likely due to the very limited information available on excretion profiles. Different options were tested to back-calculate MDMA use, including the sum of MDMA and its metabolites, to balance the biases associated with each single substance. Nevertheless, additional pharmacokinetic studies are urgently needed in order to get more accurate excretion rates and, therefore, improve the estimates of MDMA use. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Complicating factors in safety testing of drug metabolites: Kinetic differences between generated and preformed metabolites

    International Nuclear Information System (INIS)

    Prueksaritanont, Thomayant; Lin, Jiunn H.; Baillie, Thomas A.

    2006-01-01

    This paper aims to provide a scientifically based perspective on issues surrounding the proposed toxicology testing of synthetic drug metabolites as a means of ensuring adequate nonclinical safety evaluation of drug candidates that generate metabolites considered either to be unique to humans or are present at much higher levels in humans than in preclinical species. We put forward a number of theoretical considerations and present several specific examples where the kinetic behavior of a preformed metabolite given to animals or humans differs from that of the corresponding metabolite generated endogenously from its parent. The potential ramifications of this phenomenon are that the results of toxicity testing of the preformed metabolite may be misleading and fail to characterize the true toxicological contribution of the metabolite when formed from the parent. It is anticipated that such complications would be evident in situations where (a) differences exist in the accumulation of the preformed versus generated metabolites in specific tissues, and (b) the metabolite undergoes sequential metabolism to a downstream product that is toxic, leading to differences in tissue-specific toxicity. Owing to the complex nature of this subject, there is a need to treat drug metabolite issues in safety assessment on a case-by-case basis, in which a knowledge of metabolite kinetics is employed to validate experimental paradigms that entail administration of preformed metabolites to animal models

  12. An interactive program for pharmacokinetic modeling.

    Science.gov (United States)

    Lu, D R; Mao, F

    1993-05-01

    A computer program, PharmK, was developed for pharmacokinetic modeling of experimental data. The program was written in C computer language based on the high-level user-interface Macintosh operating system. The intention was to provide a user-friendly tool for users of Macintosh computers. An interactive algorithm based on the exponential stripping method is used for the initial parameter estimation. Nonlinear pharmacokinetic model fitting is based on the maximum likelihood estimation method and is performed by the Levenberg-Marquardt method based on chi 2 criterion. Several methods are available to aid the evaluation of the fitting results. Pharmacokinetic data sets have been examined with the PharmK program, and the results are comparable with those obtained with other programs that are currently available for IBM PC-compatible and other types of computers.

  13. Milk decreases urinary excretion but not plasma pharmacokinetics of cocoa flavan-3-ol metabolites in humans.

    Science.gov (United States)

    Mullen, William; Borges, Gina; Donovan, Jennifer L; Edwards, Christine A; Serafini, Mauro; Lean, Michael E J; Crozier, Alan

    2009-06-01

    Cocoa drinks containing flavan-3-ols are associated with many health benefits, and conflicting evidence exists as to whether milk adversely affects the bioavailability of flavan-3-ols. The objective was to determine the effect of milk on the bioavailability of cocoa flavan-3-ol metabolites. Nine human volunteers followed a low-flavonoid diet for 2 d before drinking 250 mL of a cocoa beverage, made with water or milk, that contained 45 micromol (-)-epicatechin and (-)-catechin. Plasma and urine samples were collected for 24 h, and flavan-3-ol metabolites were analyzed by HPLC with photodiode array and mass spectrometric detection. Milk affected neither gastric emptying nor the transit time through the small intestine. Two flavan-3-ol metabolites were detected in plasma and 4 in urine. Milk had only minor effects on the plasma pharmacokinetics of an (epi)catechin-O-sulfate and had no effect on an O-methyl-(epi)catechin-O-sulfate. However, milk significantly lowered the excretion of 4 urinary flavan-3-ol metabolites from 18.3% to 10.5% of the ingested dose (P = 0.016). Studies that showed protective effects of cocoa and those that showed no effect of milk on bioavailability used products that have a much higher flavan-3-ol content than does the commercial cocoa used in the present study. Most studies of the protective effects of cocoa have used drinks with a very high flavan-3-ol content. Whether similar protective effects are associated with the consumption of many commercial chocolate and cocoa products containing substantially lower amounts of flavan-3-ols, especially when absorption at lower doses is obstructed by milk, remains to be determined.

  14. Simultaneous determination of borneol and its metabolite in rat plasma by GC–MS and its application to pharmacokinetic study

    Directory of Open Access Journals (Sweden)

    Xiu-Man Sun

    2014-10-01

    Full Text Available A gas chromatography mass spectrometry (GC–MS method has been developed and fully validated for the simultaneous determination of natural borneol (NB and its metabolite, camphor, in rat plasma. Following a single liquid–liquid extraction, the analytes were separated using an HP-5MS capillary column (0.25 mm×30 m×0.25 μm and analyzed by MS in the selected ion monitoring mode. Selected ion monitor (m/z of borneol, camphor and internal standard was 95, 95 and 128, respectively. Linearity, accuracy, precision and extraction recovery of the analytes were all satisfactory. The method was successfully applied to pharmacokinetic studies of NB after oral administration to Wistar rats. Keywords: Borneol, Camphor, Simultaneous determination, Pharmacokinetics, GC–MS

  15. Microdose pharmacogenetic study of ¹⁴C-tolbutamide in healthy subjects with accelerator mass spectrometry to examine the effects of CYP2C9∗3 on its pharmacokinetics and metabolism.

    Science.gov (United States)

    Ikeda, Toshihiko; Aoyama, Shinsuke; Tozuka, Zenzaburo; Nozawa, Kohei; Hamabe, Yoshimi; Matsui, Takao; Kainuma, Michiko; Hasegawa, Setsuo; Maeda, Kazuya; Sugiyama, Yuichi

    2013-07-16

    Microdose study enables us to understand the pharmacokinetic profiles of drugs in humans prior to the conventional clinical trials. The advantage of microdose study is that the unexpected pharmacological/toxicological effects of drugs caused by drug interactions or genetic polymorphisms of metabolic enzymes/transporters can be avoided due to the limited dose. With a combination use of accelerator mass spectrometry (AMS) and (14)C-labaled compounds, the pharmacokinetics of both parent drug and its metabolites can be sensitively monitored. Thus, to demonstrate the usability of microdose study with AMS for the prediction of the impact of genetic polymorphisms of CYP enzyme on the pharmacokinetics of unchanged drugs and metabolites, we performed microdose pharmacogenetic study using tolbutamide as a CYP2C9 probe drug. A microdose of (14)C-tolbutamide (100 μg) was administered orally to healthy volunteers with the CYP2C9(∗)1/(∗)1 or CYP2C9(∗)1/(∗)3 diplotype. Area under the plasma concentration-time curve for the (14)C-radioactivity, determined by AMS, or that for the parent drug, determined by liquid chromatography/mass spectrometry, was about 1.6 times or 1.7 times greater in the CYP2C9(∗)1/(∗)3 than in the CYP2C9(∗)1/(∗)1 group, which was comparable to the previous reports at therapeutic dose. In the plasma and urine, tolbutamide, carboxytolbutamide, and 4-hydroxytolbutamide were detected and practically no other metabolites could be found in both diplotype groups. The fraction of metabolites in plasma radioactivity was slightly lower in the CYP2C9(∗)1/(∗)3 group. Microdose study can be used for the prediction of the effects of genetic polymorphisms of enzymes on the pharmacokinetics and metabolic profiles of drugs with minimal care of their pharmacological/toxicological effects. Copyright © 2013 Elsevier B.V. All rights reserved.

  16. Pharmacokinetics of clomipramine during pregnancy

    NARCIS (Netherlands)

    Ter Horst, P G J; Proost, J H; Smit, J P; Vries, M T; de Jong-van den Berg, Lolkje; Wilffert, B

    2015-01-01

    Clomipramine is one of the drugs for depression during pregnancy; however, pharmacokinetic data of clomipramine and its active metabolite desmethylclomipramine in this vulnerable period are lacking. In this study, we describe clomipramine and desmethylclomipramine concentrations including their

  17. [Pharmacokinetics of (-)-clausenamide and its major metabolite 6-hydroxyl-clausenamide in beagle dogs by HPLC/MS].

    Science.gov (United States)

    Song, Min; Qian, Wen; Hang, Tai-Jun; Zhang, Zheng-Xing

    2005-10-01

    To establish a sensitive and accurate method to study the pharmacokinetics of (-)-clausenamide [(-)-clau] and its major metabolite 6-hydroxyl-clausenamide (6-OH-clau) in the plasma of the Beagle dog. (-)-Clau was orally administered to six Beagle dogs at the dose of 30 mg x kg(-1), venous blood from front leg was sampled and plasma was separated for analysis. After extraction with ethyl acetate, the plasma samples were analyzed by HPLC/MS and the mobile phase was a mixture of methanol-water-acetic acid (60: 40: 0. 8) at the flow rate of 1.0 mL x min(-1). The API-ES positive ion SIM detection was carried out for the detection of both (-)-clau ([M + H] (+), m/z 298 ) and 6-OH-clau ([M + H - H2 O](+), m/z 296) with glipzide (glip) ([M + H](+), m/z 446) as internal standard. The pharmacokinetic parameters were calculated by 3P97 software. There was good linear relationship ( r > 0. 999) between the SIM responses and the concentrations for (-)-clau and 6-OH-clau at the range from 1.0 to 200 ng x mL(-1) and 0.2 to 40.0 ng x mL(-1), respectively. The absolute recovery was greater than 85%. The plasma concentration-time curves of (-)-clau and 6-OH-clau were both best fitted to a two-compartment model. The C(max) of (-)-clau and 6-OH-clau were (21 +/- 10) ng x mL(-1) and (3.9 +/- 2.2) ng x mL(-1), T(max) were (0.8 +/- 0.5) h and (1.3 +/- 0.5) h, T 1/2 alpha were (0.9 +/- 0.6) hand (1.4 +/- 0.6) h, T 1/2 beta were (19 +/- 23) hand (13 +/- 12) h, AUC(0-24 h) were (69 +/- 14) h x ng x mL(-1) and (12 +/- 7) h x ng x mL(-1) respectively. The established HPLC/MS method was sensitive and specific for the determination of (-)-clau. It was shown that the absorption and first phase elimination of (-)-clau were very quick in Beagle dogs, but the terminal elimination was very slow. The plasma concentration profile of its major metabolite 6-OH-clau was similar to (-)-clau and the AUC was relatively small in comparison with (-)-clau.

  18. Pharmacokinetics of rilmenidine in healthy subjects

    International Nuclear Information System (INIS)

    Genissel, P.; Bromet, N.; Fourtillan, J.B.; Mignot, A.; Albin, H.

    1988-01-01

    Rilmenidine is a novel alpha 2-adrenoceptor agonist, used in the treatment of mild or moderate hypertension at the oral dose of 1 mg once or twice daily. The pharmacokinetic parameters were investigated after single or repeated administration in healthy subjects, using labeled and unlabeled compounds. Rilmenidine was rapidly and extensively absorbed, with an absolute bioavailability factor close to 1 and a maximal plasma concentration achieved within 2 hours. Rilmenidine was not subject to presystemic metabolism. Distribution was independent of the free fraction because rilmenidine was weakly bound to plasma proteins (less than 10%). The volume of distribution was approximately 5 l.kg-1 (315 liters). Elimination was rapid with a total body plasma clearance of approximately 450 ml.min-1 and an elimination half-life of approximately 8 hours. Renal excretion was the major elimination process (two-thirds of the total clearance). Metabolism was very poor, with a renal elimination of rilmenidine as the parent drug (urinary fraction of rilmenidine was about 65% and no metabolite plasma levels were detected). Linear pharmacokinetics were demonstrated for rilmenidine from 0.5 to 2 mg but, at 3 mg, a slight deviation from linearity was observed. In repeated administration, the linear disposition of rilmenidine with dose was confirmed

  19. Pharmacokinetics and tissue behavior of enrofloxacin and its metabolite ciprofloxacin in turbot Scophthalmus maximus at two water temperatures

    Science.gov (United States)

    Liang, Junping; Li, Jian; Zhao, Fazhen; Liu, Ping; Chang, Zhiqiang

    2012-07-01

    Turbot Scophthalmus maximus, an important aquaculture species in China, currently suffers from epizootic diseases because of high density aquaculture. Enrofloxacin has been used to treat various systemic bacterial fish infections. However, studies concerning the pharmacokinetics of enrofloxacin in turbot are limited. In this study, the pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin, were investigated in the turbot following intravenous and oral administration at 10 mg enrofloxacin/kg body weight, at 16°C and 10°C water temperatures. The concentrations of enrofloxacin and ciprofloxacin in the main tissues (plasma, muscle, liver and kidney) were detected by HPLC. The results show that the plasma concentration-time data for enrofloxacin were best described as a two-compartment open model after intravenous and oral administration. Three pharmacokinetic equations were established between the concentrations and temperatures. The kinetic profile of enrofloxacin was temperature dependent. The absorption half-life of enrofloxacin was 1.99 h and 2.17 h after oral administration, whereas the elimination half-life of the drug was 98.63 h and 136.59 h at 16°C and 10°C, respectively. The peak concentration of enrofloxacin in plasma and tissues was higher at 16°C than that at 10°C, and the peak plasma concentration time in the liver was the shortest at both temperatures among those of other tissues. The plasma C max /MIC ratio varied between 11.08 and 5 540.00 at 16°C; and between 7.92 and 3 960.00 at 10°C. The AUC/MIC ratio was 467.82-280 690.00 at 16°C, and 359.48-215 690.00 at 10°C. These ratios indicate that it is possible to obtain therapeutic efficacy. Very low levels of ciprofloxacin were detected. The AUC ratios of ciprofloxacin and enrofloxacin in plasma suggest that plasma ciprofloxacin might play a minor role in enrofloxacin treatment for turbot.

  20. Pharmacokinetics and pharmacokinetic variability of heroin and its metabolites: review of the literature

    NARCIS (Netherlands)

    Rook, Elisabeth J.; Huitema, Alwin D. R.; van den Brink, Wim; van Ree, Jan M.; Beijnen, Jos H.

    2006-01-01

    This article reviews the pharmacokinetics of heroin after intravenous, oral, intranasal, intramuscular and rectal application and after inhalation in humans, with a special focus on heroin maintenance therapy in heroin dependent patients. In heroin maintenance therapy high doses pharmaceutically

  1. A comprehensive physiologically based pharmacokinetic ...

    Science.gov (United States)

    Published physiologically based pharmacokinetic (PBPK) models from peer-reviewed articles are often well-parameterized, thoroughly-vetted, and can be utilized as excellent resources for the construction of models pertaining to related chemicals. Specifically, chemical-specific parameters and in vivo pharmacokinetic data used to calibrate these published models can act as valuable starting points for model development of new chemicals with similar molecular structures. A knowledgebase for published PBPK-related articles was compiled to support PBPK model construction for new chemicals based on their close analogues within the knowledgebase, and a web-based interface was developed to allow users to query those close analogues. A list of 689 unique chemicals and their corresponding 1751 articles was created after analysis of 2,245 PBPK-related articles. For each model, the PMID, chemical name, major metabolites, species, gender, life stages and tissue compartments were extracted from the published articles. PaDEL-Descriptor, a Chemistry Development Kit based software, was used to calculate molecular fingerprints. Tanimoto index was implemented in the user interface as measurement of structural similarity. The utility of the PBPK knowledgebase and web-based user interface was demonstrated using two case studies with ethylbenzene and gefitinib. Our PBPK knowledgebase is a novel tool for ranking chemicals based on similarities to other chemicals associated with existi

  2. A human life-stage physiologically based pharmacokinetic and pharmacodynamic model for chlorpyrifos: development and validation.

    Science.gov (United States)

    Smith, Jordan Ned; Hinderliter, Paul M; Timchalk, Charles; Bartels, Michael J; Poet, Torka S

    2014-08-01

    Sensitivity to some chemicals in animals and humans are known to vary with age. Age-related changes in sensitivity to chlorpyrifos have been reported in animal models. A life-stage physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model was developed to predict disposition of chlorpyrifos and its metabolites, chlorpyrifos-oxon (the ultimate toxicant) and 3,5,6-trichloro-2-pyridinol (TCPy), as well as B-esterase inhibition by chlorpyrifos-oxon in humans. In this model, previously measured age-dependent metabolism of chlorpyrifos and chlorpyrifos-oxon were integrated into age-related descriptions of human anatomy and physiology. The life-stage PBPK/PD model was calibrated and tested against controlled adult human exposure studies. Simulations suggest age-dependent pharmacokinetics and response may exist. At oral doses ⩾0.6mg/kg of chlorpyrifos (100- to 1000-fold higher than environmental exposure levels), 6months old children are predicted to have higher levels of chlorpyrifos-oxon in blood and higher levels of red blood cell cholinesterase inhibition compared to adults from equivalent doses. At lower doses more relevant to environmental exposures, simulations predict that adults will have slightly higher levels of chlorpyrifos-oxon in blood and greater cholinesterase inhibition. This model provides a computational framework for age-comparative simulations that can be utilized to predict chlorpyrifos disposition and biological response over various postnatal life stages. Copyright © 2013 Elsevier Inc. All rights reserved.

  3. Sprague-Dawley rats display sex-linked differences in the pharmacokinetics of 3,4-methylenedioxymethamphetamine (MDMA) and its metabolite 3,4-methylenedioxyamphetamine (MDA)

    International Nuclear Information System (INIS)

    Fonsart, Julien; Menet, Marie-Claude; Debray, Marcel; Hirt, Deborah; Noble, Florence; Scherrmann, Jean-Michel; Decleves, Xavier

    2009-01-01

    The use of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) has increased in recent years; it can lead to life-threatening hyperthermia and serotonin syndrome. Human and rodent males appear to be more sensitive to acute toxicity than are females. MDMA is metabolized to five main metabolites by the enzymes CYP1A2, CYP2D and COMT. Little is presently known about sex-dependent differences in the pharmacokinetics of MDMA and its metabolites. We therefore analyzed MDMA disposition in male and female rats by measuring the plasma and urine concentrations of MDMA and its metabolites using a validated LC-MS method. MDA AUC last and C max were 1.6- to 1.7-fold higher in males than in females given MDMA (5 mg/kg sc), while HMMA C max and AUC last were 3.2- and 3.5-fold higher, respectively. MDMA renal clearance was 1.26-fold higher in males, and that of MDA was 2.2-fold higher. MDMA AUC last and t 1/2 were 50% higher in females given MDMA (1 mg/kg iv). MDA C max and AUC last were 75-82% higher in males, with a 2.8-fold higher metabolic index. Finally, the AUC last of MDA was 0.73-fold lower in males given 1 mg/kg iv MDA. The volumes of distribution of MDMA and MDA at steady-state were similar in the two sexes. These data strongly suggest that differences in the N-demethylation of MDMA to MDA are major influences on the MDMA and MDA pharmacokinetics in male and female rats. Hence, males are exposed to significantly more toxic MDA, which could explain previously reported sexual dysmorphism in the acute effects and toxicity of MDMA in rats.

  4. A review of morphine and morphine-6-glucuronide's pharmacokinetic-pharmacodynamic relationships in experimental and clinical pain

    DEFF Research Database (Denmark)

    Sverrisdóttir, Eva; Lund, Trine Meldgaard; Olesen, Anne Estrup

    2015-01-01

    Morphine is a widely used opioid for treatment of moderate to severe pain, but large interindividual variability in patient response and no clear guidance on how to optimise morphine dosage regimen complicates treatment strategy for clinicians. Population pharmacokinetic-pharmacodynamic models can...... a detailed overview of the published human population pharmacokinetic-pharmacodynamic studies for morphine analgesia in addition to basic drug disposition and pharmacological properties of morphine and its analgesic active metabolite, morphine-6-glucuronide, that may help identify future covariates....... Furthermore, based on simulations from key pharmacokinetic-pharmacodynamic models, the contribution of morphine-6-glucuronide to the analgesic response in patients with renal insufficiency was investigated. Simulations were also used to examine the impact of effect-site equilibration half-life on time course...

  5. Preclinical pharmacokinetic evaluation and metabolites identification of methyl salicylate-2-O-β-d-lactoside in rats using LC-MS/MS and Q-TOF-MS methods.

    Science.gov (United States)

    Zhang, Dan; Huang, Chao; Xin, Wenyu; Ma, Xiaowei; Zhang, Weiku; Zhang, Tiantai; Du, Guanhua

    2015-05-10

    Methyl salicylate-2-O-β-d-lactoside (MSL) is a natural salicylate derivative from the traditional Chinese medicine of Gaultheria yunnanensis (Franch.) Rehder (G. yunnanensis). As a non-steroidal anti-inflammatory drug (NSAID), MSL exerts a significant anti-arthritis effect but hardly has any gastrointestinal toxicity. In this paper, the pharmacokinetics, distribution, excretion and identification of MSL and its metabolites are described following rat oral and intravenous administration. The biological samples were quantified by UPLC-MS/MS and the metabolites in urine and feces were identified by using Q-TOF-MS. These results will support future investigations leading to clinical development of this drug. Copyright © 2015 Elsevier B.V. All rights reserved.

  6. Formulation of enrofloxacin SLNs and its pharmacokinetics in emu ( Dromaius novaehollandiae) birds

    Science.gov (United States)

    Senthil Kumar, P.; Arivuchelvan, A.; Jagadeeswaran, A.; Punniamurthy, N.; Selvaraj, P.; Richard Jagatheesan, P. N.; Mekala, P.

    2015-08-01

    The study was conducted to formulate the enrofloxacin solid lipid nanoparticles (SLNs) with sustained release profile and improved pharmacological activity and evaluate the pharmacokinetic behaviour of enrofloxacin SLNs after oral routes of administration in emus. The SLNs were prepared using tripalmitin as lipid carrier, Tween 80 and Span 80 as surfactants and polyvinyl alcohol (PVA) as a stabilizer by a hot homogenization coupled with ultrasonication method. The prepared enrofloxacin SLNs formulations were characterized for further investigation in emu birds. The pharmacokinetics of native enrofloxacin was studied after i.v. and oral bolus administration at 10 mg/kg in emu birds and compared with the disposition kinetics of enrofloxacin SLNs. Enrofloxacin and its metabolite ciprofloxacin in plasma were estimated using HPLC and the pharmacokinetic parameters were calculated by a non-compartmental analysis. The results demonstrated that the particle size, polydispersity index, zeta potential, encapsulation efficiency and loading capacity of the SLNs were 154.72 ± 6.11 nm, 0.42 ± 0.11, -28.83 ± 0.60 mV, 59.66 ± 3.22 and 6.13 ± 0.32 %, respectively. AFM and TEM images showed spherical to circular particles with well-defined periphery. In vitro drug release exhibited biphasic pattern with an initial burst release of 18 % within 2 h followed by sustained release over 96 h. Pharmacokinetic results showed that the t 1/2 β , AUC0-∞, V darea/ F, MRT and bioavailability were 3.107, 1.894, 1.594, 2.993 and 1.895 times enhanced ( p enrofloxacin administered orally. The ratio of AUC0- t cipro/AUC0- t enro after administration of native enrofloxacin and enrofloxacin SLNs was less than 10 %. The t 1/2 β and MRT of the metabolite were longer than those of the parent substance. The PK/PD results confirmed that the SLNs extended the enrofloxacin concentration upto 48 h against pathogens susceptible to 0.125 μg/mL in emus. The results indicated that SLNs might be a

  7. Pharmacokinetic and pharmacodynamic interaction for a binary mixture of chlorpyrifos and diazinon in the rat

    International Nuclear Information System (INIS)

    Timchalk, C.; Poet, T.S.; Hinman, M.N.; Busby, A.L.; Kousba, A.A.

    2005-01-01

    Chlorpyrifos (CPF) and diazinon (DZN) are two commonly used organophosphorus (OP) insecticides and a potential exists for concurrent exposures. The primary neurotoxic effects from OP pesticide exposures result from the inhibition of acetylcholinesterase (AChE). The pharmacokinetic and pharmacodynamic impact of acute binary exposures of rats to CPF and DZN was evaluated in this study. Rats were orally administered CPF, DZN, or a CPF/DZN mixture (0, 15, 30, or 60 mg/kg) and blood (plasma and RBC), and brain were collected at 0, 3, 6, 12, and 24 h postdosing, urine was also collected at 24 h. Chlorpyrifos, DZN, and their respective metabolites, 3,5,6-trichloro-2-pyridinol (TCP) and 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMHP), were quantified in blood and/or urine and cholinesterase (ChE) inhibition was measured in brain, RBC, and plasma. Coexposure to CPF/DZN at the low dose of 15/15 mg/kg did not alter the pharmacokinetics of CPF, DZN, or their metabolites in blood. A high binary dose of 60/60 mg/kg increased the C max and AUC and decreased the clearance for both parent compounds, likely due to competition between CPF and DZN for CYP450 metabolism. At lower doses, most likely to be encountered in occupational or environmental exposures, the pharmacokinetics were linear. A dose-dependent inhibition of ChE was noted in tissues for both the single and coexposures, and the extent of inhibition was plasma > RBC ≥ brain. The overall relative potency for ChE inhibition was CPF/DZN > CPF > DZN. A comparison of the ChE response at the low binary dose (15/15 mg/kg), where there were no apparent pharmacokinetic interactions, suggested that the overall ChE response was additive. These experiments represent important data concerning the potential pharmacokinetic and pharmacodynamic interactions for pesticide mixtures and will provide needed insight for assessing the potential cumulative risk associated with occupational or environmental exposures to these insecticides

  8. Pharmacokinetics and dosimetry of the antiandrogen vinclozolin after oral administration in the rat.

    Science.gov (United States)

    Sierra-Santoyo, Adolfo; Castañeda-Hernández, Gilberto; Harrison, Randy A; Barton, Hugh A; Hughes, Michael F

    2008-11-01

    Vinclozolin (V) is a fungicide with antiandrogenic properties. To determine the pharmacokinetics and dosimetry of V, adult male rats were administered an oral dose of V (100 mg/kg) in corn oil and sacrificed over time after dosing. V and its metabolites were analyzed in serum and tissues by high performance liquid chromatography/diode array detector/mass spectrometer. V, 2-[[(3,5-dichlorophenyl)-carbamoyl]oxy]-2-methyl-3-butenoic acid (M1), and 3',5'-dichloro-2-hydroxy-2-methylbut-3-enanilide (M2), and five other metabolites were detected in serum and tissues. One metabolite was identified as 3',5'-dichloro-2,3,4-trihydroxy-2-methylbutylanilide (M5). The mean serum concentration data for V were fitted to a one-compartment model for kinetic analysis. At 2 h, V serum concentration peaked; whereas only trace levels were detected at 24 h (t(1/2 elim) = 3.6 h). V was detected in all tissues and preferentially accumulated in fat. M1 serum levels increased until 8 h, being at least 2-fold higher than those of V at this time, and then declined with a t(1/2) = 3.3 h. M5 was the main metabolite in serum and tissues. Serum M5 levels were 5-fold higher than V and 2-fold greater than M1 at all times. At 48 h, M5 remained the main metabolite (t(1/2 elim) = 13.1 h). Liver and kidney exhibited the highest levels of M5, V, and M1. M2 and 3,5-dichloroaniline had the lowest levels of V metabolites in serum and tissues. V is well absorbed, extensively metabolized and widely distributed. M5, the most abundant V metabolite, may be used as an exposure biomarker for pharmacokinetic modeling. These results may clarify the relationship between toxicity and tissue dose of V and its metabolites.

  9. Extensive intestinal first-pass metabolism of arctigenin: evidenced by simultaneous monitoring of both parent drug and its major metabolites.

    Science.gov (United States)

    Gao, Qiong; Zhang, Yufeng; Wo, Siukwan; Zuo, Zhong

    2014-03-01

    The current study aims to investigate intestinal absorption and metabolism of arctigenin (AR) through simultaneous monitoring of AR and its major metabolites in rat plasma. An UPLC/MS/MS assay was developed with chromatographic separation of all analytes achieved by a C18 Column (3.9mm×150mm, 3.5μm) and a gradient elution with acetonitrile and 0.1% formic acid within 9min. Sample extraction with acetonitrile was optimized to achieve satisfactory recovery for both AR and its major metabolites. The lower limit of quantification (LLOQ) for all analytes was 25ng/ml. The intra-day and inter-day precision and accuracy of each analyte at LLOQ and three quality control (QC) concentrations (low, middle and high) in rat plasma was within 15.0% RSD and 15.0% bias. The extraction recoveries were within the range of 83.8-94.0% for all analytes. The developed and validated assay was then applied to the absorption study of AR in both Caco-2 cell monolayer model and in situ single-pass rat intestinal perfusion model. High absorption permeability of AR was demonstrated in both models with Papp of (1.76±0.48)×10(-5) (A→B) (Caco-2) and Pblood of (8.6±3.0)×10(-6)cm/s (intestinal perfusion). Extensive first-pass metabolism of AR to arctigenic acid (AA) and arctigenin-4'-O-glucuronide (AG) was identified in rat intestinal perfusion study with Cummins's extraction ratios of 0.458±0.012 and 0.085±0.013, respectively. The current assay method demonstrated to be a practical tool for pharmacokinetics investigation of AR with complicated metabolism pathways and multiple metabolites. Copyright © 2013 Elsevier B.V. All rights reserved.

  10. Absorption and pharmacokinetics of grapefruit flavanones in beagles

    OpenAIRE

    Mata Bilbao, María de Lourdes; Andrés Lacueva, Ma. Cristina; Roura Carvajal, Elena; Jáuregui Pallarés, Olga; Escribano Ferrer, Elvira; Torre, Celina; Lamuela Raventós, Rosa Ma.

    2007-01-01

    The present study evaluated the pharmacokinetics of three different grapefruit flavanone forms in dog plasma and demonstrated their absorption after an oral intake of a grapefruit extract; pharmacokinetic parameters of these forms were also determined. Ten healthy beagles were administered 70 mg citrus flavonoids as a grapefruit extract contained in capsules, while two additional dogs were used as controls and given an excipient. The grapefruit flavanone naringin, along with its metabolites n...

  11. Pharmacokinetic study of benfotiamine and the bioavailability assessment compared to thiamine hydrochloride.

    Science.gov (United States)

    Xie, Feifan; Cheng, Zeneng; Li, Sanwang; Liu, Xingling; Guo, Xin; Yu, Peng; Gu, Zhenkun

    2014-06-01

    Benfotiamine is a lipid-soluble thiamine precursor which can transform to thiamine in vivo and subsequently be metabolized to thiamine monophosphate (TMP) and thiamine diphosphate (TDP). This study investigated the pharmacokinetic profiles of thiamine and its phosphorylated metabolites after single- and multiple-dose administration of benfotiamine in healthy Chinese volunteers, and assessed the bioavailability of orally benfotiamine administration compared to thiamine hydrochloride. In addition, concentration of hippuric acid in urine which is produced in the transformation process of benfotiamine was determined. The results showed that thiamine and its phosphorylated metabolites exhibited different pharmacokinetic characteristics in plasma, blood and erythrocyte, and one-compartment model provided the best fit for pharmacokinetic profiles of thiamine. The transformation process of benfotiamine to thiamine produced large amount of hippuric acid. No accumulation of hippuric acid was observed after multiple-dose of benfotiamine. Compared to thiamine hydrochloride, the bioavailability of thiamine in plasma and TDP in erythrocyte after oral administration of benfotiamine were 1147.3 ± 490.3% and 195.8 ± 33.8%, respectively. The absorption rate and extent of benfotiamine systemic availability of thiamine were significantly increased indicating higher bioavailability of thiamine from oral dose of benfotiamine compared to oral dose of thiamine hydrochloride. © 2014, The American College of Clinical Pharmacology.

  12. Grey-Box Modelling of Pharmacokinetic /Pharmacodynamic Systems

    DEFF Research Database (Denmark)

    Tornøe, Christoffer Wenzel; Jacobsen, Judith L.; Pedersen, Oluf

    2004-01-01

    Grey-box pharmacokinetic/pharmacodynamic (PK/PD) modelling is presented as a promising way of modelling PK/PD systems. The concept behind grey-box modelling is based on combining physiological knowledge along with information from data in the estimation of model parameters. Grey-box modelling...

  13. Mass balance, metabolic disposition, and pharmacokinetics of a single oral dose of regorafenib in healthy human subjects.

    Science.gov (United States)

    Gerisch, Michael; Hafner, Frank-Thorsten; Lang, Dieter; Radtke, Martin; Diefenbach, Konstanze; Cleton, Adriaan; Lettieri, John

    2018-01-01

    To evaluate the mass balance, metabolic disposition, and pharmacokinetics of a single dose of regorafenib in healthy volunteers. In addition, in vitro metabolism of regorafenib in human hepatocytes was investigated. Four healthy male subjects received one 120 mg oral dose of regorafenib containing approximately 100 µCi (3.7 MBq) [ 14 C]regorafenib. Plasma concentrations of parent drug were derived from HPLC-MS/MS analysis and total radioactivity from liquid scintillation counting (LSC). Radiocarbon analyses used HPLC with fraction collection followed by LSC for all urine samples, plasma, and fecal homogenate extracts. For the in vitro study, [ 14 C]regorafenib was incubated with human hepatocytes and analyzed using HPLC-LSC and HPLC-HRMS/MS. Regorafenib was the major component in plasma, while metabolite M-2 (pyridine N-oxide) was the most prominent metabolite. Metabolites M-5 (demethylated pyridine N-oxide) and M-7 (N-glucuronide) were identified as minor plasma components. The mean concentration of total radioactivity in plasma/whole blood appeared to plateau at 1-4 h and again at 6-24 h post-dose. In total, 90.5% of administered radioactivity was recovered in the excreta within a collection interval of 12 days, most of which (71.2%) was eliminated in feces, while excretion via urine accounted for 19.3%. Regorafenib (47.2%) was the most prominent component in feces and was not excreted into urine. Excreted metabolites resulted from oxidative metabolism and glucuronidation. Regorafenib was eliminated predominantly in feces as well as by hepatic biotransformation. The multiple biotransformation pathways of regorafenib decrease the risk of pharmacokinetic drug-drug interactions.

  14. The plasma and cerebrospinal fluid pharmacokinetics of erlotinib and its active metabolite (OSI-420) after intravenous administration of erlotinib in non-human primates.

    Science.gov (United States)

    Meany, Holly J; Fox, Elizabeth; McCully, Cynthia; Tucker, Chris; Balis, Frank M

    2008-08-01

    Erlotinib hydrochloride is a small molecule inhibitor of epidermal growth factor receptor (EGFR). EGFR is over-expressed in primary brain tumors and solid tumors that metastasize to the central nervous system. We evaluated the plasma and cerebrospinal fluid (CSF) pharmacokinetics of erlotinib and its active metabolite OSI-420 after an intravenous (IV) dose in a non-human primate model. Erlotinib was administered as a 1 h IV infusion to four adult rhesus monkeys. Serial blood and CSF samples were drawn over 48 h and erlotinib and OSI-420 were quantified with an HPLC/tandem mass spectroscopic assay. Pharmacokinetic parameters were estimated using non-compartmental and compartmental methods. CSF penetration was calculated from the AUC(CSF):AUC(plasma). Erlotinib disappearance from plasma after a short IV infusion was biexponential with a mean terminal half-life of 5.2 h and a mean clearance of 128 ml/min per m(2). OSI-420 exposure (AUC) in plasma was 30% (range 12-59%) of erlotinib, and OSI-420 clearance was more than 5-fold higher than erlotinib. Erlotinib and OSI-420 were detectable in CSF. The CSF penetration (AUC(CSF):AUC(plasma)) of erlotinib and OSI-420 was OSI-420 are measurable in CSF after an IV dose. The drug exposure (AUC) in the CSF is limited relative to total plasma concentrations but is substantial relative the free drug exposure in plasma.

  15. Modeling of corneal and retinal pharmacokinetics after periocular drug administration.

    Science.gov (United States)

    Amrite, Aniruddha C; Edelhauser, Henry F; Kompella, Uday B

    2008-01-01

    To develop pharmacokinetics models to describe the disposition of small lipophilic molecules in the cornea and retina after periocular (subconjunctival or posterior subconjunctival) administration. Compartmental pharmacokinetics analysis was performed on the corneal and retinal data obtained after periocular administration of 3 mg of celecoxib (a selective COX-2 inhibitor) to Brown Norway (BN) rats. Berkeley Madonna, a differential and difference equation-based modeling software, was used for the pharmacokinetics modeling. The data were fit to different compartment models with first-order input and disposition, and the best fit was selected on the basis of coefficient of regression and Akaike information criteria (AIC). The models were validated by using the celecoxib data from a prior study in Sprague-Dawley (SD) rats. The corneal model was also fit to the corneal data for prednisolone at a dose of 2.61 mg in albino rabbits, and the model was validated at two other doses of prednisolone (0.261 and 26.1 mg) in these rabbits. Model simulations were performed with the finalized model to understand the effect of formulation on corneal and retinal pharmacokinetics after periocular administration. Celecoxib kinetics in the BN rat cornea can be described by a two-compartment (periocular space and cornea, with a dissolution step for periocular formulation) model, with parallel elimination from the cornea and the periocular space. The inclusion of a distribution compartment or a dissolution step for celecoxib suspension did not lead to an overall improvement in the corneal data fit compared with the two-compartment model. The more important parameter for enhanced fit and explaining the apparent lack of an increase phase in the corneal levels is the inclusion of the initial leak-back of the dose from the periocular space into the precorneal area. The predicted celecoxib concentrations from this model also showed very good correlation (r = 0.99) with the observed values in

  16. A Human Life-Stage Physiologically Based Pharmacokinetic and Pharmacodynamic Model for Chlorpyrifos: Development and Validation

    Energy Technology Data Exchange (ETDEWEB)

    Smith, Jordan N.; Hinderliter, Paul M.; Timchalk, Charles; Bartels, M. J.; Poet, Torka S.

    2014-08-01

    Sensitivity to chemicals in animals and humans are known to vary with age. Age-related changes in sensitivity to chlorpyrifos have been reported in animal models. A life-stage physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model was developed to computationally predict disposition of CPF and its metabolites, chlorpyrifos-oxon (the ultimate toxicant) and 3,5,6-trichloro-2-pyridinol (TCPy), as well as B-esterase inhibition by chlorpyrifos-oxon in humans. In this model, age-dependent body weight was calculated from a generalized Gompertz function, and compartments (liver, brain, fat, blood, diaphragm, rapid, and slow) were scaled based on body weight from polynomial functions on a fractional body weight basis. Blood flows among compartments were calculated as a constant flow per compartment volume. The life-stage PBPK/PD model was calibrated and tested against controlled adult human exposure studies. Model simulations suggest age-dependent pharmacokinetics and response may exist. At oral doses ≥ 0.55 mg/kg of chlorpyrifos (significantly higher than environmental exposure levels), 6 mo old children are predicted to have higher levels of chlorpyrifos-oxon in blood and higher levels of red blood cell cholinesterase inhibition compared to adults from equivalent oral doses of chlorpyrifos. At lower doses that are more relevant to environmental exposures, the model predicts that adults will have slightly higher levels of chlorpyrifos-oxon in blood and greater cholinesterase inhibition. This model provides a computational framework for age-comparative simulations that can be utilized to predict CPF disposition and biological response over various postnatal life-stages.

  17. Lack of effect of bilateral nephrectomy on the pharmacokinetics of 14C-indapamide (REV 2555) and its metabolites in the dog

    International Nuclear Information System (INIS)

    Klunk, L.J.; Mangat, S.; Treitman, J.A.; Grebow, P.E.

    1983-01-01

    Renal impairment can affect the disposition of metabolites, as well as unchanged drug, especially when there is significant renal clearance of metabolites. The pharmacokinetics of indapamide, a highly metabolized drug, and total indapamide equivalents (as an indicator of metabolites plus unchanged drug) were determined in the anephric dog. An intravenous dose of 14 C-indapamide was administered to dogs first after a sham-operation, and then following bilateral nephrectomy. The disposition of total indapamide equivalents, calculated from total radioactivity, was not substantially different after nephrectomy as compared to after sham-operation, with an increase after nephrectomy in the area under the blood level curve (+26.2%), and decreases in the elimination rate constant (-6.9%), volume of distribution (-12.7%) and total blood clearance (-21.9%). The only statistically significant change was the decrease in the volume of distribution. The elimination kinetics of unchanged drug were also qualitatively similar in both cases. After nephrectomy, a decrease was seen in the elimination rate constant (-10.9%) and the volume of distribution (-16.3%) while slight increases in the total blood clearance (+1.9%) and the area under the blood level curve (+4.8%) were noted. These findings could have important implications for advantageous use of indapamide in treatment of hypertensive patients with renal failure since these data suggest that metabolites as well as unchanged drug could still be effectively eliminated by an alternate, non-renal route, thus minimizing accumulation of these compounds

  18. Metronidazole pharmacokinetics in patients with acute renal failure.

    Science.gov (United States)

    Somogyi, A A; Kong, C B; Gurr, F W; Sabto, J; Spicer, W J; McLean, A J

    1984-02-01

    The pharmacokinetics and metabolism of intravenous metronidazole were studied in six patients with acute renal failure. In two of the patients a single dose (500 mg) of metronidazole was administered, whereas in four patients the steady-state pharmacokinetics were studied after four days therapy of 500 mg twice daily. Plasma concentrations of metronidazole and its hydroxy and acetic acid metabolites were measured by a specific and sensitive HPLC method. The volume of distribution was 0.65 +/- 0.13 l/kg (mean +/- S.D.), elimination half-life was 9.9 +/- 2.5 h and total plasma clearance was 55.5 +/- 17.7 ml/min. Renal clearance was almost non-existent (1.4 +/- 1.4 ml/min), whereas non-renal clearance was 54.0 +/- 18.2 ml/min. Steady-state plasma concentrations of metronidazole were 15.3 +/- 3.8 mg/l, the hydroxy metabolite were 17.4 +/- 2.0 mg/l and the acetic acid metabolite were 1.2 +/- 0.8 mg/l. In the patients studied, a dosing regimen of 500 mg twice daily resulted in therapeutically adequate blood levels of metronidazole.

  19. Modeling in biopharmaceutics, pharmacokinetics and pharmacodynamics homogeneous and heterogeneous approaches

    CERN Document Server

    Macheras, Panos

    2016-01-01

    The state of the art in Biopharmaceutics, Pharmacokinetics, and Pharmacodynamics Modeling is presented in this new second edition book. It shows how advanced physical and mathematical methods can expand classical models in order to cover heterogeneous drug-biological processes and therapeutic effects in the body. The book is divided into four parts; the first deals with the fundamental principles of fractals, diffusion and nonlinear dynamics; the second with drug dissolution, release, and absorption; the third with epirical, compartmental, and stochastic pharmacokinetic models, with two new chapters, one on fractional pharmacokinetics and one on bioequivalence; and the fourth mainly with classical and nonclassical aspects of pharmacodynamics. The classical models that have relevance and application to these sciences are also considered throughout. This second edition has new information on reaction limited models of dissolution, non binary biopharmaceutic classification system, time varying models, and interf...

  20. Rationalization and prediction of in vivo metabolite exposures: The role of metabolite kinetics, clearance predictions and in vitro parameters

    Science.gov (United States)

    Lutz, Justin D.; Fujioka, Yasushi; Isoherranen, Nina

    2010-01-01

    Importance of the field Due to growing concerns over toxic or active metabolites, significant efforts have been focused on qualitative identification of potential in vivo metabolites from in vitro data. However, limited tools are available to quantitatively predict their human exposures. Areas covered in this review Theory of clearance predictions and metabolite kinetics is reviewed together with supporting experimental data. In vitro and in vivo data of known circulating metabolites and their parent drugs was collected and the predictions of in vivo exposures of the metabolites were evaluated. What the reader will gain The theory and data reviewed will be useful in early identification of human metabolites that will circulate at significant levels in vivo and help in designing in vivo studies that focus on characterization of metabolites. It will also assist in rationalization of metabolite-to-parent ratios used as markers of specific enzyme activity. Take home message The relative importance of a metabolite in comparison to the parent compound as well as other metabolites in vivo can only be predicted using the metabolites in vitro formation and elimination clearances, and the in vivo disposition of a metabolite can only be rationalized when the elimination pathways of that metabolite are known. PMID:20557268

  1. Benzene: a case study in parent chemical and metabolite interactions.

    Science.gov (United States)

    Medinsky, M A; Kenyon, E M; Schlosser, P M

    1995-12-28

    Benzene, an important industrial solvent, is also present in unleaded gasoline and cigarette smoke. The hematotoxic effects of benzene in humans are well documented and include aplastic anemia and pancytopenia, and acute myelogenous leukemia. A combination of metabolites (hydroquinone and phenol for example) is apparently necessary to duplicate the hematotoxic effect of benzene, perhaps due in part to the synergistic effect of phenol on myeloperoxidase-mediated oxidation of hydroquinone to the reactive metabolite benzoquinone. Since benzene and its hydroxylated metabolites (phenol, hydroquinone and catechol) are substrates for the same cytochrome P450 enzymes, competitive interactions among the metabolites are possible. In vivo data on metabolite formation by mice exposed to various benzene concentrations are consistent with competitive inhibition of phenol oxidation by benzene. In vitro studies of the metabolic oxidation of benzene, phenol and hydroquinone are consistent with the mechanism of competitive interaction among the metabolites. The dosimetry of benzene and its metabolites in the target tissue, bone marrow, depends on the balance of activation processes such as enzymatic oxidation and deactivation processes such as conjugation and excretion. Phenol, the primary benzene metabolite, can undergo both oxidation and conjugation. Thus, the potential exists for competition among various enzymes for phenol. However, zonal localization of Phase I and Phase II enzymes in various regions of the liver acinus regulates this competition. Biologically-based dosimetry models that incorporate the important determinants of benzene flux, including interactions with other chemicals, will enable prediction of target tissue doses of benzene and metabolites at low exposure concentrations relevant for humans.

  2. Prediction and evaluation of route dependent dosimetry of BPA in rats at different life stages using a physiologically based pharmacokinetic model

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Xiaoxia, E-mail: Xiaoxia.Yang@fda.hhs.gov; Doerge, Daniel R.; Fisher, Jeffrey W.

    2013-07-01

    Bisphenol A (BPA) has received considerable attention throughout the last decade due to its widespread use in consumer products. For the first time a physiologically based pharmacokinetic (PBPK) model was developed in neonatal and adult rats to quantitatively evaluate age-dependent pharmacokinetics of BPA and its phase II metabolites. The PBPK model was calibrated in adult rats using studies on BPA metabolism and excretion in the liver and gastrointestinal tract, and pharmacokinetic data with BPA in adult rats. For immature rats the hepatic and gastrointestinal metabolism of BPA was inferred from studies on the maturation of phase II enzymes coupled with serum time course data in pups. The calibrated model predicted the measured serum concentrations of BPA and BPA conjugates after administration of 100 μg/kg of d6-BPA in adult rats (oral gavage and intravenous administration) and postnatal days 3, 10, and 21 pups (oral gavage). The observed age-dependent BPA serum concentrations were partially attributed to the immature metabolic capacity of pups. A comparison of the dosimetry of BPA across immature rats and monkeys suggests that dose adjustments would be necessary to extrapolate toxicity studies from neonatal rats to infant humans. - Highlights: • A PBPK model predicts the kinetics of bisphenol A (BPA) in young and adult rats. • BPA metabolism within enterocytes is required for fitting of oral BPA kinetic data. • BPA dosimetry in young rats is different than adult rats and young monkeys.

  3. Prediction and evaluation of route dependent dosimetry of BPA in rats at different life stages using a physiologically based pharmacokinetic model

    International Nuclear Information System (INIS)

    Yang, Xiaoxia; Doerge, Daniel R.; Fisher, Jeffrey W.

    2013-01-01

    Bisphenol A (BPA) has received considerable attention throughout the last decade due to its widespread use in consumer products. For the first time a physiologically based pharmacokinetic (PBPK) model was developed in neonatal and adult rats to quantitatively evaluate age-dependent pharmacokinetics of BPA and its phase II metabolites. The PBPK model was calibrated in adult rats using studies on BPA metabolism and excretion in the liver and gastrointestinal tract, and pharmacokinetic data with BPA in adult rats. For immature rats the hepatic and gastrointestinal metabolism of BPA was inferred from studies on the maturation of phase II enzymes coupled with serum time course data in pups. The calibrated model predicted the measured serum concentrations of BPA and BPA conjugates after administration of 100 μg/kg of d6-BPA in adult rats (oral gavage and intravenous administration) and postnatal days 3, 10, and 21 pups (oral gavage). The observed age-dependent BPA serum concentrations were partially attributed to the immature metabolic capacity of pups. A comparison of the dosimetry of BPA across immature rats and monkeys suggests that dose adjustments would be necessary to extrapolate toxicity studies from neonatal rats to infant humans. - Highlights: • A PBPK model predicts the kinetics of bisphenol A (BPA) in young and adult rats. • BPA metabolism within enterocytes is required for fitting of oral BPA kinetic data. • BPA dosimetry in young rats is different than adult rats and young monkeys

  4. The specific radioimmunoassay in pharmacokinetics: potency, requirements and development for routine use as illustrated with an assay for Pirenzepin

    International Nuclear Information System (INIS)

    Bozler, G.

    1977-01-01

    Requirements for using RIA in pharmacokinetics are specified. An assay system developed for Pirenzepin was used as example to illustrate the general strategy striving mainly for specificity, sensitivity and reliability. The type of error in the final data is considered. It is a widespread assumption that weak crossreactions with metabolites result in a 'relative' error and, therefore, don't have relevance for the determination of the parent drug. In contrast, it was shown for biological samples that such weak crossreactivity gives rise to a concentration independent (absolute) error, which is analogous to that caused by a 'blank value' in chemical analysis. (orig.) [de

  5. Human physiologically based pharmacokinetic model for propofol

    Directory of Open Access Journals (Sweden)

    Schnider Thomas W

    2005-04-01

    Full Text Available Abstract Background Propofol is widely used for both short-term anesthesia and long-term sedation. It has unusual pharmacokinetics because of its high lipid solubility. The standard approach to describing the pharmacokinetics is by a multi-compartmental model. This paper presents the first detailed human physiologically based pharmacokinetic (PBPK model for propofol. Methods PKQuest, a freely distributed software routine http://www.pkquest.com, was used for all the calculations. The "standard human" PBPK parameters developed in previous applications is used. It is assumed that the blood and tissue binding is determined by simple partition into the tissue lipid, which is characterized by two previously determined set of parameters: 1 the value of the propofol oil/water partition coefficient; 2 the lipid fraction in the blood and tissues. The model was fit to the individual experimental data of Schnider et. al., Anesthesiology, 1998; 88:1170 in which an initial bolus dose was followed 60 minutes later by a one hour constant infusion. Results The PBPK model provides a good description of the experimental data over a large range of input dosage, subject age and fat fraction. Only one adjustable parameter (the liver clearance is required to describe the constant infusion phase for each individual subject. In order to fit the bolus injection phase, for 10 or the 24 subjects it was necessary to assume that a fraction of the bolus dose was sequestered and then slowly released from the lungs (characterized by two additional parameters. The average weighted residual error (WRE of the PBPK model fit to the both the bolus and infusion phases was 15%; similar to the WRE for just the constant infusion phase obtained by Schnider et. al. using a 6-parameter NONMEM compartmental model. Conclusion A PBPK model using standard human parameters and a simple description of tissue binding provides a good description of human propofol kinetics. The major advantage of a

  6. Pharmacokinetics and absolute bioavailability of phenobarbital in neonates and young infants, a population pharmacokinetic modelling approach.

    Science.gov (United States)

    Marsot, Amélie; Brevaut-Malaty, Véronique; Vialet, Renaud; Boulamery, Audrey; Bruguerolle, Bernard; Simon, Nicolas

    2014-08-01

    Phenobarbital is widely used for treatment of neonatal seizures. Its optimal use in neonates and young infants requires information regarding pharmacokinetics. The objective of this study is to characterize the absolute bioavailability of phenobarbital in neonates and young infants, a pharmacokinetic parameter which has not yet been investigated. Routine clinical pharmacokinetic data were retrospectively collected from 48 neonates and infants (weight: 0.7-10 kg; patient's postnatal age: 0-206 days; GA: 27-42 weeks) treated with phenobarbital, who were administered as intravenous or suspension by oral routes and hospitalized in a paediatric intensive care unit. Total mean dose of 4.6 mg/kg (3.1-10.6 mg/kg) per day was administered by 30-min infusion or by oral route. Pharmacokinetic analysis was performed using a nonlinear mixed-effect population model software). Data were modelled with an allometric pharmacokinetic model, using three-fourths scaling exponent for clearance (CL). The population typical mean [per cent relative standard error (%RSE)] values for CL, apparent volume of distribution (Vd ) and bioavailability (F) were 0.0054 L/H/kg (7%), 0.64 L/kg (15%) and 48.9% (22%), respectively. The interindividual variability of CL, Vd , F (%RSE) and residual variability (%RSE) was 17% (31%), 50% (27%), 39% (27%) and 7.2 mg/L (29%), respectively. The absolute bioavailability of phenobarbital in neonates and infants was estimated. The dose should be increased when switching from intravenous to oral administration. © 2013 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.

  7. Prediction of human CNS pharmacokinetics using a physiologically-based pharmacokinetic modeling approach

    NARCIS (Netherlands)

    Yamamoto, Yumi; Valitalo, Pyry A.; Wong, Yin Cheong; Huntjens, Dymphy R.; Proost, Johannes H.; Vermeulen, An; Krauwinkel, Walter; Beukers, Margot W.; Kokki, Hannu; Kokki, Merja; Danhof, Meindert; van Hasselt, Johan G. C.; de Lange, Elizabeth C. M.

    2018-01-01

    Knowledge of drug concentration-time profiles at the central nervous system (CNS) target-site is critically important for rational development of CNS targeted drugs. Our aim was to translate a recently published comprehensive CNS physiologically-based pharmacokinetic (PBPK) model from rat to human,

  8. Pharmacokinetic/Pharmacodynamic Modelling of Receptor Internalization with CRTH2 Antagonists to Optimize Dose Selection.

    Science.gov (United States)

    Krause, Andreas; Zisowsky, Jochen; Strasser, Daniel S; Gehin, Martine; Sidharta, Patricia N; Groenen, Peter M A; Dingemanse, Jasper

    2016-07-01

    The chemoattractant receptor-homologous molecule expressed on T helper-2 cells (CRTH2) is a G-protein-coupled receptor for prostaglandin D2 (PGD2), a key mediator in inflammatory disorders. Two selective and potent CRTH2 antagonists currently in clinical development, ACT-453859 and setipiprant, were compared with respect to their (predicted) clinical efficacy. Population pharmacokinetic (PK) and pharmacodynamic (PD) models were developed to characterize how plasma concentrations (PK) of ACT-453859, its active metabolite ACT-463036 and setipiprant related to their effect on blocking PGD2-induced internalization of CRTH2 on eosinophils (PD). Simulations were used to identify doses and dosing regimens leading to 90 % of maximum blockade of CRTH2 internalization at trough. A combined concentration of ACT-453859 and its metabolite ACT-463036, with weights proportional to potency (based on an eosinophil shape change assay), enabled good characterization of the PD effect. The modelling and simulation results facilitated decision making by suggesting an ACT-453859 dose of 400 mg once daily (or 100 mg twice daily) for clinically relevant CRTH2 antagonism. Pharmacometric quantification demonstrated that CRTH2 internalization is a useful new biomarker to study CRTH2 antagonism. Ninety percent of maximum blockade of CRTH2 internalization at trough is suggested as a quantitative PD target in clinical studies.

  9. Effect of gemfibrozil and rifampicin on the pharmacokinetics of selexipag and its active metabolite in healthy subjects.

    Science.gov (United States)

    Bruderer, Shirin; Petersen-Sylla, Marc; Boehler, Margaux; Remeňová, Tatiana; Halabi, Atef; Dingemanse, Jasper

    2017-12-01

    Based on in vitro data, there is evidence to suggest that cytochrome P450 (CYP) 2C8 is involved in the metabolism of selexipag and its active metabolite, ACT-333679. The present study evaluated the possible pharmacokinetic interactions of selexipag with gemfibrozil, a strong CYP2C8 inhibitor, and rifampicin, an inducer of CYP2C8. The study consisted of two independent parts, each conducted according to an open-label, randomized, crossover design. The pharmacokinetics and safety of selexipag and ACT-333679 were studied following single-dose administration either alone or in the presence of multiple-dose gemfibrozil (part I) or rifampicin (part II) in healthy male subjects. Gemfibrozil had comparatively small effects on selexipag (less than 2-fold difference in any pharmacokinetic variable) but, with respect to ACT-333679, increased the maximum plasma concentration (C max ) 3.6-fold [90% confidence interval (CI) 3.1, 4.3] and the area under the plasma concentration-time curve from zero to infinity (AUC 0-∞ ) 11.1-fold (90% CI 9.2, 13.4). The marked increased exposure to ACT-333679, which mediates the majority of the pharmacological activity of selexipag, was accompanied by significantly more adverse events such as headache, nausea and vomiting. Coadministration of rifampicin increased the C max of selexipag 1.8-fold (90% CI 1.4, 2.2) and its AUC0 -∞ 1.3-fold (90% CI 1.1, 1.4); its effects on ACT-333679 were to increase its C max 1.3-fold (90% CI 1.1, 1.6), shorten its half-life by 63% and reduce its AUC0 -∞ by half (90% CI 0.45, 0.59). Concomitant administration of selexipag and strong inhibitors of CYP2C8 must be avoided, whereas when coadministered with inducers of CYP2C8, dose adjustments of selexipag should be envisaged. © 2017 The British Pharmacological Society.

  10. Pharmacokinetic modeling of 4,4'-methylenedianiline released from reused polyurethane dialyzer potting materials.

    Science.gov (United States)

    Do Luu, H M; Hutter, J C

    2000-01-01

    4, 4'-Methylenedianiline (MDA) is a hydrolysis degradation product that can be released from polyurethanes commonly used in medical device applications. MDA is mutagenic and carcinogenic in animals. In humans, it is hepatotoxic, a known contact and respiratory allergen, and a suspected carcinogen. A physiologically based pharmacokinetic (PBPK) model was developed to estimate the absorption, distribution, metabolism, and excretion of MDA in patients exposed to MDA leached from the potting materials of hemodialyzers. A worst-case reuse situation and a single use case were investigated. The PBPK model included five tissue compartments: liver, kidney, gastrointestinal tract, slowly perfused tissues, and richly perfused tissues. Physiological and chemical parameters of a healthy individual used in the model were obtained from the literature. The model was calibrated using previously published kinetic studies of IV administered doses of (14) C-MDA to rats. The model was validated using independent data published for MDA-exposed workers. The PBPK results indicated that dialysis patients who are exposed to MDA released from dialyzers (new or reused) could accumulate low levels of MDA and metabolites (total MDA) over time. Copyright 2000 John Wiley & Sons, Inc.

  11. Evaluation of pharmacokinetic model designs for subcutaneous infusion of insulin aspart

    DEFF Research Database (Denmark)

    Mansell, Erin J.; Schmidt, Signe; Docherty, Paul D.

    2017-01-01

    Effective mathematical modelling of continuous subcutaneous infusion pharmacokinetics should aid understanding and control in insulin therapy. Thorough analysis of candidate model performance is important for selecting the appropriate models. Eight candidate models for insulin pharmacokinetics...... included a range of modelled behaviours, parameters and complexity. The models were compared using clinical data from subjects with type 1 diabetes with continuous subcutaneous insulin infusion. Performance of the models was compared through several analyses: R2 for goodness of fit; the Akaike Information...

  12. Two-Compartment Pharmacokinetic Models for Chemical Engineers

    Science.gov (United States)

    Kanneganti, Kumud; Simon, Laurent

    2011-01-01

    The transport of potassium permanganate between two continuous-stirred vessels was investigated to help chemical and biomedical engineering students understand two-compartment pharmacokinetic models. Concepts of modeling, mass balance, parameter estimation and Laplace transform were applied to the two-unit process. A good agreement was achieved…

  13. Pharmacokinetics and metabolism of cyadox and its main metabolites in beagle dogs following oral, intramuscular and intravenous administration

    Directory of Open Access Journals (Sweden)

    Adeel Sattar

    2016-08-01

    Full Text Available Cyadox (Cyx is an antibacterial drug of the quinoxaline group that exerts markedly lower toxicity in animals, compared to its congeners. Here, the pharmacokinetics and metabolism of Cyx after oral (PO, intramuscular (IM and intravenous (IV routes of administration were studied to establish safety criteria for the clinical use of Cyx in animals. Six beagle dogs (3 males, 3 females were administered Cyx through PO (40 mg kg-1 b.w., IM (10 mg kg-1 b.w. and IV (10 mg kg-1 b.w. routes with a washout period of 2 weeks in a crossover design. Highly sensitive high-performance liquid chromatography with ultraviolet detection (HPLC-UV was employed for determination of Cyx and its main metabolites, 1, 4-bisdesoxycyadox (Cy1, cyadox-1-monoxide (Cy2, N-(quinoxaline-2-methyl-cyanide acetyl hydrazine (Cy4 and quinoxaline-2-carboxylic acid (Cy6 in plasma, urine and feces of dogs. The oral bioavailability of Cyx was 4.75%, suggesting first-pass effect in dogs. The concentration vs. time profile in plasma after PO administration indicates that Cyx is rapidly dissociated into its metabolites and eliminated from plasma earlier, compared to its metabolites. The areas under the curve (AUC of Cyx after PO, IM and IV administration were 1.22 h×µg mL-1, 6.3 h×µg mL-1, and 6.66 h×µg mL-1, while mean resident times (MRT were 7.32, 3.58 and 0.556 h, respectively. Total recovery of Cyx and its metabolites was >60% with each administration route. In feces, 48.83% drug was recovered after PO administration, while 18.15% and 17.11% after IM and IV injections, respectively, suggesting renal clearance as the major route of excretion with IM and IV administration and feces as the major route with PO delivery. Our comprehensive evaluation of Cyx has uncovered detailed information that should facilitate its judicious use in animals by improving understanding of its pharmacology.

  14. Metabolic profiles of pomalidomide in human plasma simulated with pharmacokinetic data in control and humanized-liver mice.

    Science.gov (United States)

    Shimizu, Makiko; Suemizu, Hiroshi; Mitsui, Marina; Shibata, Norio; Guengerich, F Peter; Yamazaki, Hiroshi

    2017-10-01

    1. Pomalidomide has been shown to be potentially teratogenic in thalidomide-sensitive animal species such as rabbits. Screening for thalidomide analogs devoid of teratogenicity/toxicity - attributable to metabolites formed by cytochrome P450 enzymes - but having immunomodulatory properties is a strategic pathway towards development of new anticancer drugs. 2. In this study, plasma concentrations of pomalidomide, its primary 5-hydroxylated metabolite, and its glucuronide conjugate(s) were investigated in control and humanized-liver mice. Following oral administration of pomalidomide (100 mg/kg), plasma concentrations of 7-hydroxypomalidomide and 5-hydroxypomalidomide glucuronide were slightly higher in humanized-liver mice than in control mice. 3. Simulations of human plasma concentrations of pomalidomide were achieved with simplified physiologically-based pharmacokinetic models in both groups of mice in accordance with reported pomalidomide concentrations after low dose administration in humans. 4. The results indicate that pharmacokinetic profiles of pomalidomide were roughly similar between control mice and humanized-liver mice and that control and humanized-liver mice mediated pomalidomide 5-hydroxylation in vivo. Introducing one aromatic amino group into thalidomide resulted in less species differences in in vivo pharmacokinetics in control and humanized-liver mice.

  15. Investigation of an alternative generic model for predicting pharmacokinetic changes during physiological stress.

    Science.gov (United States)

    Peng, Henry T; Edginton, Andrea N; Cheung, Bob

    2013-10-01

    Physiologically based pharmacokinetic models were developed using MATLAB Simulink® and PK-Sim®. We compared the capability and usefulness of these two models by simulating pharmacokinetic changes of midazolam under exercise and heat stress to verify the usefulness of MATLAB Simulink® as a generic PBPK modeling software. Although both models show good agreement with experimental data obtained under resting condition, their predictions of pharmacokinetics changes are less accurate in the stressful conditions. However, MATLAB Simulink® may be more flexible to include physiologically based processes such as oral absorption and simulate various stress parameters such as stress intensity, duration and timing of drug administration to improve model performance. Further work will be conducted to modify algorithms in our generic model developed using MATLAB Simulink® and to investigate pharmacokinetics under other physiological stress such as trauma. © The Author(s) 2013.

  16. Population pharmacokinetics of ifosfamide and its 2-and 3-dechloroethylated and 4-hydroxylated metabolites in resistant small-cell lung cancer patients

    NARCIS (Netherlands)

    Kerbusch, T; vanPutten, JWG; Groen, HJM; Huitema, ADR; Mathot, RAA; Beijnen, JH

    The aim of this study was to develop a population pharmacokinetic model that could describe the pharmacokinetics of ifosfamide, 2- and 3-dechloroethylifosfamide and 4-hydroxyifosfamide, and calculate their plasma exposure and urinary excretion. A group of 14 patients with small-cell lung cancer

  17. A validated HPLC-MS/MS assay for quantifying unstable pharmacologically active metabolites of clopidogrel in human plasma: application to a clinical pharmacokinetic study.

    Science.gov (United States)

    Furlong, Michael T; Savant, Ishani; Yuan, Moucun; Scott, Laura; Mylott, William; Mariannino, Thomas; Kadiyala, Pathanjali; Roongta, Vikram; Arnold, Mark E

    2013-05-01

    Clopidogrel is prescribed for the treatment of Acute Coronary Syndrome and recent myocardial infarction, recent stroke, or established peripheral arterial disease. A sensitive and reliable high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) assay was developed and validated to enable reliable quantification of four diastereomeric and chemically reactive thiol metabolites, two of which are pharmacologically active, in human plasma. The metabolites were stabilized by alkylation of their reactive thiol moieties with 2-bromo-3'-methoxyacetophenone (MPB). Following organic solvent mediated-protein precipitation in a 96-well plate format, chromatographic separation was achieved by gradient elution on an Ascentis Express RP-amide column. Chromatographic conditions were optimized to ensure separation of the four derivatized active metabolites. Derivatized metabolites and stable isotope-labeled internal standards were detected by positive ion electrospray tandem mass spectrometry. The HPLC-MS/MS assay was validated over concentration ranges of 0.125-125 ng/mL for metabolites H1-H3 and 0.101-101 ng/mL for H4. Intra- and inter-assay precision values for replicate quality control samples were within 14.3% for all analytes during the assay validation. Mean quality control accuracy values were within ±6.3% of nominal values for all analytes. Assay recoveries were high (>79%). The four derivatized analytes were stable in human blood for at least 2 h at room temperature and on ice. The analytes were also stable in human plasma for at least 25 h at room temperature, 372 days at -20 °C and -70 °C, and following at least five freeze-thaw cycles. The validated assay was successfully applied to the quantification of all four thiol metabolites in human plasma in support of a human pharmacokinetic study. Copyright © 2013 Elsevier B.V. All rights reserved.

  18. In Silico Ocular Pharmacokinetic Modeling: Delivery of Topical FK962 to Retina.

    Science.gov (United States)

    Mori, Ayumi; Yabuta, Chiho; Kishimoto, Yayoi; Kozai, Seiko; Ohtori, Akira; Shearer, Thomas R; Azuma, Mitsuyoshi

    2017-09-01

    To establish the in silico ocular pharmacokinetic modeling for eye drops, and to simulate the dose regimen for FK962 in human choroid/retinal diseases. Pharmacokinetics for FK962 in vivo was performed by a single instillation of drops containing 0.1% 14 C-FK962 in rabbit eyes. Permeation of FK962 across the cornea, sclera, and choroid/retina was measured in vitro. Neurite elongation by FK962 was measured in cultured rat retinal ganglion cells. Parameters from the experimental data were used in an improved in silico model of ocular pharmacokinetics of FK962 in man. The mean concentration of FK962 in ocular tissues predicted by in silico modeling was consistent with in vivo results, validating the in silico model. FK962 rapidly penetrated into the anterior and posterior segments of the eye and then diffused into the vitreous body. The in silico pharmacokinetic modeling also predicted that a dose regimen of 0.0054% FK962 twice per day would produce biologically effective concentrations of FK962 in the choroid/retina, where FK962 facilitates rat neurite elongation. Our in silico model for ocular pharmacokinetics is useful (1) for predicting drug concentrations in specific ocular tissues after topical instillation, and (2) for suggesting the optimal dose regimens for eye drops. The pharmacodynamics for FK962 produced by this model may be useful for clinical trials against retinal neuropathy.

  19. Pharmacokinetics of Fluoxetine in Pregnant Baboons (Papio spp.)

    Science.gov (United States)

    Shoulson, Rivka L; Stark, Raymond L; Garland, Marianne

    2014-01-01

    Fluoxetine is used to treat a number of psychiatric conditions in humans and behavioral problems in animals. Its use in pregnancy must balance maternal benefit with potential risk to the fetus. Knowledge of adult and fetal drug disposition can assist clinicians in selecting therapy that minimizes adverse effects to the fetus. Nonhuman primate models are used frequently in drug dose-translation studies, and pregnancy in baboons has many similarities to human pregnancy. Accordingly, pharmacokinetic analysis of a series of fluoxetine and norfluoxetine administrations to pregnant baboons was performed. The mean maternal baboon steady-state clearance of fluoxetine (42 mL/min/kg) was considerably higher than that in humans. Norfluoxetine, the major active metabolite, had a higher metabolite-to-drug ratio (8.7) than that found in humans, particularly with oral dosing. These results are consistent with more extensive metabolism in baboons than in humans and leads to a higher clearance than would be expected from allometric scaling. Fetal-to-maternal fluoxetine and norfluoxetine ratios under steady-state conditions were similar to those in humans, with fetal concentrations of fluoxetine 42% and norfluoxetine 47% of maternal concentrations. The fetal clearance of fluoxetine (303 ± 176 mL/min) and norfluoxetine (450 mL/min) exceeded reported placental blood flow. Understanding these species-associated differences in metabolism is a prerequisite to extrapolating data between species. Nonetheless, nonhuman primates are likely to remain valuable models for pharmacokinetic studies during pregnancy, particularly those directed toward fetal neurodevelopmental effects. Our results also are applicable to determining appropriate dosing of nonhuman primates in clinical settings. PMID:25650979

  20. UNCERTAINTIES IN TRICHLOROETHYLENE PHARMACOKINETIC MODELS

    Science.gov (United States)

    Understanding the pharmacokinetics of a chemical¯its absorption, distribution, metabolism, and excretion in humans and laboratory animals ¯ is critical to the assessment of its human health risks. For trichloroethylene (TCE), numerous physiologically-based pharmacokinetic (PBPK)...

  1. Physiologically-based pharmacokinetic modeling of tamoxifen and its metabolites in women of different CYP2D6 phenotypes provides new insight into the tamoxifen mass balance

    Directory of Open Access Journals (Sweden)

    Kristin eDickschen

    2012-05-01

    Full Text Available Tamoxifen is a first-line endocrine agent in the mechanism-based treatment of estrogen receptor positive (ER+ mammary carcinoma and applied to breast cancer patients all over the world. Endoxifen is a secondary and highly active metabolite of tamoxifen that is formed among others by the polymorphic cytochrome P450 2D6 (CYP2D6. It is widely accepted that CYP2D6 poor metabolizers (PM exert a pronounced decrease in endoxifen steady-state plasma concentrations compared to CYP2D6 extensive metabolizers (EM. Nevertheless, an in-depth understanding of the chain of cause and effect between CYP2D6 genotype, endoxifen steady-state plasma concentration, and subsequent tamoxifen treatment benefit still remains to be evolved.In this context, physiologically-based pharmacokinetic (PBPK-modeling provides a useful tool to mechanistically investigate the impact of CYP2D6 phenotype on endoxifen formation in female breast cancer patients undergoing tamoxifen therapy.It has long been thought that only a minor percentage of endoxifen is formed via 4-hydroxytamoxifen. However, the current investigation supports very recently published data that postulates a contribution of 4-hydroxytamoxifen above 20 % to total endoxifen formation. The developed PBPK-model describes tamoxifen PK in rats and humans. Moreover, tamoxifen metabolism in dependence of CYP2D6 phenotype in populations of European female individuals is well described, thus providing a good basis to further investigate the linkage of PK, mode of action, and treatment outcome in dependence of factors such as phenotype, ethnicity or co-treatment with CYP2D6 inhibitors.

  2. An HPLC tandem mass spectrometry for quantification of ET-26-HCl and its major metabolite in plasma and application to a pharmacokinetic study in rats.

    Science.gov (United States)

    Chen, Xu; Zhang, Wensheng; Rios, Sandy; Morkos, Miriam B; Ye, Xiaoli; Li, Gen; Jiang, Xuehua; Wang, Zhijun; Wang, Ling

    2018-02-05

    ET-26-HCl is a new analog of etomidate, a short-acting anesthetic drug, with less adrenal cortex inhibition. The pharmacokinetics of ET-26-HCl in rats needs to be determined for future clinical trials in human subjects. In order to facilitate the pharmacokinetic study, a liquid chromatography based tandem mass spectrometric (HPLC-MS/MS) method was developed and validated for quantification of ET-26-HCl and its major metabolite, ET-26-acid. These two compounds and gabapentin (internal standard) were extracted using a protein precipitation method with methanol and detected by Multiple Reaction Monitoring of m/z transition of 275.6-170.9, 217.7-113.1, and 172.5-154.3 for ET-26-HCl, ET-26-acid, and gabapentin respectively. This method was validated in terms of sensitivity, linearity, reproducibility, and stability. The HPLC-MS/MS method was found linear over the concentration ranges of 21.76-4352ng/mL, and 18.62-3724ng/mL with LLOQ of 21.76 and 18.62ng/mL for ET-26-HCl and ET-26-acid respectively. The mean intra-day and inter-day accuracy was between 94.11-107.78%, while the precision was within the limit of 15.0% for all the quality control samples. A pharmacokinetic study was then conducted in rats following intravenous injection of 2.1, 4.2, and 8.4mg/kg. The linear pharmacokinetics of ET-26-HCl was observed over the dose range of 2.1-8.4mg/kg. The average terminal phase elimination half-lives were 0.87 and 1.03h for ET-26-HCl and ET-26-acid respectively. In summary, an HPLC-MS/MS method for quantification of ET-26-HCl in rat plasma has been developed and successfully applied to a pharmacokinetic study. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Pharmacokinetic studies of 131 I-stevioside and his metabolites

    International Nuclear Information System (INIS)

    Cardoso, V.N.

    1993-01-01

    Stevia rebaudiana is a shrub widely in Paraguay and Brazil, belonging to the compositae family. The leaves of this plant contain large amounts of stevioside. Since the use of stevioside as sugar substitute continues to increase, the purpose of this study is to investigate the biological distribution, excretion and the possibility of stevioside to be degraded to steviol 'in vitro'. 131 -I-stevioside (1,10 MBq) was i.v. injected in Wistar male rats its distribution in the body and metabolism were studied. The highest concentration of radioactivity was observed in the liver and the small intestine after 10 and 120 minutes respectively. RP-HPLC analysis of the bile showed that steviol appeared as a major metabolite, representing 47,3% of the radioactivity while stevioside represented 37,3% and the remaining 15,4% was due to an unidentified metabolite. The results showed that stevioside was partially degraded 'in vivo' to steviol and other metabolite, and that part of the radioactivity was absorbed from the small intestine. (author)

  4. PBPK modeling of the cis- and trans-permethrin isomers and their major urinary metabolites in rats

    Energy Technology Data Exchange (ETDEWEB)

    Willemin, Marie-Emilie [Institut National de l' Environnement Industriel et des Risques (INERIS), Unité Modèles pour l' Ecotoxicologie et la Toxicologie (METO), Parc ALATA BP2, 60550, Verneuil en Halatte (France); Sorbonne University, Université de Technologie de Compiègne, CNRS, UMR 7338 Biomechanics and Bioengineering, Centre de recherche Royallieu CS 60319,60203 Compiègnee Cedex (France); Desmots, Sophie [Institut National de l' Environnement Industriel et des Risques (INERIS), Unité Toxicologie Expérimentale (TOXI), Parc ALATA BP2, 60550, Verneuil en Halatte (France); Le Grand, Rozenn [Centre Hospitalo-Universitaire de Limoges, Service de Pharmacologie et de Toxicologie — Pharmacovigilance, 2, avenue Martin Luther King, 87042 Limoges (France); Lestremau, François [Institut National de l' Environnement Industriel et des Risques (INERIS), Unité Innovation pour la Mesure (NOVA), Parc ALATA BP2, 60550, Verneuil en Halatte (France); Zeman, Florence A. [Institut National de l' Environnement Industriel et des Risques (INERIS), Unité Modèles pour l' Ecotoxicologie et la Toxicologie (METO), Parc ALATA BP2, 60550, Verneuil en Halatte (France); Leclerc, Eric [Sorbonne University, Université de Technologie de Compiègne, CNRS, UMR 7338 Biomechanics and Bioengineering, Centre de recherche Royallieu CS 60319,60203 Compiègnee Cedex (France); Moesch, Christian [Centre Hospitalo-Universitaire de Limoges, Service de Pharmacologie et de Toxicologie — Pharmacovigilance, 2, avenue Martin Luther King, 87042 Limoges (France); and others

    2016-03-01

    Permethrin, a pyrethroid insecticide, is suspected to induce neuronal and hormonal disturbances in humans. The widespread exposure of the populations has been confirmed by the detection of the urinary metabolites of permethrin in biomonitoring studies. Permethrin is a chiral molecule presenting two forms, the cis and the trans isomers. Because in vitro studies indicated a metabolic interaction between the trans and cis isomers of permethrin, we adapted and calibrated a PBPK model for trans- and cis-permethrin separately in rats. The model also describes the toxicokinetics of three urinary metabolites, cis- and trans-3-(2,2 dichlorovinyl)-2,2-dimethyl-(1-cyclopropane) carboxylic acid (cis- and trans-DCCA), 3-phenoxybenzoic acid (3-PBA) and 4′OH-phenoxybenzoic acid (4′-OH-PBA). In vivo experiments performed in Sprague–Dawley rats were used to calibrate the PBPK model in a Bayesian framework. The model captured well the toxicokinetics of permethrin isomers and their metabolites including the rapid absorption, the accumulation in fat, the extensive metabolism of the parent compounds, and the rapid elimination of metabolites in urine. Average hepatic clearances in rats were estimated to be 2.4 and 5.7 L/h/kg for cis- and trans-permethrin, respectively. High concentrations of the metabolite 4′-OH-PBA were measured in urine compared to cis- and trans-DCCA and 3-PBA. The confidence in the extended PBPK model was then confirmed by good predictions of published experimental data obtained using the isomers mixture. The extended PBPK model could be extrapolated to humans to predict the internal dose of exposure to permethrin from biomonitoring data in urine. - Highlights: • A PBPK model of isomers of permethrin and its urinary metabolites was developed. • A quantitative link was established for permethrin and its biomarkers of exposure. • The bayesian framework allows getting confidence interval on the estimated parameters. • The PBPK model can be extrapolated

  5. PBPK modeling of the cis- and trans-permethrin isomers and their major urinary metabolites in rats

    International Nuclear Information System (INIS)

    Willemin, Marie-Emilie; Desmots, Sophie; Le Grand, Rozenn; Lestremau, François; Zeman, Florence A.; Leclerc, Eric; Moesch, Christian

    2016-01-01

    Permethrin, a pyrethroid insecticide, is suspected to induce neuronal and hormonal disturbances in humans. The widespread exposure of the populations has been confirmed by the detection of the urinary metabolites of permethrin in biomonitoring studies. Permethrin is a chiral molecule presenting two forms, the cis and the trans isomers. Because in vitro studies indicated a metabolic interaction between the trans and cis isomers of permethrin, we adapted and calibrated a PBPK model for trans- and cis-permethrin separately in rats. The model also describes the toxicokinetics of three urinary metabolites, cis- and trans-3-(2,2 dichlorovinyl)-2,2-dimethyl-(1-cyclopropane) carboxylic acid (cis- and trans-DCCA), 3-phenoxybenzoic acid (3-PBA) and 4′OH-phenoxybenzoic acid (4′-OH-PBA). In vivo experiments performed in Sprague–Dawley rats were used to calibrate the PBPK model in a Bayesian framework. The model captured well the toxicokinetics of permethrin isomers and their metabolites including the rapid absorption, the accumulation in fat, the extensive metabolism of the parent compounds, and the rapid elimination of metabolites in urine. Average hepatic clearances in rats were estimated to be 2.4 and 5.7 L/h/kg for cis- and trans-permethrin, respectively. High concentrations of the metabolite 4′-OH-PBA were measured in urine compared to cis- and trans-DCCA and 3-PBA. The confidence in the extended PBPK model was then confirmed by good predictions of published experimental data obtained using the isomers mixture. The extended PBPK model could be extrapolated to humans to predict the internal dose of exposure to permethrin from biomonitoring data in urine. - Highlights: • A PBPK model of isomers of permethrin and its urinary metabolites was developed. • A quantitative link was established for permethrin and its biomarkers of exposure. • The bayesian framework allows getting confidence interval on the estimated parameters. • The PBPK model can be extrapolated

  6. Time-dependent pharmacokinetics of dexamethasone and its efficacy in human breast cancer xenograft mice: a semi-mechanism-based pharmacokinetic/pharmacodynamic model.

    Science.gov (United States)

    Li, Jian; Chen, Rong; Yao, Qing-Yu; Liu, Sheng-Jun; Tian, Xiu-Yun; Hao, Chun-Yi; Lu, Wei; Zhou, Tian-Yan

    2018-03-01

    Dexamethasone (DEX) is the substrate of CYP3A. However, the activity of CYP3A could be induced by DEX when DEX was persistently administered, resulting in auto-induction and time-dependent pharmacokinetics (pharmacokinetics with time-dependent clearance) of DEX. In this study we investigated the pharmacokinetic profiles of DEX after single or multiple doses in human breast cancer xenograft nude mice and established a semi-mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model for characterizing the time-dependent PK of DEX as well as its anti-cancer effect. The mice were orally given a single or multiple doses (8 mg/kg) of DEX, and the plasma concentrations of DEX were assessed using LC-MS/MS. Tumor volumes were recorded daily. Based on the experimental data, a two-compartment model with first order absorption and time-dependent clearance was established, and the time-dependence of clearance was modeled by a sigmoid E max equation. Moreover, a semi-mechanism-based PK/PD model was developed, in which the auto-induction effect of DEX on its metabolizing enzyme CYP3A was integrated and drug potency was described using an E max equation. The PK/PD model was further used to predict the drug efficacy when the auto-induction effect was or was not considered, which further revealed the necessity of adding the auto-induction effect into the final PK/PD model. This study established a semi-mechanism-based PK/PD model for characterizing the time-dependent pharmacokinetics of DEX and its anti-cancer effect in breast cancer xenograft mice. The model may serve as a reference for DEX dose adjustments or optimization in future preclinical or clinical studies.

  7. Prediction of Relative In Vivo Metabolite Exposure from In Vitro Data Using Two Model Drugs: Dextromethorphan and Omeprazole

    Science.gov (United States)

    Lutz, Justin D.

    2012-01-01

    Metabolites can have pharmacological or toxicological effects, inhibit metabolic enzymes, and be used as probes of drug-drug interactions or specific cytochrome P450 (P450) phenotypes. Thus, better understanding and prediction methods are needed to characterize metabolite exposures in vivo. This study aimed to test whether in vitro data could be used to predict and rationalize in vivo metabolite exposures using two model drugs and P450 probes: dextromethorphan and omeprazole with their primary metabolites dextrorphan, 5-hydroxyomeprazole (5OH-omeprazole), and omeprazole sulfone. Relative metabolite exposures were predicted using metabolite formation and elimination clearances. For dextrorphan, the formation clearances of dextrorphan glucuronide and 3-hydroxymorphinan from dextrorphan in human liver microsomes were used to predict metabolite (dextrorphan) clearance. For 5OH-omeprazole and omeprazole sulfone, the depletion rates of the metabolites in human hepatocytes were used to predict metabolite clearance. Dextrorphan/dextromethorphan in vivo metabolite/parent area under the plasma concentration versus time curve ratio (AUCm/AUCp) was overpredicted by 2.1-fold, whereas 5OH-omeprazole/omeprazole and omeprazole sulfone/omeprazole were predicted within 0.75- and 1.1-fold, respectively. The effect of inhibition or induction of the metabolite's formation and elimination on the AUCm/AUCp ratio was simulated. The simulations showed that unless metabolite clearance pathways are characterized, interpretation of the metabolic ratios is exceedingly difficult. This study shows that relative in vivo metabolite exposure can be predicted from in vitro data and characterization of secondary metabolism of probe metabolites is critical for interpretation of phenotypic data. PMID:22010218

  8. Alterations in Pharmacokinetics of Gemcitabine and Erlotinib by Concurrent Administration of Hyangsayukgunja-Tang, a Gastroprotective Herbal Medicine.

    Science.gov (United States)

    Kim, Tae Hwan; Shin, Soyoung; Kim, Sarah; Bulitta, Jürgen B; Weon, Kwon-Yeon; Joo, Sang Hoon; Ma, Eunsook; Yoo, Sun Dong; Park, Gi-Young; Kwon, Dong Rak; Jeong, Seok Won; Lee, Da Young; Shin, Beom Soo

    2017-09-10

    Gemcitabine and erlotinib are the chemotherapeutic agents used in the treatment of various cancers and their combination is being accepted as a first-line treatment of advanced pancreatic cancer. Hyangsayukgunja-tang (HYT) is a traditional oriental medicine used in various digestive disorders and potentially helpful to treat gastrointestinal adverse effects related to chemotherapy. The present study was aimed to evaluate the effect of HYT on the pharmacokinetics of gemcitabine and erlotinib given simultaneously in rats. Rats were pretreated with HYT at an oral dose of 1200 mg/kg/day once daily for a single day or 14 consecutive days. Immediately after pretreatment with HYT, gemcitabine and erlotinib were administered by intravenous injection (10 mg/kg) and oral administration (20 mg/kg), respectively. The effects of HYT on pharmacokinetics of the two drugs were estimated by non-compartmental analysis and pharmacokinetic modeling. The pharmacokinetics of gemcitabine and erlotinib were not altered by single dose HYT pretreatment. However, the plasma levels of OSI-420 and OSI-413, active metabolites of erlotinib, were significantly decreased in the multiple dose HYT pretreatment group. The pharmacokinetic model estimated increased systemic clearances of OSI-420 and OSI-413 by multiple doses of HYT. These data suggest that HYT may affect the elimination of OSI-420 and OSI-413.

  9. Mixed-effects modelling of the interspecies pharmacokinetic scaling of pegylated human erythropoietin.

    Science.gov (United States)

    Jolling, Koen; Perez Ruixo, Juan Jose; Hemeryck, Alex; Vermeulen, An; Greway, Tony

    2005-04-01

    The aim of this study was to develop a population pharmacokinetic model for interspecies allometric scaling of pegylated r-HuEPO (PEG-EPO) pharmacokinetics to man. A total of 927 serum concentrations from 193 rats, 6 rabbits, 34 monkeys, and 9 dogs obtained after a single dose of PEG-EPO, administered by the i.v. (dose range: 12.5-550 microg/kg) and s.c. (dose range: 12.5-500 microg/kg) routes, were pooled in this analysis. An open two-compartment model with first-order absorption and lag time (Tlag) and linear elimination from the central compartment was fitted to the data using the NONMEM V software. Body weight (WT) was used as a scaling factor and the effect of brain weight (BW), sex, and pregnancy status on the pharmacokinetic parameters was investigated. The final model was evaluated by means of a non-parametric bootstrap analysis and used to predict the PEG-EPO pharmacokinetic parameters in healthy male subjects. The systemic clearance (CL) in males was estimated to be 4.08WT1.030xBW-0.345 ml/h. In females, the CL was 90.7% of the CL in males. The volumes of the central (Vc) and the peripheral (Vp) compartment were characterized as 57.8WT0.959 ml, and 48.1WT1.150 ml, respectively. Intercompartmental flow was estimated at 2.32WT0.930 ml/h. Absorption rate constant (Ka) was estimated at 0.0538WT-0.149. The absolute s.c. bioavailability F was calculated at 52.5, 80.2, and 49.4% in rat, monkey, and dog, respectively. The interindividual variability in the population pharmacokinetic parameters was fairly low (parametric bootstrap confirmed the accuracy of the NONMEM estimates. The mean model predicted pharmacokinetic parameters in healthy male subjects of 70 kg were estimated at: CL: 26.2 ml/h; Vc: 3.6l; Q: 286 l/h; Vp: 6.9l, and Ka: 0.031 h-1. The population pharmacokinetic model developed was appropriate to describe the time course of PEG-EPO serum concentrations and their variability in different species. The model predicted pharmacokinetics of PEG-EPO in

  10. Developing a novel dual PI3K–mTOR inhibitor from the prodrug of a metabolite

    Directory of Open Access Journals (Sweden)

    Zhou Y

    2017-10-01

    Full Text Available Yan Zhou,1,2 Genyan Zhang,2 Feng Wang,2 Jin Wang,2 Yanwei Ding,2 Xinyu Li,2 Chongtie Shi,2 Jiakui Li,2 Chengkon Shih,2 Song You1 1The School of Life Science and Biopharmaceutical, Shenyang Pharmaceutical University, Shenyang, 2Department of Project Management, Medicinal Chemistry, Pharmacology, Drug Metabolism, and Pharmacokinetics, Toxicology, Xuanzhu Pharma, Jinan, China Abstract: This study presents a process of developing a novel PI3K–mTOR inhibitor through the prodrug of a metabolite. The lead compound (compound 1 was identified with similar efficacy as that of NVP-BEZ235 in a tumor xenograft model, but the exposure of compound 1 was much lower than that of NVP-BEZ235. After reanalysis of the blood sample, a major metabolite (compound 2 was identified. Compound 2 exerted similar in vitro activity as compound 1, which indicated that compound 2 was an active metabolite and that the in vivo efficacy in the animal model came from compound 2 instead of compound 1. However, compound 1 was metabolized into compound 2 predominantly in the liver microsomes of mouse, but not in the liver microsomes of rat, dog, or human. In order to translate the efficacy in the animal model into clinical development or predict the pharmacokinetic/pharmacodynamic parameters in the clinical study using a preclinical model, we developed the metabolite (compound 2 instead of compound 1. Due to the low bioavailability of compound 2, its prodrug (compound 3 was designed and synthesized to improve the solubility. The prodrug was quickly converted to compound 2 through both intravenous and oral administrations. Because the prodrug (compound 3 did not improve the oral exposure of compound 2, developing compound 3 as an intravenous drug was considered by our team, and the latest results will be reported in the future. Keywords: PI3K, mTOR, NVP-BEZ235, prodrug, metabolite, antitumor

  11. Developing a Physiologically-Based Pharmacokinetic Model Knowledgebase in Support of Provisional Model Construction

    Science.gov (United States)

    Grulke, Christopher M.; Chang, Daniel T.; Brooks, Raina D.; Leonard, Jeremy A.; Phillips, Martin B.; Hypes, Ethan D.; Fair, Matthew J.; Tornero-Velez, Rogelio; Johnson, Jeffre; Dary, Curtis C.; Tan, Yu-Mei

    2016-01-01

    Developing physiologically-based pharmacokinetic (PBPK) models for chemicals can be resource-intensive, as neither chemical-specific parameters nor in vivo pharmacokinetic data are easily available for model construction. Previously developed, well-parameterized, and thoroughly-vetted models can be a great resource for the construction of models pertaining to new chemicals. A PBPK knowledgebase was compiled and developed from existing PBPK-related articles and used to develop new models. From 2,039 PBPK-related articles published between 1977 and 2013, 307 unique chemicals were identified for use as the basis of our knowledgebase. Keywords related to species, gender, developmental stages, and organs were analyzed from the articles within the PBPK knowledgebase. A correlation matrix of the 307 chemicals in the PBPK knowledgebase was calculated based on pharmacokinetic-relevant molecular descriptors. Chemicals in the PBPK knowledgebase were ranked based on their correlation toward ethylbenzene and gefitinib. Next, multiple chemicals were selected to represent exact matches, close analogues, or non-analogues of the target case study chemicals. Parameters, equations, or experimental data relevant to existing models for these chemicals and their analogues were used to construct new models, and model predictions were compared to observed values. This compiled knowledgebase provides a chemical structure-based approach for identifying PBPK models relevant to other chemical entities. Using suitable correlation metrics, we demonstrated that models of chemical analogues in the PBPK knowledgebase can guide the construction of PBPK models for other chemicals. PMID:26871706

  12. Development of a physiologically based pharmacokinetic model for bisphenol A in pregnant mice

    International Nuclear Information System (INIS)

    Kawamoto, Yuko; Matsuyama, Wakoto; Wada, Masahiro; Hishikawa, Junko; Chan, Melissa Pui Ling; Nakayama, Aki; Morisawa, Shinsuke

    2007-01-01

    Bisphenol A (BPA) is a weakly estrogenic monomer used to produce polymers for food contact and other applications, so there is potential for oral exposure of humans to trace amounts via ingestion. To date, no physiologically based pharmacokinetic (PBPK) model has been located for BPA in pregnant mice with or without fetuses. An estimate by a mathematical model is essential since information on humans is difficult to obtain experimentally. The PBPK model was constructed based on the pharmacokinetic data of our experiment following single oral administration of BPA to pregnant mice. The risk assessment of bisphenol A (BPA) on the development of human offspring is an important issue. There have been limited data on the exposure level of human fetuses to BPA (e.g. BPA concentration in cord blood) and no information is available on the pharmacokinetics of BPA in humans with or without fetuses. In the present study, we developed a physiologically based pharmacokinetic (PBPK) model describing the pharmacokinetics of BPA in a pregnant mouse with the prospect of future extrapolation to humans. The PBPK model was constructed based on the pharmacokinetic data of an experiment we executed on pregnant mice following single oral administration of BPA. The model could describe the rapid transfer of BPA through the placenta to the fetus and the slow disappearance from fetuses. The simulated time courses after three-time repeated oral administrations of BPA by the constructed model fitted well with the experimental data, and the simulation for the 10 times lower dose was also consistent with the experiment. This suggested that the PBPK model for BPA in pregnant mice was successfully verified and is highly promising for extrapolation to humans who are expected to be exposed more chronically to lower doses

  13. Improving Predictive Modeling in Pediatric Drug Development: Pharmacokinetics, Pharmacodynamics, and Mechanistic Modeling

    Energy Technology Data Exchange (ETDEWEB)

    Slikker, William; Young, John F.; Corley, Rick A.; Dorman, David C.; Conolly, Rory B.; Knudsen, Thomas; Erstad, Brian L.; Luecke, Richard H.; Faustman, Elaine M.; Timchalk, Chuck; Mattison, Donald R.

    2005-07-26

    A workshop was conducted on November 18?19, 2004, to address the issue of improving predictive models for drug delivery to developing humans. Although considerable progress has been made for adult humans, large gaps remain for predicting pharmacokinetic/pharmacodynamic (PK/PD) outcome in children because most adult models have not been tested during development. The goals of the meeting included a description of when, during development, infants/children become adultlike in handling drugs. The issue of incorporating the most recent advances into the predictive models was also addressed: both the use of imaging approaches and genomic information were considered. Disease state, as exemplified by obesity, was addressed as a modifier of drug pharmacokinetics and pharmacodynamics during development. Issues addressed in this workshop should be considered in the development of new predictive and mechanistic models of drug kinetics and dynamics in the developing human.

  14. Oral Administration of (S)-Allyl-l-Cysteine and Aged Garlic Extract to Rats: Determination of Metabolites and Their Pharmacokinetics.

    Science.gov (United States)

    Park, Taehoon; Oh, Ju-Hee; Lee, Joo Hyun; Park, Sang Cheol; Jang, Young Pyo; Lee, Young-Joo

    2017-11-01

    ( S )-Allyl-l-cysteine is the major bioactive compound in garlic. ( S )-Allyl-l-cysteine is metabolized to ( S )-allyl-l-cysteine sulfoxide, N -acetyl-( S )-allyl-l-cysteine, and N -acetyl-( S )-allyl-l-cysteine sulfoxide after oral administration. An accurate LC-MS/MS method was developed and validated for the simultaneous quantification of ( S )-allyl-l-cysteine and its metabolites in rat plasma, and the feasibility of using it in pharmacokinetic studies was tested. The analytes were quantified by multiple reaction monitoring using an atmospheric pressure ionization mass spectrometer. Because significant quantitative interference was observed between ( S )-allyl-l-cysteine and N -acetyl-( S )-allyl-l-cysteine as a result of the decomposition of N -acetyl-( S )-allyl-l-cysteine at the detector source, chromatographic separation was required to discriminate ( S )-allyl-l-cysteine and its metabolites on a reversed-phase C 18 analytical column with a gradient mobile phase consisting of 0.1% formic acid and acetonitrile. The calibration curves of ( S )-allyl-l-cysteine, ( S )-allyl-l-cysteine sulfoxide, N -acetyl-( S )-allyl-l-cysteine, and N -acetyl-( S )-allyl-l-cysteine sulfoxide were linear over each concentration range, and the lower limits of quantification were 0.1 µg/mL [( S )-allyl-l-cysteine and N -acetyl-( S )-allyl-l-cysteine] and 0.25 µg/mL [( S )-allyl-l-cysteine sulfoxide and N -acetyl-( S )-allyl-l-cysteine sulfoxide]. Acceptable intraday and inter-day precisions and accuracies were obtained at three concentration levels. The method satisfied the regulatory requirements for matrix effects, recovery, and stability. The validated LC-MS/MS method was successfully used to determine the concentration of ( S )-allyl-l-cysteine and its metabolites in rat plasma samples after the administration of ( S )-allyl-l-cysteine or aged garlic extract. Georg Thieme Verlag KG Stuttgart · New York.

  15. A Mathematical Model of the Effect of Immunogenicity on Therapeutic Protein Pharmacokinetics

    OpenAIRE

    Chen, Xiaoying; Hickling, Timothy; Kraynov, Eugenia; Kuang, Bing; Parng, Chuenlei; Vicini, Paolo

    2013-01-01

    A mathematical pharmacokinetic/anti-drug-antibody (PK/ADA) model was constructed for quantitatively assessing immunogenicity for therapeutic proteins. The model is inspired by traditional pharmacokinetic/pharmacodynamic (PK/PD) models, and is based on the observed impact of ADA on protein drug clearance. The hypothesis for this work is that altered drug PK contains information about the extent and timing of ADA generation. By fitting drug PK profiles while accounting for ADA-mediated drug cle...

  16. The pharmacokinetics and metabolism of lumiracoxib in chimeric humanized and murinized FRG mice.

    Science.gov (United States)

    Dickie, A P; Wilson, C E; Schreiter, K; Wehr, R; Wilson, E M; Bial, J; Scheer, N; Wilson, I D; Riley, R J

    2017-07-01

    The pharmacokinetics and metabolism of lumiracoxib were studied, after administration of single 10mg/kg oral doses to chimeric liver-humanized and murinized FRG mice. In the chimeric humanized mice, lumiracoxib reached peak observed concentrations in the blood of 1.10±0.08μg/mL at 0.25-0.5h post-dose with an AUC inf of 1.74±0.52μgh/mL and an effective half-life for the drug of 1.42±0.72h (n=3). In the case of the murinized animals peak observed concentrations in the blood were determined as 1.15±0.08μg/mL at 0.25h post-dose with an AUC inf of 1.94±0.22μgh/mL and an effective half-life of 1.28±0.02h (n=3). Analysis of blood indicated only the presence of unchanged lumiracoxib. Metabolic profiling of urine, bile and faecal extracts revealed a complex pattern of metabolites for both humanized and murinized animals with, in addition to unchanged parent drug, a variety of hydroxylated and conjugated metabolites detected. The profiles obtained in humanized mice were different compared to murinized animals with e.g., a higher proportion of the dose detected in the form of acyl glucuronide metabolites and much reduced amounts of taurine conjugates. Comparison of the metabolic profiles obtained from the present study with previously published data from C57bl/6J mice and humans, revealed a greater though not complete match between chimeric humanized mice and humans, such that the liver-humanized FRG model may represent a useful approach to assessing the biotransformation of such compounds in humans. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Dynamic contrast-enhanced magnetic resonance imaging and pharmacokinetic models in prostate cancer

    International Nuclear Information System (INIS)

    Franiel, Tobias; Hamm, Bernd; Hricak, Hedvig

    2011-01-01

    Dynamic contrast-enhanced MRI enables noninvasive analysis of prostate vascularization as well as tumour angiogenesis and capillary permeability characteristics in prostate cancers. Pharmacokinetic models summarizing the complex information provided by signal intensity-time curves for a few quantitative pharmacokinetic parameters are increasingly being used in the routine clinical setting. This review consists of two parts. The first part discusses the advantages and disadvantages of the MR pulse sequences that can be used for performing DCE-MRI and also of the most widely used pharmacokinetic parameters and models and the parameters they describe. The second part outlines the range of current and potential future clinical applications of DCE-MRI and pharmacokinetic parametric maps in patients with prostate cancer, with reference to the current scientific literature on the topic. The potential clinical applications of DCE-MRI for prostate cancer include detection, localization, and staging, differentiation of recurrent cancer and estimation of the patient's prognosis, as well as monitoring of treatment response. (orig.)

  18. Influence of covariate distribution on the predictive performance of pharmacokinetic models in paediatric research

    Science.gov (United States)

    Piana, Chiara; Danhof, Meindert; Della Pasqua, Oscar

    2014-01-01

    Aims The accuracy of model-based predictions often reported in paediatric research has not been thoroughly characterized. The aim of this exercise is therefore to evaluate the role of covariate distributions when a pharmacokinetic model is used for simulation purposes. Methods Plasma concentrations of a hypothetical drug were simulated in a paediatric population using a pharmacokinetic model in which body weight was correlated with clearance and volume of distribution. Two subgroups of children were then selected from the overall population according to a typical study design, in which pre-specified body weight ranges (10–15 kg and 30–40 kg) were used as inclusion criteria. The simulated data sets were then analyzed using non-linear mixed effects modelling. Model performance was assessed by comparing the accuracy of AUC predictions obtained for each subgroup, based on the model derived from the overall population and by extrapolation of the model parameters across subgroups. Results Our findings show that systemic exposure as well as pharmacokinetic parameters cannot be accurately predicted from the pharmacokinetic model obtained from a population with a different covariate range from the one explored during model building. Predictions were accurate only when a model was used for prediction in a subgroup of the initial population. Conclusions In contrast to current practice, the use of pharmacokinetic modelling in children should be limited to interpolations within the range of values observed during model building. Furthermore, the covariate point estimate must be kept in the model even when predictions refer to a subset different from the original population. PMID:24433411

  19. Assessment of chimeric mice with humanized livers in new drug development: generation of pharmacokinetics, metabolism and toxicity data for selecting the final candidate compound.

    Science.gov (United States)

    Kamimura, Hidetaka; Ito, Satoshi

    2016-01-01

    1. Chimeric mice with humanized livers are expected to be a novel tool for new drug development. This review discusses four applications where these animals can be used efficiently to collect supportive data for selecting the best compound in the final stage of drug discovery. 2. The first application is selection of the final compound based on estimated pharmacokinetic parameters in humans. Since chimeric mouse livers are highly repopulated with human hepatocytes, hepatic clearance values in vivo could be used preferentially to estimate pharmacokinetic profiles for humans. 3. The second is prediction of human-specific or disproportionate metabolites. Chimeric mice reproduce human-specific metabolites of drugs under development to conform to ICH guidance M3(R2), except for compounds that were extensively eliminated by co-existing mouse hepatocytes. 4. The third is identifying metabolites with distinct pharmacokinetic profiles in humans. Slow metabolite elimination specifically in humans increases its exposure level, but if its elimination is faster in laboratory animals, the animal exposure level might not satisfy ICH guidance M3(R2). 5. Finally, two examples of reproducing acute liver toxicity in chimeric mice are introduced. Integrated pharmacokinetics, metabolism and toxicity information are expected to assist pharmaceutical scientists in selecting the best candidate compound in new drug development.

  20. Effect of correlation on covariate selection in linear and nonlinear mixed effect models.

    Science.gov (United States)

    Bonate, Peter L

    2017-01-01

    The effect of correlation among covariates on covariate selection was examined with linear and nonlinear mixed effect models. Demographic covariates were extracted from the National Health and Nutrition Examination Survey III database. Concentration-time profiles were Monte Carlo simulated where only one covariate affected apparent oral clearance (CL/F). A series of univariate covariate population pharmacokinetic models was fit to the data and compared with the reduced model without covariate. The "best" covariate was identified using either the likelihood ratio test statistic or AIC. Weight and body surface area (calculated using Gehan and George equation, 1970) were highly correlated (r = 0.98). Body surface area was often selected as a better covariate than weight, sometimes as high as 1 in 5 times, when weight was the covariate used in the data generating mechanism. In a second simulation, parent drug concentration and three metabolites were simulated from a thorough QT study and used as covariates in a series of univariate linear mixed effects models of ddQTc interval prolongation. The covariate with the largest significant LRT statistic was deemed the "best" predictor. When the metabolite was formation-rate limited and only parent concentrations affected ddQTc intervals the metabolite was chosen as a better predictor as often as 1 in 5 times depending on the slope of the relationship between parent concentrations and ddQTc intervals. A correlated covariate can be chosen as being a better predictor than another covariate in a linear or nonlinear population analysis by sheer correlation These results explain why for the same drug different covariates may be identified in different analyses. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  1. Pharmacokinetic-Pharmacodynamic modeling of enrofloxacin against Escherichia coli in broilers

    Directory of Open Access Journals (Sweden)

    Sang eKana

    2016-01-01

    Full Text Available The purpose of the present study was to establish a pharmacokinetic/pharmacodynamic (PK/PD modeling approach for the dosage schedule design and decreasing the emergence of drug-resistant bacteria. The minimal inhibitory concentration (MIC of 929 E. coli isolates from broilers to enrofloxacin and ciprofloxacin were determined following CLSI guidance. The MIC50 was calculated as the populational PD parameter for enrofloxacin against E. coli in broilers. The 101 E. coli strains with MIC closest to the MIC50 (0.05µg/mL were submitted for serotype identification. The 13 E. coli strains with O and K serotype were further utilitzed for determining pathogencity in mice. Of all the strains tested, the E. coli designated strain Anhui 112 was selected for establishing the disease model and PK/PD study. The pharmacokinetics (PKs of enrofloxacin after oral administration at the dose of 10mg/kg body weights (BW in healthy and infected broilers was evaluated with high-performance liquid chromatography (HPLC method. For intestinal contents after oral administration, the peak concentration (Cmax, the time when the maximum concentration reached (Tmax, and the area under the concentration-time curve (AUC were 21.69~31.69μg/mL, 1.13~1.23h, and 228.97~444.86μg.hr/mL, respectively. The MIC and minimal bactericidal concentration (MBC of enrofloxacin against E. coli (Anhui 112 in Mueller-Hinton (MH broth and intestinal contents were determined to be similar, 0.25μg/mL and 0.5μg/mL respectively. In this study, the sum of concentrations of enrofloxacin and its metabolite (ciprofloxacin was used for the PK/PD integration and modeling. The ex vivo growth inhibition data were fitted to the sigmoid Emax (Hill equation to provide values for intestinal contents of 24h area under concentration–time curve/MIC ratios (AUC0~24h/MIC producing, bacteriostasis (624.94h, bactericidal activity (1065.93h and bacterial eradication (1343.81h. PK/PD modeling was established to

  2. Endogenous metabolites that are substrates of organic anion transporter's (OATs) predict methotrexate clearance.

    Science.gov (United States)

    Muhrez, Kienana; Benz-de Bretagne, Isabelle; Nadal-Desbarats, Lydie; Blasco, Hélène; Gyan, Emmanuel; Choquet, Sylvain; Montigny, Frédéric; Emond, Patrick; Barin-Le Guellec, Chantal

    2017-04-01

    Variable pharmacokinetics of high-dose-methotrexate (MTX) is responsible for severe toxicities. Unpredictable overexposure still occurs during some courses despite having controlled the main factors known to play a role in its elimination. The aim of our study was to evaluate whether the urine metabolomic profile measured at the time of MTX administration is predictive of the drug's clearance and/or of treatment-related toxicity. We analyzed the urine content of endogenous metabolites before MTX administration in a cohort of adult patients treated for lymphoid malignancies. Individual MTX clearance (MTX CL ) was estimated from population pharmacokinetic analyses of therapeutic drug monitoring data. We determined the urine metabolite content by gas chromatography-mass spectrometry (GC-MS) and applied Partial Least Square (PLS) analysis to assess the relationship between the urine metabolome and MTX CL . External validation was applied to evaluate the performances of the PLS model. We used orthogonal partial least squares discriminant analysis (OPLS-DA) to distinguish patients with normal or delayed elimination, and patients with or without toxicity. Sixty-two patients were studied. We obtained a very good prediction of individual MTX clearance using a set of 28 metabolites present in patient urine at baseline. The mean prediction error and precision were -0.36% and 21.4%, respectively, for patients not included in the model. The model included a set of endogenous organic anions, of which the tubular secretion depends on organic anion transporter (OAT) function. Our analyses did not allow us to discriminate between patients with or without delayed elimination or those who did or did not experience toxicity. Urinary metabolomics can be informative about an individual's ability to clear MTX. More broadly, it paves the way for the development of a biomarker of tubular secretion, easily measurable from endogenous substances. Copyright © 2016 Elsevier Ltd. All rights

  3. Biphasic Elimination of Tenofovir Diphosphate and Nonlinear Pharmacokinetics of Zidovudine Triphosphate in a Microdosing Study

    Science.gov (United States)

    Chen, Jianmeng; Flexner, Charles; Liberman, Rosa G.; Skipper, Paul L.; Louissaint, Nicolette; Tannenbaum, Steven R.; Hendrix, Craig; Fuchs, Edward

    2012-01-01

    Objective Phase 0 studies can provide initial pharmacokinetics (PK) data in humans and help to facilitate early drug development, but their predictive value for standard dosing is controversial. To evaluate the prediction of microdosing for active intracellular drug metabolites, we compared the PK profile of two antiretroviral drugs, zidovudine (ZDV) and tenofovir (TFV), in microdose and standard dosing regimens. Study Design We administered a microdose (100 μg) of 14C-labeled drug (ZDV or tenofovir disoproxil fumarate (TDF)) with or without a standard unlabelled dose (300 mg) to healthy volunteers. Both the parent drug in plasma and the active metabolite, ZDV-triphosphate (ZDV-TP) or TFV-diphosphate (TFV-DP) in PBMCs and CD4+ cells were measured by AMS. Results The intracellular ZDV-TP concentration increased less than proportionally over the dose range studied (100 μg to 300 mg), while the intracellular TFV-DP PK were linear over the same dose range. ZDV-TP concentrations were lower in CD4+ cells versus total peripheral blood mononuclear cells (PBMCs), while TFV-DP concentrations were not different in CD4+ cells and PBMCs. Conclusion Our data were consistent with a rate-limiting step in the intracellular phosphorylation of ZDV but not TFV. AMS shows promise for predicting the PK of active intracellular metabolites of nucleosides, but nonlinearity of PK may be seen with some drugs. PMID:23187888

  4. Nonstandard Finite Difference Method Applied to a Linear Pharmacokinetics Model

    Directory of Open Access Journals (Sweden)

    Oluwaseun Egbelowo

    2017-05-01

    Full Text Available We extend the nonstandard finite difference method of solution to the study of pharmacokinetic–pharmacodynamic models. Pharmacokinetic (PK models are commonly used to predict drug concentrations that drive controlled intravenous (I.V. transfers (or infusion and oral transfers while pharmacokinetic and pharmacodynamic (PD interaction models are used to provide predictions of drug concentrations affecting the response of these clinical drugs. We structure a nonstandard finite difference (NSFD scheme for the relevant system of equations which models this pharamcokinetic process. We compare the results obtained to standard methods. The scheme is dynamically consistent and reliable in replicating complex dynamic properties of the relevant continuous models for varying step sizes. This study provides assistance in understanding the long-term behavior of the drug in the system, and validation of the efficiency of the nonstandard finite difference scheme as the method of choice.

  5. Modeling in biopharmaceutics, pharmacokinetics, and pharmacodynamics homogeneous and heterogeneous approaches

    CERN Document Server

    Macheras, Panos

    2006-01-01

    The state of the art in Biopharmaceutics, Pharmacokinetics, and Pharmacodynamics Modeling is presented in this book. It shows how advanced physical and mathematical methods can expand classical models in order to cover heterogeneous drug-biological processes and therapeutic effects in the body. The book is divided into four parts; the first deals with the fundamental principles of fractals, diffusion and nonlinear dynamics; the second with drug dissolution, release, and absorption; the third with empirical, compartmental, and stochastic pharmacokinetic models, and the fourth mainly with nonclassical aspects of pharmacodynamics. The classical models that have relevance and application to these sciences are also considered throughout. Many examples are used to illustrate the intrinsic complexity of drug administration related phenomena in the human, justifying the use of advanced modeling methods. This timely and useful book will appeal to graduate students and researchers in pharmacology, pharmaceutical scienc...

  6. Assessing human variability in kinetics for exposures to multiple environmental chemicals: a physiologically based pharmacokinetic modeling case study with dichloromethane, benzene, toluene, ethylbenzene, and m-xylene.

    Science.gov (United States)

    Valcke, Mathieu; Haddad, Sami

    2015-01-01

    The objective of this study was to compare the magnitude of interindividual variability in internal dose for inhalation exposure to single versus multiple chemicals. Physiologically based pharmacokinetic models for adults (AD), neonates (NEO), toddlers (TODD), and pregnant women (PW) were used to simulate inhalation exposure to "low" (RfC-like) or "high" (AEGL-like) air concentrations of benzene (Bz) or dichloromethane (DCM), along with various levels of toluene alone or toluene with ethylbenzene and xylene. Monte Carlo simulations were performed and distributions of relevant internal dose metrics of either Bz or DCM were computed. Area under the blood concentration of parent compound versus time curve (AUC)-based variability in AD, TODD, and PW rose for Bz when concomitant "low" exposure to mixtures of increasing complexities occurred (coefficient of variation (CV) = 16-24%, vs. 12-15% for Bz alone), but remained unchanged considering DCM. Conversely, AUC-based CV in NEO fell (15 to 5% for Bz; 12 to 6% for DCM). Comparable trends were observed considering production of metabolites (AMET), except for NEO's CYP2E1-mediated metabolites of Bz, where an increased CV was observed (20 to 71%). For "high" exposure scenarios, Cmax-based variability of Bz and DCM remained unchanged in AD and PW, but decreased in NEO (CV= 11-16% to 2-6%) and TODD (CV= 12-13% to 7-9%). Conversely, AMET-based variability for both substrates rose in every subpopulation. This study analyzed for the first time the impact of multiple exposures on interindividual variability in toxicokinetics. Evidence indicates that this impact depends upon chemical concentrations and biochemical properties, as well as the subpopulation and internal dose metrics considered.

  7. A novel LC-MS/MS assay for the simultaneous determination of melatonin and its two major metabolites, 6-hydroxymelatonin and 6-sulfatoxymelatonin in dog plasma: Application to a pharmacokinetic study.

    Science.gov (United States)

    Zhao, Huimin; Wang, Yifei; Yuan, Bo; Liu, Shu; Man, Shuang; Xu, Haiyan; Lu, Xiumei

    2016-01-05

    A convenient and specific liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous quantification of melatonin (MEL) and its major metabolites, 6-hydroxymelatonin (6-O-MEL) and 6-sulfatoxymelationin (S-O-MEL) in dog plasma. After plasma samples were deproteinized with acetonitrile, the post-treatment samples were analyzed on a Phenomenex Kinetex C18 column (50×2.1 mm, 1.7 μm) interfaced with a triple quadrupole tandem mass spectrometer. Electrospray ionization mode (ESI) and multiple reaction monitoring were used to assay MEL and its metabolites. Acetonitrile and 5 mM ammonium acetate were used as the mobile phase with a gradient elution at a flow rate of 0.2 mL/min. The analytical run time of 6.5 min was divided into two periods according to ionization mode. S-O-MEL was monitored in negative ionization mode (period 1), while MEL and 6-O-MEL were detected in positive ionization mode (period 2). All calibration curves showed good linearity (r>0.991) over the concentration range with a lower limit of quantification (LLOQ) of 0.02 ng/mL for MEL, 0.04 ng/mL for 6-O-MEL and 0.50 ng/mL for S-O-MEL. The intra- and inter-day precision was within 13.5% in terms of relative standard deviation (RSD%) and the accuracy within 13.0% in terms of relative error. This convenient and specific LC-MS/MS method was successfully applied to the pharmacokinetic study of MEL and its metabolites in Beagle dogs after an oral dose of 2.0mg MEL. After ingestion of MEL, S-O-MEL was the predominant component circulating in blood. 6-O-MEL showed similar pharmacokinetic profile to that of MEL. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. Pharmacokinetics of methyl salicylate-2-O-β-D-lactoside, a novel salicylic acid analog isolated from Gaultheria yunnanensis, in dogs.

    Science.gov (United States)

    Zhang, Dan; Ma, Xiaowei; Xin, Wenyu; Huang, Chao; Zhang, Weiku; Zhang, Tiantai; Du, Guanhua

    2013-12-01

    Methyl salicylate-2-O-β-D-lactoside (MSL), a natural salicylate derivative of Gaultheria yunnanensis (Franch.) Rehder (G. yunnanensis), has been shown to provide a beneficial anti-inflammatory effect in animal models. Studies on the pharmacokinetics and bioavailability of MSL can provide both a substantial foundation for understanding its mechanism and empirical evidence to support its use in clinical practice. A simple and sensitive high-performance liquid chromatography (HPLC) method, coupled with ultraviolet analyte detection, was developed for determining the concentration of MSL and its metabolite in beagle plasma. Chromatographic separation was achieved on a Agilent Zorbax SB-C18 column (5 μM,4.6 × 250 mm). The mobile phase consisted of aqueous solution containing 0.1% phosphoric acid and acetonitrile (82:90, v/v), at a flow rate of 1 mL/min. Validation of the assay demonstrated that the developed HPLC method was sensitive, accurate and selective for the determination of MSL and its metabolite in dog plasma. After orally administering three doses of MSL, it could no longer be detected in dog plasma and its metabolite, salicylic acid, was detected. Salicylic acid showed a single peak in the plasma concentration-time curves and linear pharmacokinetics following the three oral doses (r(2) > 0.99). In contrast, only MSL was detected in plasma following intravenous administration. These results will aid in understanding the pharmacological significance of MSL. The developed method was successfully used for evaluation of the oral and intravenous pharmacokinetic profile of MSL in dogs. Copyright © 2013 John Wiley & Sons, Ltd.

  9. Chromatographic separation of piracetam and its metabolite in a mixture of microsomal preparations, followed by an MS/MS analysis.

    Science.gov (United States)

    Sahu, Kapendra; Siddiqui, Anees A; Shaharyar, Mohammad; Ahmad, Niyaz; Anwar, Mohammad; Ahmad, Farhan J

    2013-07-01

    A rapid bioanalytical method was evaluated for the simultaneous determination of piracetam and its metabolite (M1) in human microsomal preparations by fast ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS). In addition, a validated method of M1 in rat plasma was developed and successfully applied on pharmacokinetic studies. The present study was carried out to determine the metabolic pathways of piracetam for phase I metabolism and used cytochrome P450 isoforms responsible for the piracetam metabolism in human liver microsomes (HLMs). While additional potential metabolites of piracetam were suggested by computer-modeling. The resulting 2-(2-oxopyrrolidin-1-yl) acetic acid was the sole metabolite detected after the microsomal treatment. The amide hydrolysis mainly underwent to form a metabolite i.e., 2-(2-oxopyrrolidin-1-yl) acetic acid (M1). Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  10. A metabolic and pharmacokinetic comparison of theophylline and aminophylline (theophylline ethylenediamine).

    Science.gov (United States)

    Monks, T J; Smith, R L; Caldwell, J

    1981-02-01

    The metabolism and pharmacokinetics of intravenously administered theophylline and aminophylline (theophylline ethylenediamine) have been studied in 3 volunteers, using 14C-labelled theophylline. Both compounds were metabolized extensively and 1,3-dimethyluric acid, 1-methyluric acid, 3-methylxanthine and two unknown minor metabolites were excreted in the urine, in addition to theophylline. The elimination of theophylline, 1,3-dimethyluric acid, 1-methyluric acid and the unknown metabolites followed first-order kinetics, but that of 3-methylxanthine followed Michaelis-Menten kinetics. When given as aminophylline, theophylline was metabolized more rapidly and extensively than when given alone. The recovery of 14C in the urine was significantly higher after aminophylline than after theophylline. Abstention from intake of dietary methylxanthines for 7 days resulted in more rapid and extensive metabolism of aminophylline compared with results from the same subjects on their usual diets. The results indicate that, from a metabolic and pharmacokinetic viewpoint, aminophylline and theophylline are not equivalent.

  11. PK/DB: database for pharmacokinetic properties and predictive in silico ADME models.

    Science.gov (United States)

    Moda, Tiago L; Torres, Leonardo G; Carrara, Alexandre E; Andricopulo, Adriano D

    2008-10-01

    The study of pharmacokinetic properties (PK) is of great importance in drug discovery and development. In the present work, PK/DB (a new freely available database for PK) was designed with the aim of creating robust databases for pharmacokinetic studies and in silico absorption, distribution, metabolism and excretion (ADME) prediction. Comprehensive, web-based and easy to access, PK/DB manages 1203 compounds which represent 2973 pharmacokinetic measurements, including five models for in silico ADME prediction (human intestinal absorption, human oral bioavailability, plasma protein binding, blood-brain barrier and water solubility). http://www.pkdb.ifsc.usp.br

  12. Unique and common metabolites of thiamethoxam, clothianidin, and dinotefuran in mice.

    Science.gov (United States)

    Ford, Kevin A; Casida, John E

    2006-11-01

    The established neonicotinoid insecticides have chloropyridylmethyl (imidacloprid, thiacloprid, acetamiprid, and nitenpyram), chlorothiazolylmethyl (thiamethoxam or TMX and clothianidin or CLO) or tetrahydrofuranylmethyl (dinotefuran or DIN) substituents. We recently reported the metabolic fate of the chloropyridylmethyl neonicotinoids in mice as the first half of a comparative study that now considers the chlorothiazolylmethyl and tetrahydrofuranylmethyl analogues. TMX, CLO, two desmethyl derivatives (TMX-dm and CLO-dm), and DIN were administered ip to mice at 20 mg/kg for characterization of metabolites and pharmacokinetic analysis of brain, liver, plasma, and urine by HPLC/DAD and LC/MSD. Each compound is excreted 19-55% unmetabolized in urine within 24 h, and tissue residues are largely dissipated by 4 h. Thirty-seven metabolites of TMX, TMX-dm, CLO, and CLO-dm are identified by comparison with synthetic standards or their structures are proposed by molecular weights and 35Cl:37Cl ratios often supplemented by previous reports or sequence studies in which intermediates are readministered. A facile reaction sequence involves TMX --> TMX-dm or CLO --> CLO-dm. CLO-dm, reported to be a contributor to TMX hepatocarcinogenesis in mice, is unexpectedly remethylated in part to CLO in brain. The nitrosoguanidine, aminoguanidine, and urea derivatives of the parent compounds are detected in the tissues and methylnitroguanidine, methylguanidine, and nitroguanidine in the urine. Chlorothiazolecarboxaldehyde from oxidative cleavage of TMX and CLO is quite persistent in brain, liver, and particularly plasma compared with chloropyridinecarboxaldehyde and tetrahydrofurancarboxaldehyde from the other neonicotinoids. Chlorothiazolecarboxylic acid is conjugated with glycine or glucuronic acid or converted to S-methyl and mercapturate derivatives. DIN metabolism involves nitro reduction, N-demethylation, N-methylene hydroxylation, and amine cleavage, and tetrahydrofuranylmethyl

  13. Pharmacokinetic models relevant to toxicity and metabolism for uranium in humans and animals

    International Nuclear Information System (INIS)

    Wrenn, M.E.

    1989-01-01

    Models to predict short and long term accumulation of uranium in the human kidney are reviewed and summarised. These are generally first order linear compartmental models or pseudo-pharmacokinetic models such as the retention model of the ICRP. Pharmacokinetic models account not only for transfer from blood to organs, but also recirculation from the organ to blood. The most recent information on mammalian and human metabolism of uranium is used to establish a revised model. The model is applied to the short term accumulation of uranium in the human kidney after a single rapid dosage to the blood, such as that obtained by inhaling UF6 or its hydrolysis products. It is shown that the maximum accumulation in the kidney under these conditions is less than the fraction of the material distributed from the blood to kidney if a true pharmacokinetic model is used. The best coefficients applicable to man in the authors' view are summarised in model V. For a half-time of two days in the mammalian kidney, the maximum concentration in kidney is 75% of that predicted by a retention model such as that used by the ICRP following a single acute intake. We conclude that one must use true pharmacokinetic models, which incorporate recirculation from the organs to the blood, in order to realistically predict time dependent uptake in the kidneys and other organs. Information is presented showing that the half-time for urinary excretion of soluble uranium in man after inhalation of UF6 is about one quarter of a day. (author)

  14. Design of optimized hypoxia-activated prodrugs using pharmacokinetic/pharmacodynamic modeling

    Directory of Open Access Journals (Sweden)

    Annika Bettina Foehrenbacher

    2013-12-01

    Full Text Available Hypoxia contributes to resistance of tumors to some cytotoxic drugs and to radiotherapy, but can in principle be exploited with hypoxia-activated prodrugs (HAP. HAP in clinical development fall into two broad groups. Class I HAP (like the benzotriazine N-oxides tirapazamine and SN30000, are activated under relatively mild hypoxia. In contrast, Class II HAP (such as the nitro compounds PR-104A or TH-302 are maximally activated only under extreme hypoxia, but their active metabolites (effectors diffuse to cells at intermediate O2 and thus also eliminate moderately hypoxic cells. Here, we use a spatially resolved pharmacokinetic/pharmacodynamic (SR-PK/PD model to compare these two strategies and to identify the features required in an optimal Class II HAP. The model uses a Green’s function approach to calculate spatial and longitudinal gradients of O2, prodrug and effector concentrations, and resulting killing in a digitized 3D tumor microregion to estimate activity as monotherapy and in combination with radiotherapy. An analogous model for a normal tissue with mild hypoxia and short intervesssel distances (based on a cremaster muscle microvessel network was used to estimate tumor selectivity of cell killing. This showed that Class II HAP offer advantages over Class I including higher tumor selectivity and greater freedom to vary prodrug diffusibility and rate of metabolic activation. The model suggests that the largest gains in class II HAP antitumor activity could be realized by optimizing effector stability and prodrug activation rates. We also use the model to show that diffusion of effector into blood vessels is unlikely to materially increase systemic exposure for realistic tumor burdens and effector clearances. However, we show that the tumor selectivity achievable by hypoxia-dependent prodrug activation alone is limited if dose-limiting normal tissues are even mildly hypoxic

  15. Evaluation of the Effects of Ketoconazole and Voriconazole on the Pharmacokinetics of Oxcarbazepine and Its Main Metabolite MHD in Rats by UPLC-MS-MS.

    Science.gov (United States)

    Chen, Xinxin; Gu, Ermin; Wang, Shuanghu; Zheng, Xiang; Chen, Mengchun; Wang, Li; Hu, Guoxin; Cai, Jian-ping; Zhou, Hongyu

    2016-03-01

    Oxcarbazepine (OXC), a second-generation antiepileptic drug, undergoes rapid reduction with formation of the active metabolite 10,11-dihydro-10-hydroxy-carbazepine (MHD) in vivo. In this study, a method for simultaneous determination of OXC and MHD in rat plasma using ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-MS-MS) was developed and validated. Under given chromatographic conditions, OXC, MHD and internal standard diazepam were separated well and quantified by electrospray positive ionization mass spectrometry in the multiple reaction monitoring transitions mode. The method validation demonstrated good linearity over the range of 10-2,000 ng/mL for OXC and 5-1,000 ng/mL for MHD. The lower limit of quantification was 5 ng/mL for OXC and 2.5 ng/mL for MHD, respectively. The method was successfully applied to the evaluation of the pharmacokinetics of OXC and MHD in rats, with or without pretreatment by ketoconazole (KET) and voriconazole (VOR). Statistics indicated that KET and VOR significantly affected the disposition of OXC and MHD in vivo, whereas VOR predominantly interfered with the disposition of MHD. This method is suitable for pharmacokinetic study in small animals. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  16. What matters most - what parents model or what parents eat?

    Science.gov (United States)

    Vaughn, Amber E; Martin, Chantel L; Ward, Dianne S

    2018-03-28

    Parents have a strong influence on their children's eating habits; however, researchers struggle to identify which food parenting practices to recommend. This study examined the influence of parents modeling of healthy eating ("parent role modeling") and parents' actual food intake ("parent dietary intake") on child diet quality, and explored whether these practices work together to influence children's diets. Baseline data from a larger intervention trial were used for this analysis. The sample included parents of preschool-age children from households with at least one overweight parent. The Comprehensive Feeding Practices Questionnaire was used to assess parent modeling of healthy eating ("healthy modeling"). Three days of dietary recalls were used to collect parents' report of their own intake and their children's intake (excluding food at child care). Associations between parent healthy modeling and parent intake of healthy and unhealthy foods were explored using Pearson correlations. Associations between parent healthy modeling and parent Healthy Eating Index (HEI) score on child HEI score were examined with linear regression. Additionally, the interaction between parent healthy modeling and HEI score on child HEI score was tested. Parent healthy modeling was significantly correlated with parent intake of healthy foodsLinear regression showed a significant association between parent modeling and child HEI score, even after controlling for parent diet (β = 3.08, SE = 0.87, p parents had high parent healthy modeling scores had higher HEI scores (mean = 61.5 ± 10.4) regardless of parent HEI score. We did not find evidence that parent healthy modeling and diet quality interact to influence child diet quality. Parents' healthy modeling is an important practice in influencing children's diet quality, possibly more so than the quality of parents' diets. Copyright © 2018. Published by Elsevier Ltd.

  17. Towards Controlling the Glycoform: A Model Framework Linking Extracellular Metabolites to Antibody Glycosylation

    Directory of Open Access Journals (Sweden)

    Philip M. Jedrzejewski

    2014-03-01

    Full Text Available Glycoproteins represent the largest group of the growing number of biologically-derived medicines. The associated glycan structures and their distribution are known to have a large impact on pharmacokinetics. A modelling framework was developed to provide a link from the extracellular environment and its effect on intracellular metabolites to the distribution of glycans on the constant region of an antibody product. The main focus of this work is the mechanistic in silico reconstruction of the nucleotide sugar donor (NSD metabolic network by means of 34 species mass balances and the saturation kinetics rates of the 60 metabolic reactions involved. NSDs are the co-substrates of the glycosylation process in the Golgi apparatus and their simulated dynamic intracellular concentration profiles were linked to an existing model describing the distribution of N-linked glycan structures of the antibody constant region. The modelling framework also describes the growth dynamics of the cell population by means of modified Monod kinetics. Simulation results match well to experimental data from a murine hybridoma cell line. The result is a modelling platform which is able to describe the product glycoform based on extracellular conditions. It represents a first step towards the in silico prediction of the glycoform of a biotherapeutic and provides a platform for the optimisation of bioprocess conditions with respect to product quality.

  18. Trophic transfer of pyrene metabolites between aquatic invertebrates

    International Nuclear Information System (INIS)

    Carrasco Navarro, V.; Leppänen, M.T.; Kukkonen, J.V.K.; Godoy Olmos, S.

    2013-01-01

    The trophic transfer of pyrene metabolites was studied using Gammarus setosus as a predator and the invertebrates Lumbriculus variegatus and Chironomus riparius as prey. The results obtained by liquid scintillation counting confirmed that the pyrene metabolites produced by the aquatic invertebrates L. variegatus and C. riparius were transferred to G. setosus through the diet. More detailed analyses by liquid chromatography discovered that two of the metabolites produced by C. riparius appeared in the chromatograms of G. setosus tissue extracts, proving their trophic transfer. These metabolites were not present in chromatograms of G. setosus exclusively exposed to pyrene. The present study supports the trophic transfer of PAH metabolites between benthic macroinvertebrates and common species of an arctic amphipod. As some PAH metabolites are more toxic than the parent compounds, the present study raises concerns about the consequences of their trophic transfer and the fate and effects of PAHs in natural environments. - Highlights: ► The trophic transfer of pyrene metabolites between invertebrates was evaluated. ► Biotransformation of pyrene by L. variegatus and C. riparius is different. ► Metabolites produced by L. variegatus and C. riparius are transferred to G. setosus. ► Specifically, two metabolites produced by C. riparius were transferred. - Some of the pyrene metabolites produced by the model invertebrates L. variegatus and C. riparius are transferred to G. setosus through the diet, proving their trophic transfer.

  19. Pharmacokinetics for regulatory risk analysis: the case of trichloroethylene.

    Science.gov (United States)

    Bogen, K T

    1988-12-01

    Physiologically based pharmacokinetic (PBPK) models describing the uptake, metabolism, and excretion of volatile organic compounds (VOCs) are now proposed for use in regulatory health-risk assessment. A steady-state analysis of one such model is shown to provide simple, convenient predicted relationships between an applied dose and the corresponding toxicologically effective, metabolized dose for certain VOCs like trichloroethylene (TCE). A version of this PBPK model was fit to data on human metabolism of TCE to urinary metabolites in chronically exposed workers, yielding a direct estimate of PBPK parameters governing human capacity to metabolize TCE. It is shown that this estimate is consistent with others based on experimental studies of TCE metabolism in humans exposed to TCE by inhalation for short periods. These results are applied to human cancer-risk assessment using rodent bioassay data on TCE-induced tumorigenesis.

  20. Bioavailability and pharmacokinetic profile of grape pomace phenolic compounds in humans.

    Science.gov (United States)

    Castello, Fabio; Costabile, Giuseppina; Bresciani, Letizia; Tassotti, Michele; Naviglio, Daniele; Luongo, Delia; Ciciola, Paola; Vitale, Marilena; Vetrani, Claudia; Galaverna, Gianni; Brighenti, Furio; Giacco, Rosalba; Del Rio, Daniele; Mena, Pedro

    2018-05-15

    Grape pomace, the major byproduct of the wine and juice industry, is a relevant source of bioactive phenolic compounds. However, polyphenol bioavailability in humans is not well understood, and the inter-individual variability in the production of phenolic metabolites has not been comprehensively assessed to date. The pharmacokinetic and excretive profiles of phenolic metabolites after the acute administration of a drink made from red grape pomace was here investigated in ten volunteers. A total of 35 and 28 phenolic metabolites were quantified in urine and plasma, respectively. The main circulating metabolites included phenyl-γ-valerolactones, hydroxybenzoic acids, simple phenols, hydroxyphenylpropionic acids, hydroxycinnamates, and (epi)catechin phase II conjugates. A high inter-individual variability was shown both in urine and plasma samples, and different patterns of circulating metabolites were unravelled by applying unsupervised multivariate analysis. Besides the huge variability in the production of microbial metabolites of colonic origin, an important variability was observed due to phase II conjugates. These results are of interest to further understand the potential health benefits of phenolic metabolites on individual basis. Copyright © 2018 Elsevier Inc. All rights reserved.

  1. Prediction of the Pharmacokinetics, Pharmacodynamics, and Efficacy of a Monoclonal Antibody, Using a Physiologically Based Pharmacokinetic FcRn Model

    Science.gov (United States)

    Chetty, Manoranjenni; Li, Linzhong; Rose, Rachel; Machavaram, Krishna; Jamei, Masoud; Rostami-Hodjegan, Amin; Gardner, Iain

    2015-01-01

    Although advantages of physiologically based pharmacokinetic models (PBPK) are now well established, PBPK models that are linked to pharmacodynamic (PD) models to predict pharmacokinetics (PK), PD, and efficacy of monoclonal antibodies (mAbs) in humans are uncommon. The aim of this study was to develop a PD model that could be linked to a physiologically based mechanistic FcRn model to predict PK, PD, and efficacy of efalizumab. The mechanistic FcRn model for mAbs with target-mediated drug disposition within the Simcyp population-based simulator was used to simulate the pharmacokinetic profiles for three different single doses and two multiple doses of efalizumab administered to virtual Caucasian healthy volunteers. The elimination of efalizumab was modeled with both a target-mediated component (specific) and catabolism in the endosome (non-specific). This model accounted for the binding between neonatal Fc receptor (FcRn) and efalizumab (protective against elimination) and for changes in CD11a target concentration. An integrated response model was then developed to predict the changes in mean Psoriasis Area and Severity Index (PASI) scores that were measured in a clinical study as an efficacy marker for efalizumab treatment. PASI scores were approximated as continuous and following a first-order asymptotic progression model. The reported steady state asymptote (Y ss) and baseline score [Y (0)] was applied and parameter estimation was used to determine the half-life of progression (Tp) of psoriasis. Results suggested that simulations using this model were able to recover the changes in PASI scores (indicating efficacy) observed during clinical studies. Simulations of both single dose and multiple doses of efalizumab concentration-time profiles as well as suppression of CD11a concentrations recovered clinical data reasonably well. It can be concluded that the developed PBPK FcRn model linked to a PD model adequately predicted PK, PD, and efficacy of efalizumab. PMID

  2. Computational Analysis of Pharmacokinetic Behavior of Ampicillin

    Directory of Open Access Journals (Sweden)

    Mária Ďurišová

    2016-07-01

    Full Text Available orrespondence: Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, 841 04 Bratislava, Slovak Republic. Phone + 42-1254775928; Fax +421254775928; E-mail: maria.durisova@savba.sk 84 RESEARCH ARTICLE The objective of this study was to perform a computational analysis of the pharmacokinetic behavior of ampicillin, using data from the literature. A method based on the theory of dynamic systems was used for modeling purposes. The method used has been introduced to pharmacokinetics with the aim to contribute to the knowledge base in pharmacokinetics by including the modeling method which enables researchers to develop mathematical models of various pharmacokinetic processes in an identical way, using identical model structures. A few examples of a successful use of the modeling method considered here in pharmacokinetics can be found in full texts articles available free of charge at the website of the author, and in the example given in the this study. The modeling method employed in this study can be used to develop a mathematical model of the pharmacokinetic behavior of any drug, under the condition that the pharmacokinetic behavior of the drug under study can be at least partially approximated using linear models.

  3. Investigation of a Potential Pharmacokinetic Interaction Between Nebivolol and Fluvoxamine in Healthy Volunteers.

    Science.gov (United States)

    Gheldiu, Ana-Maria; Vlase, Laurian; Popa, Adina; Briciu, Corina; Muntean, Dana; Bocsan, Corina; Buzoianu, Anca; Achim, Marcela; Tomuta, Ioan; Todor, Ioana; Neag, Maria

    2017-01-01

    To investigate whether fluvoxamine coadministration can influence the pharmacokinetic properties of nebivolol and its active hydroxylated metabolite (4-OH-nebivolol) and to assess the consequences of this potential pharmacokinetic interaction upon nebivolol pharmacodynamics. This open-label, non-randomized, sequential clinical trial consisted of two periods: Period 1 (Reference), during which each volunteer received a single dose of 5 mg nebivolol and Period 2 (Test), when a combination of 5 mg nebivolol and 100 mg fluvoxamine was given to all subjects, after a 6-days pretreatment regimen with fluvoxamine (50-100 mg/day). Non-compartmental analysis was used to determine the pharmacokinetic parameters of nebivolol and its active metabolite. The pharmacodynamic parameters (blood pressure and heart rate) were assessed at rest after each nebivolol intake, during both study periods. Fluvoxamine pretreatment increased Cmax and AUC0-∞  of nebivolol (Cmax: 1.67 ± 0.690  vs 2.20 ± 0.970  ng/mL; AUC0-∞: 12.1 ± 11.0  vs 19.3 ± 19.5  ng*h/mL ) and of its active metabolite (Cmax: 0.680  ± 0.220  vs 0.960 ± 0.290  ng/mL; AUC0-∞: 17.6 ±20.1  vs 25.5 ± 29.9  ng*h/mL). Apart from Cmax,AUC0-t and AUC0-∞, the other pharmacokinetic parameters (tmax, kel and t½) were not significantly different between study periods. As for the pharmacodynamic analysis, decreases in blood pressure and heart rate after nebivolol administration were similar with and without fluvoxamine concomitant intake. Due to enzymatic inhibition, fluvoxamine increases the exposure to nebivolol and its active hydroxylated metabolite in healthy volunteers. This did not influence the blood pressure and heart-rate lowering effects of the beta-blocker administered as single-dose. However, more detail studies involving actual patients are required to further investigate the clinical relevance of this drug interaction. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For

  4. Deducing hybrid performance from parental metabolic profiles of young primary roots of maize by using a multivariate diallel approach.

    Directory of Open Access Journals (Sweden)

    Kristen Feher

    Full Text Available Heterosis, the greater vigor of hybrids compared to their parents, has been exploited in maize breeding for more than 100 years to produce ever better performing elite hybrids of increased yield. Despite extensive research, the underlying mechanisms shaping the extent of heterosis are not well understood, rendering the process of selecting an optimal set of parental lines tedious. This study is based on a dataset consisting of 112 metabolite levels in young roots of four parental maize inbred lines and their corresponding twelve hybrids, along with the roots' biomass as a heterotic trait. Because the parental biomass is a poor predictor for hybrid biomass, we established a model framework to deduce the biomass of the hybrid from metabolite profiles of its parental lines. In the proposed framework, the hybrid metabolite levels are expressed relative to the parental levels by incorporating the standard concept of additivity/dominance, which we name the Combined Relative Level (CRL. Our modeling strategy includes a feature selection step on the parental levels which are demonstrated to be predictive of CRL across many hybrid metabolites. We demonstrate that these selected parental metabolites are further predictive of hybrid biomass. Our approach directly employs the diallel structure in a multivariate fashion, whereby we attempt to not only predict macroscopic phenotype (biomass, but also molecular phenotype (metabolite profiles. Therefore, our study provides the first steps for further investigations of the genetic determinants to metabolism and, ultimately, growth. Finally, our success on the small-scale experiments implies a valid strategy for large-scale experiments, where parental metabolite profiles may be used together with profiles of selected hybrids as a training set to predict biomass of all possible hybrids.

  5. Mechanism-based population pharmacokinetic modelling in diabetes: vildagliptin as a tight binding inhibitor and substrate of dipeptidyl peptidase IV

    Science.gov (United States)

    Landersdorfer, Cornelia B; He, Yan-Ling; Jusko, William J

    2012-01-01

    AIMS To assess the pharmacokinetics of vildagliptin at different doses and build a mechanism-based population model that simultaneously describes vildagliptin pharmacokinetics and its effects on DPP-4 activity based on underlying physiology and biology. METHODS Vildagliptin concentrations and DPP-4 activity vs. time from 13 type 2 diabetic patients after oral vildagliptin 10, 25 or 100 mg and placebo twice daily for 28 days were co-modelled. NONMEM VI and S-ADAPT were utilized for population modelling. RESULTS A target-mediated drug disposition (TMDD) model accounting for capacity-limited high affinity binding of vildagliptin to DPP-4 in plasma and tissues had good predictive performance. Modelling the full time course of the vildagliptin-DPP-4 interaction suggested parallel vildagliptin dissociation from DPP-4 by a slow first-order process and hydrolysis by DPP-4 to an inactive metabolite as a disposition mechanism. Due to limited amounts of DPP-4, vildagliptin concentrations increased slightly more than dose proportionally. This newly proposed model and the parameter estimates are supported by published in vitro studies. Mean parameter estimates (inter-individual coefficient of variation) were: non-saturable clearance 36 l h−1 (25%), central volume of distribution 22 l (37%), half-life of dissociation from DPP-4 1.1 h (94%) and half-life of hydrolysis 6.3 h (81%). CONCLUSIONS Vildagliptin is both an inhibitor and substrate for DPP-4. By utilizing the TMDD approach, slow dissociation of vildagliptin from DPP-4 was found in patients and the half-life of hydrolysis by DPP-4 estimated. This model can be used to predict DPP-4 inhibition effects of other dosage regimens and be modified for other DPP-4 inhibitors to differentiate their properties. PMID:22442826

  6. Non-linear mixed-effects pharmacokinetic/pharmacodynamic modelling in NLME using differential equations

    DEFF Research Database (Denmark)

    Tornøe, Christoffer Wenzel; Agersø, Henrik; Madsen, Henrik

    2004-01-01

    The standard software for non-linear mixed-effect analysis of pharmacokinetic/phar-macodynamic (PK/PD) data is NONMEM while the non-linear mixed-effects package NLME is an alternative as tong as the models are fairly simple. We present the nlmeODE package which combines the ordinary differential...... equation (ODE) solver package odesolve and the non-Linear mixed effects package NLME thereby enabling the analysis of complicated systems of ODEs by non-linear mixed-effects modelling. The pharmacokinetics of the anti-asthmatic drug theophylline is used to illustrate the applicability of the nlme...

  7. Application of physiologically based pharmacokinetic modeling in predicting drug–drug interactions for sarpogrelate hydrochloride in humans

    Directory of Open Access Journals (Sweden)

    Min JS

    2016-09-01

    Full Text Available Jee Sun Min,1 Doyun Kim,1 Jung Bae Park,1 Hyunjin Heo,1 Soo Hyeon Bae,2 Jae Hong Seo,1 Euichaul Oh,1 Soo Kyung Bae1 1Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, Bucheon, 2Department of Pharmacology, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul, South Korea Background: Evaluating the potential risk of metabolic drug–drug interactions (DDIs is clinically important. Objective: To develop a physiologically based pharmacokinetic (PBPK model for sarpogrelate hydrochloride and its active metabolite, (R,S-1-{2-[2-(3-methoxyphenylethyl]-phenoxy}-3-(dimethylamino-2-propanol (M-1, in order to predict DDIs between sarpogrelate and the clinically relevant cytochrome P450 (CYP 2D6 substrates, metoprolol, desipramine, dextromethorphan, imipramine, and tolterodine. Methods: The PBPK model was developed, incorporating the physicochemical and pharmacokinetic properties of sarpogrelate hydrochloride, and M-1 based on the findings from in vitro and in vivo studies. Subsequently, the model was verified by comparing the predicted concentration-time profiles and pharmacokinetic parameters of sarpogrelate and M-1 to the observed clinical data. Finally, the verified model was used to simulate clinical DDIs between sarpogrelate hydrochloride and sensitive CYP2D6 substrates. The predictive performance of the model was assessed by comparing predicted results to observed data after coadministering sarpogrelate hydrochloride and metoprolol. Results: The developed PBPK model accurately predicted sarpogrelate and M-1 plasma concentration profiles after single or multiple doses of sarpogrelate hydrochloride. The simulated ratios of area under the curve and maximum plasma concentration of metoprolol in the presence of sarpogrelate hydrochloride to baseline were in good agreement with the observed ratios. The predicted fold-increases in the area under the curve ratios of metoprolol

  8. Pharmacokinetics of cotinine in rats: a potential therapeutic agent for disorders of cognitive function.

    Science.gov (United States)

    Li, Pei; Beck, Wayne D; Callahan, Patrick M; Terry, Alvin V; Bartlett, Michael G

    2015-06-01

    Attention has been paid to cotinine (COT), one of the major metabolites of nicotine (NIC), for its pro-cognitive effects and potential therapeutic activities against Alzheimer's disease (AD) and other types of cognitive impairment. In order to facilitate pharmacological and toxicological studies on COT for its pro-cognitive activities, we conducted a pharmacokinetic (PK) study of COT in rats, providing important oral and intravenously (iv) PK information. In this study, plasma samples were obtained up to 48 h after COT was dosed to rats orally and iv at a dose of 3mg/kg. Plasma samples were prepared and analyzed using a sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) bioanalytical method, providing concentration profiles of COT and metabolites after oral and iv administrations. The data were fitted into a one-compartment model and a two-compartment model for the oral and iv groups, respectively, providing important PK information for COT including PK profiles, half-life, clearance and bioavailability. The results suggested fast absorption, slow elimination and high bioavailability of COT in rats. Several important facts about the PK properties in rats suggested COT could be a potential pro-cognitive agent. Information about the pharmacokinetics of COT in rats revealed in this study is of great importance for the future studies on COT or potential COT analogs as agents for improving cognition. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  9. Tracer kinetic modelling of receptor data with mathematical metabolite correction

    International Nuclear Information System (INIS)

    Burger, C.; Buck, A.

    1996-01-01

    Quantitation of metabolic processes with dynamic positron emission tomography (PET) and tracer kinetic modelling relies on the time course of authentic ligand in plasma, i.e. the input curve. The determination of the latter often requires the measurement of labelled metabilites, a laborious procedure. In this study we examined the possibility of mathematical metabolite correction, which might obviate the need for actual metabolite measurements. Mathematical metabilite correction was implemented by estimating the input curve together with kinetic tissue parameters. The general feasibility of the approach was evaluated in a Monte Carlo simulation using a two tissue compartment model. The method was then applied to a series of five human carbon-11 iomazenil PET studies. The measured cerebral tissue time-activity curves were fitted with a single tissue compartment model. For mathematical metabolite correction the input curve following the peak was approximated by a sum of three decaying exponentials, the amplitudes and characteristic half-times of which were then estimated by the fitting routine. In the simulation study the parameters used to generate synthetic tissue time-activity curves (K 1 -k 4 ) were refitted with reasonable identifiability when using mathematical metabolite correciton. Absolute quantitation of distribution volumes was found to be possible provided that the metabolite and the kinetic models are adequate. If the kinetic model is oversimplified, the linearity of the correlation between true and estimated distribution volumes is still maintained, although the linear regression becomes dependent on the input curve. These simulation results were confirmed when applying mathematical metabolite correction to the 11 C iomazenil study. Estimates of the distribution volume calculated with a measured input curve were linearly related to the estimates calculated using mathematical metabolite correction with correlation coefficients >0.990. (orig./MG)

  10. Determination of piperphentonamine and metabolites M1 and M6 in human plasma and urine by LC/MS/MS and its application in a pharmacokinetics study in Chinese healthy volunteers.

    Science.gov (United States)

    Shi, Aixin; Hu, Xin; Li, Kexin; Li, Jian; Han, Liping; Wan, Huayin; Li, Rubing

    2012-11-01

    Piperphentonamine hydrochloride (PPTA) is a new calcium sensitizer. A liquid chromatography-tandem mass spectrometry (LC/MS/MS) method for determination of piperphentonamine and its metabolites M1 and M6 was developed for the first time and applied to a pharmacokinetics study. Protein precipitation was used for pre-treatment of plasma samples, and solid phase extraction method was used for pre-treatment of urine samples. The chromatographic separation was achieved on a C(18) column using gradient elution in this study: A: 1% acetic acid aqueous solution, and B: acetonitrile. The whole analysis lasted for 10.5min and the gradient flow rate was 0.25mL/min constantly. The detection was performed of a triple quadrupole tandem mass spectrometer by multiple reaction monitoring (MRM) mode via a positive electrospray ionization source. The results were that the m/z ratios of monitored precursor ions and product ions of PPTA, M1 and M6 were 354.0→191.8, 356.0→148.7 and 358.0→148.7, respectively. From the standard curve, the concentration ranges of both PPTA and M1 in blood and urine samples were 0.1-500ng/mL and 0.1-200ng/mL, respectively; the concentration ranges of M6 in blood sample and urine sample were 0.2-500ng/mL and 0.2-200ng/mL, respectively; and the correlation coefficient of standard curve was r>0.99. A total of 31 healthy Chinese subjects participated in the pharmacokinetic study of single bolus intravenous injection of piperphentonamine hydrochloride. They were divided into three dosage groups and given 0.2, 0.4 and 0.6mg/kg of PPTA. After drug administration, concentrations of PPTA, M1 and M6 in human plasma and urine samples were determined to evaluation the pharmacokinetic characteristics of PPTA and its metabolites M1 and M6. Copyright © 2012 Elsevier B.V. All rights reserved.

  11. Simultaneous determination of sibutramine and its active metabolites in human plasma by LC-MS/MS and its application to a pharmacokinetic study.

    Science.gov (United States)

    Bae, Jung-Woo; Choi, Chang-Ik; Jang, Choon-Gon; Lee, Seok-Yong

    2011-11-01

    A simple and sensitive liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) technique was developed and validated for the determination of sibutramine and its N-desmethyl metabolites (M1 and M2) in human plasma. After extraction with methyl t-butyl ether, chromatographic separation of analytes in human plasma was performed using a reverse-phase Luna C18 column with a mobile phase of acetonitrile-10 mm ammonium formate buffer (50:50, v/v) and quantified by ESI-MS/MS detection in positive ion mode. The flow rate of the mobile phase was 200 μL/min and the retention times of sibutramine, M1, M2 and internal standard (chlorpheniramine) were 1.5, 1.4, 1.3 and 0.9 min, respectively. The calibration curves were linear over the range 0.05-20 ng/mL, for sibutramine, M1 and M2. The lower limit of quantification was 0.05 ng/mL using 500 μL of human plasma. The mean accuracy and the precision in the intra- and inter-day validation for sibutramine, M1 and M2 were acceptable. This LC-MS/MS method showed improved sensitivity and a short run time for the quantification of sibutramine and its two active metabolites in plasma. The validated method was successfully applied to a pharmacokinetic study in human. Copyright © 2011 John Wiley & Sons, Ltd.

  12. Population pharmacokinetic model of THC integrates oral, intravenous, and pulmonary dosing and characterizes short- and long-term pharmacokinetics.

    Science.gov (United States)

    Heuberger, Jules A A C; Guan, Zheng; Oyetayo, Olubukayo-Opeyemi; Klumpers, Linda; Morrison, Paul D; Beumer, Tim L; van Gerven, Joop M A; Cohen, Adam F; Freijer, Jan

    2015-02-01

    Δ(9)-Tetrahydrocannobinol (THC), the main psychoactive compound of Cannabis, is known to have a long terminal half-life. However, this characteristic is often ignored in pharmacokinetic (PK) studies of THC, which may affect the accuracy of predictions in different pharmacologic areas. For therapeutic use for example, it is important to accurately describe the terminal phase of THC to describe accumulation of the drug. In early clinical research, the THC challenge test can be optimized through more accurate predictions of the dosing sequence and the wash-out between occasions in a crossover setting, which is mainly determined by the terminal half-life of the compound. The purpose of this study is to better quantify the long-term pharmacokinetics of THC. A population-based PK model for THC was developed describing the profile up to 48 h after an oral, intravenous, and pulmonary dose of THC in humans. In contrast to earlier models, the current model integrates all three major administration routes and covers the long terminal phase of THC. Results show that THC has a fast initial and intermediate half-life, while the apparent terminal half-life is long (21.5 h), with a clearance of 38.8 L/h. Because the current model characterizes the long-term pharmacokinetics, it can be used to assess the accumulation of THC in a multiple-dose setting and to forecast concentration profiles of the drug under many different dosing regimens or administration routes. Additionally, this model could provide helpful insights into the THC challenge test used for the development of (novel) compounds targeting the cannabinoid system for different therapeutic applications and could improve decision making in future clinical trials.

  13. Significance of metabolites in bioequivalence: losartan potassium as a case study.

    Science.gov (United States)

    Charoo, Naseem Ahmad; Cristofoletti, Rodrigo; Khatri, Aamer Roshanali; Ali, Areeg Anwer

    2014-06-01

    Estimation of metabolite data as a supportive evidence of comparable therapeutic outcome is recommended by various guidance documents. However, a consensus on using it solely to establish bioequivalence (BE) is lacking as parent drug is believed to detect pharmacokinetic differences between test and reference formulations better. Four BE studies of losartan potassium reported in the literature are reviewed. In all the four studies, 90% confidence intervals (CIs) of geometric mean ratios of the test and reference formulations for maximum blood drug concentration (Cmax ) of losartan potassium were outside the acceptable range of 80%-125%, whereas, 90% CIs for its active metabolite, losartan carboxylic acid (LCA), were within the acceptance criteria. Although BE with respect to area under the plasma concentration versus time profile curve was demonstrated in all the cases, BE with respect to Cmax could not be established. However, marketing authorization in all the four cases was granted based on scientific evidence that LCA is 10-40 times more potent than losartan, LCA exhibited higher plasma concentration levels than losartan, pharmacodynamic effects correlate with LCA, and losartan shows wide therapeutic index. Further, widened CI limits for losartan were accepted. Losartan presents an opportunity in the diligence of the principles of quality risk management for selecting moiety on which BE decision must be based. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

  14. Estimation of caffeine intake from analysis of caffeine metabolites in wastewater

    DEFF Research Database (Denmark)

    Gracia-Lor, Emma; Rousis, Nikolaos I.; Zuccato, Ettore

    2017-01-01

    with the human urinary excretion profile. A good match was found for 1,7-dimethyluric acid, an exclusive caffeine metabolite, suggesting that might be a suitable biomarker in wastewater for assessing population-level caffeine consumption. A correction factor was developed considering the percentage of excretion......Caffeine metabolites in wastewater were investigated as potential biomarkers for assessing caffeine intake in a population. The main human urinary metabolites of caffeine were measured in the urban wastewater of ten European cities and the metabolic profiles in wastewater were compared...... of this metabolite in humans, according to published pharmacokinetic studies. Daily caffeine intake estimated from wastewater analysis was compared with the average daily intake calculated from the average amount of coffee consumed by country per capita. Good agreement was found in some cities but further...

  15. A correlative study of polymorphisms of CYP2C19 and MDR1 C3435T with the pharmacokinetic profiles of lansoprazole and its main metabolites following single oral administration in healthy adult Chinese subjects.

    Science.gov (United States)

    Li, Chang-Yin; Zhang, Jun; Chu, Ji-Hong; Xu, Mei-Juan; Ju, Wen-Zheng; Liu, Fang; Jian-Dong, Zou

    2014-06-01

    Considering that the genotypes of CYP2C19 and MDRI C3435T are two major factors attributed to the inter-individual pharmacokinetic variability of lansoprazole (LSZ), the aim of the study was to simultaneously elucidate the effects of CYP2C19 and MDRI C3435T polymorphisms on the pharmacokinetics difference of LSZ and its metabolites 5'-hydroxy lansoprazole (HLSZ) and lansoprazole sulphone (LSZS) following oral administration of LSZ tablets in healthy Chinese subjects. Plasma concentration of LSZ, HLSZ and LSZS were quantified by a sensitive and specific LC-MS/MS method, while the genotypes of CYP2C19 and MDRI C3435T for each subject were identified by a direct sequencing method. Statistical analysis was performed in the pharmacokinetic parameters including Cmax, t1/2, Tmax, MRTo_-, AUCO-2 and AUCo_r among different genotype groups of CYP2C 19 and MDRI C3435T. Compared to the CYP2Cl9 EMs, the CYP2C 19 PM group showed slower elimination and betteroral bioavailability of LSZ, much higher plasma concentrations of LSZS and lower concentrations of HLSZ with statistically significance. Despite a tendency of more favorable absorption and rapid elimination of LSZ in wild genotype, no significant pharmacokinetics difference was observed between the wild genotype of MDR1 C3435T and its mutant types. In conclusion, the pharmacokinetics of MDRI C3435T.

  16. Evaluation of the whole body physiologically based pharmacokinetic (WB-PBPK) modeling of drugs.

    Science.gov (United States)

    Munir, Anum; Azam, Shumaila; Fazal, Sahar; Bhatti, A I

    2018-08-14

    The Physiologically based pharmacokinetic (PBPK) modeling is a supporting tool in drug discovery and improvement. Simulations produced by these models help to save time and aids in examining the effects of different variables on the pharmacokinetics of drugs. For this purpose, Sheila and Peters suggested a PBPK model capable of performing simulations to study a given drug absorption. There is a need to extend this model to the whole body entailing all another process like distribution, metabolism, and elimination, besides absorption. The aim of this scientific study is to hypothesize a WB-PBPK model through integrating absorption, distribution, metabolism, and elimination processes with the existing PBPK model.Absorption, distribution, metabolism, and elimination models are designed, integrated with PBPK model and validated. For validation purposes, clinical records of few drugs are collected from the literature. The developed WB-PBPK model is affirmed by comparing the simulations produced by the model against the searched clinical data. . It is proposed that the WB-PBPK model may be used in pharmaceutical industries to create of the pharmacokinetic profiles of drug candidates for better outcomes, as it is advance PBPK model and creates comprehensive PK profiles for drug ADME in concentration-time plots. Copyright © 2018 Elsevier Ltd. All rights reserved.

  17. Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults.

    Science.gov (United States)

    Brown, Randall T; Nicholas, Christopher R; Cozzi, Nicholas V; Gassman, Michele C; Cooper, Karen M; Muller, Daniel; Thomas, Chantelle D; Hetzel, Scott J; Henriquez, Kelsey M; Ribaudo, Alexandra S; Hutson, Paul R

    2017-12-01

    Psilocybin is a psychedelic tryptamine that has shown promise in recent clinical trials for the treatment of depression and substance use disorders. This open-label study of the pharmacokinetics of psilocybin was performed to describe the pharmacokinetics and safety profile of psilocybin in sequential, escalating oral doses of 0.3, 0.45, and 0.6 mg/kg in 12 healthy adults. Eligible healthy adults received 6-8 h of preparatory counseling in anticipation of the first dose of psilocybin. The escalating oral psilocybin doses were administered at approximately monthly intervals in a controlled setting and subjects were monitored for 24 h. Blood and urine samples were collected over 24 h and assayed by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for psilocybin and psilocin, the active metabolite. The pharmacokinetics of psilocin were determined using both compartmental (NONMEM) and noncompartmental (WinNonlin) methods. No psilocybin was found in plasma or urine, and renal clearance of intact psilocin accounted for less than 2% of the total clearance. The pharmacokinetics of psilocin were linear within the twofold range of doses, and the elimination half-life of psilocin was 3 h (standard deviation 1.1). An extended elimination phase in some subjects suggests hydrolysis of the psilocin glucuronide metabolite. Variation in psilocin clearance was not predicted by body weight, and no serious adverse events occurred in the subjects studied. The small amount of psilocin renally excreted suggests that no dose reduction is needed for subjects with mild-moderate renal impairment. Simulation of fixed doses using the pharmacokinetic parameters suggest that an oral dose of 25 mg should approximate the drug exposure of a 0.3 mg/kg oral dose of psilocybin. Although doses of 0.6 mg/kg are in excess of likely therapeutic doses, no serious physical or psychological events occurred during or within 30 days of any dose. NCT02163707.

  18. Pharmacokinetic modeling of therapies for systemic lupus erythematosus

    OpenAIRE

    Yang, Xiaoyan; Sherwin, Catherine MT; Yu, Tian; Yellepeddi, Venkata K; Brunner, Hermine I; Vinks, Alexander A

    2015-01-01

    With the increasing use of different types of therapies in treating autoimmune diseases such as systemic lupus erythematosus (SLE), there is a need to utilize pharmacokinetic (PK) strategies to optimize the clinical outcome of these treatments. Various PK analysis approaches, including population PK modeling and physiologically based PK modeling, have been used to evaluate drug PK characteristics and population variability or to predict drug PK profiles in a mechanistic manner. This review ou...

  19. Plasma Pharmacokinetics of Polyphenols in a Traditional Japanese Medicine, Jumihaidokuto, Which Suppresses Propionibacterium acnes-Induced Dermatitis in Rats

    Directory of Open Access Journals (Sweden)

    Takashi Matsumoto

    2015-09-01

    Full Text Available Most orally administered polyphenols are metabolized, with very little absorbed as aglycones and/or unchanged forms. Metabolic and pharmacokinetic studies are therefore necessary to understand the pharmacological mechanisms of polyphenols. Jumihaidokuto (JHT, a traditional Japanese medicine, has been used for treatment of skin diseases including inflammatory acne. Because JHT contains various types of bioactive polyphenols, our aim was to clarify the metabolism and pharmacokinetics of the polyphenols in JHT and identify active metabolites contributing to its antidermatitis effects. Orally administered JHT inhibited the increase in ear thickness in rats induced by intradermal injection of Propionibacterium acnes. Quantification by LC-MS/MS indicated that JHT contains various types of flavonoids and is also rich in hydrolysable tannins, such as 1,2,3,4,6-penta-O-galloyl glucose. Pharmacokinetic and antioxidant analyses showed that some flavonoid conjugates, such as genistein 7-O-glucuronide and liquiritigenin 7-O-glucuronide, appeared in rat plasma and had an activity to inhibit hydrogen peroxide-dependent oxidation. Furthermore, 4-O-methylgallic acid, a metabolite of Gallic acid, appeared in rat plasma and inhibited the nitric oxide reaction. JHT has numerous polyphenols; it inhibited dermatitis probably via the antioxidant effect of its metabolites. Our study is beneficial for understanding in vivo actions of orally administered polyphenol drugs.

  20. A distributed delay approach for modeling delayed outcomes in pharmacokinetics and pharmacodynamics studies.

    Science.gov (United States)

    Hu, Shuhua; Dunlavey, Michael; Guzy, Serge; Teuscher, Nathan

    2018-04-01

    A distributed delay approach was proposed in this paper to model delayed outcomes in pharmacokinetics and pharmacodynamics studies. This approach was shown to be general enough to incorporate a wide array of pharmacokinetic and pharmacodynamic models as special cases including transit compartment models, effect compartment models, typical absorption models (either zero-order or first-order absorption), and a number of atypical (or irregular) absorption models (e.g., parallel first-order, mixed first-order and zero-order, inverse Gaussian, and Weibull absorption models). Real-life examples were given to demonstrate how to implement distributed delays in Phoenix ® NLME™ 8.0, and to numerically show the advantages of the distributed delay approach over the traditional methods.

  1. Direct cell writing of 3D microorgan for in vitro pharmacokinetic model.

    Science.gov (United States)

    Chang, Robert; Nam, Jae; Sun, Wei

    2008-06-01

    A novel targeted application of tissue engineering is the development of an in vitro pharmacokinetic model for drug screening and toxicology. An in vitro pharmacokinetic model is needed to realistically and reliably predict in vivo human response to drug administrations and potential toxic exposures. This paper details the fabrication process development and adaptation of microfluidic devices for the creation of such a physiologically relevant pharmacokinetic model. First, an automated syringe-based, layered direct cell writing (DCW) bioprinting process creates a 3D microorgan that biomimics the cell's natural microenvironment with enhanced functionality. Next, soft lithographic micropatterning techniques are used to fabricate a microscale in vitro device to house the 3D microorgan. This paper demonstrates the feasibility of the DCW process for freeform biofabrication of 3D cell-encapsulated hydrogel-based tissue constructs with defined reproducible patterns, direct integration of 3D constructs onto a microfluidic device for continuous perfusion drug flow, and characterization of 3D tissue constructs with predictable cell viability/proliferation outcomes and enhanced functionality over traditional culture methods.

  2. A comprehensive review of recent studies on pharmacokinetics of traditional Chinese medicines (2014-2017) and perspectives.

    Science.gov (United States)

    Shi, Peiying; Lin, Xinhua; Yao, Hong

    2018-05-01

    Traditional Chinese medicines (TCMs) have a long history for safely treating human diseases. Unlike western medicine, TCMs usually contain multiple components synergistically and holistically acting on the diseases. It remains a big challenge to represent rationally the in vivo process of multiple components of TCMs for understanding the relationship between administration and therapeutic effects. For years, efforts were always made to face the challenge, and the achievements were obvious. Here, we give an comprehensive overview of the recent investigation progress (from 2015 to 2017, except the part of 'integrated pharmacokinetics of TCMs' from 2014 to 2017 and the part of 'reverse pharmacokinetics in drug discovery from natural medicines' in 2014) on pharmacokinetics of TCMs, mainly referring to the following six aspects: (1) classical pharmacokinetic studies on TCMs; (2) absorbed components and metabolites identification of TCMs; (3) pharmacokinetic herb-drug interactions and herb-herb interactions with TCMs; (4) integrated pharmacokinetics of TCMs; (5) pharmacokinetic and pharmacodynamic combination studies to dissect the action mechanisms of TCMs; and (6) reverse pharmacokinetics in drug discovery from natural medicines. Finally, based on the insights from the recent progress and our latest efforts, we propose new perspectives on the integrated pharmacokinetics of TCMs.

  3. Phenobarbital in intensive care unit pediatric population: predictive performances of population pharmacokinetic model.

    Science.gov (United States)

    Marsot, Amélie; Michel, Fabrice; Chasseloup, Estelle; Paut, Olivier; Guilhaumou, Romain; Blin, Olivier

    2017-10-01

    An external evaluation of phenobarbital population pharmacokinetic model described by Marsot et al. was performed in pediatric intensive care unit. Model evaluation is an important issue for dose adjustment. This external evaluation should allow confirming the proposed dosage adaptation and extending these recommendations to the entire intensive care pediatric population. External evaluation of phenobarbital published population pharmacokinetic model of Marsot et al. was realized in a new retrospective dataset of 35 patients hospitalized in a pediatric intensive care unit. The published population pharmacokinetic model was implemented in nonmem 7.3. Predictive performance was assessed by quantifying bias and inaccuracy of model prediction. Normalized prediction distribution errors (NPDE) and visual predictive check (VPC) were also evaluated. A total of 35 infants were studied with a mean age of 33.5 weeks (range: 12 days-16 years) and a mean weight of 12.6 kg (range: 2.7-70.0 kg). The model predicted the observed phenobarbital concentrations with a reasonable bias and inaccuracy. The median prediction error was 3.03% (95% CI: -8.52 to 58.12%), and the median absolute prediction error was 26.20% (95% CI: 13.07-75.59%). No trends in NPDE and VPC were observed. The model previously proposed by Marsot et al. in neonates hospitalized in intensive care unit was externally validated for IV infusion administration. The model-based dosing regimen was extended in all pediatric intensive care unit to optimize treatment. Due to inter- and intravariability in pharmacokinetic model, this dosing regimen should be combined with therapeutic drug monitoring. © 2017 Société Française de Pharmacologie et de Thérapeutique.

  4. Classical Michaelis-Menten and system theory approach to modeling metabolite formation kinetics.

    Science.gov (United States)

    Popović, Jovan

    2004-01-01

    When single doses of drug are administered and kinetics are linear, techniques, which are based on the compartment approach and the linear system theory approach, in modeling the formation of the metabolite from the parent drug are proposed. Unlike the purpose-specific compartment approach, the methodical, conceptual and computational uniformity in modeling various linear biomedical systems is the dominant characteristic of the linear system approach technology. Saturation of the metabolic reaction results in nonlinear kinetics according to the Michaelis-Menten equation. The two compartment open model with Michaelis-Menten elimination kinetics is theorethicaly basic when single doses of drug are administered. To simulate data or to fit real data using this model, one must resort to numerical integration. A biomathematical model for multiple dosage regimen calculations of nonlinear metabolic systems in steady-state and a working example with phenytoin are presented. High correlation between phenytoin steady-state serum levels calculated from individual Km and Vmax values in the 15 adult epileptic outpatients and the observed levels at the third adjustment of phenytoin daily dose (r=0.961, p<0.01) were found.

  5. Pharmacokinetics, tissue distribution and identification of putative metabolites of JI-101 - a novel triple kinase inhibitor in rats.

    Science.gov (United States)

    Gurav, S D; Gilibili, R R; Jeniffer, S; Mohd, Z; Giri, S; Govindarajan, R; Srinivas, N R; Mullangi, R

    2012-01-01

    JI-101, chemically 1-[1-(2-amino-pyridin-4-ylmethyl)-1H-indol-4-yl]-3-(5-bromo-2-methoxy-phenyl)-urea hydrochloride, is a novel orally active kinase inhibitor, which has shown potent in vitro and in vivo anticancer activity against a variety of cancer cell lines and xenografts. It is currently entering Phase II clinical development for the treatment of solid tumors. The aim of the study is to assess the metabolic stability of JI-101 in various pre-clinical and human liver microsomes, to identify the major CYPs (cytochrome β450) involved in the metabolism of JI-101 and identification of putative metabolites. We have also studied the pharmacokinetics, tissue distribution and excretion of JI-101 in Sprague Dawley rats. JI-101 was found to be stable in various liver microsomes tested. JI-101 is highly permeable and not a substrate for P-gp (permeability glycoprotein). JI-101 excreted through bile along with its mono- and di-hydroxy metabolites. Following oral administration, JI-101 was rapidly absorbed, reaching Cmax within 2 h. The t½ of JI-101 with intravenous and oral route was found to be 1.75 ± 0.79 and 2.66 ± 0.13 h, respectively. The Cl and Vd by intravenous route for JI-101 were found to be 13.0 ± 2.62 mL/min/kg and 2.11 ± 1.42 L/kg, respectively. The tissue distribution of JI-101 was extensive with rapid and preferred uptake into lung tissue. Overall, the oral bioavailability of JI-101 is 55% and the primary route of elimination for JI-101 is feces. © Georg Thieme Verlag KG Stuttgart · New York.

  6. Identification of absolute conversion to geraldol from fisetin and pharmacokinetics in mouse.

    Science.gov (United States)

    Jo, Jun Hyeon; Jo, Jung Jae; Lee, Jae-Mok; Lee, Sangkyu

    2016-12-01

    Fisetin (3,3',4',7-tetrahydroxyflavone) is a flavonoid found in several fruits, vegetables, nuts, and wine and has anti-oxidant, anti-inflammatory, and anti-angiogenic properties. Geraldol is the 3'-methoxylated metabolite of fisetin (3,4',7-trihydroxy-3'-methoxyflavone). The concentration of fisetin and geraldol in mouse plasma was determined by LC-MS/MS, following direct protein precipitation. These concentrations were determined after administration of fisetin at doses of 2mg/kg (i.v.) and 100 and 200mg/kg (p.o.). The method was validated in terms of linearity, accuracy, precision, matrix effect, and stability. The pharmacokinetics parameters of fisetin and geraldol were successfully determined using a validated method in mice. Results indicated that fisetin was very rapidly methylated to geraldol in vivo. Following administration of fisetin, it was observed that the C max and AUC values for geraldol were higher than those of fisetin. The absolute bioavailability of fisetin was calculated as 7.8% and 31.7% after oral administration of 100 and 200mg/kg fisetin, respectively. This method was successfully applied to determine the pharmacokinetic parameters of fisetin and its main metabolite geraldol in mouse plasma. Geraldol was the dominant circulating metabolite after fisetin administration in vivo. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. Pharmacokinetic comparison of different flubendazole formulations in pigs: A further contribution to its development as a macrofilaricide molecule

    Directory of Open Access Journals (Sweden)

    L. Ceballos

    2015-12-01

    Full Text Available Despite the well established ivermectin activity against microfilaria, the success of human filariasis control programmes requires the use of a macrofilaricide compound. Different in vivo trials suggest that flubendazole (FLBZ, an anthelmintic benzimidazole compound, is a highly efficacious and potent macrofilaricide. However, since serious injection site reactions were reported in humans after the subcutaneous FLBZ administration, the search for alternative pharmaceutical strategies to improve the systemic availability of FLBZ has acquired special relevance both in human and veterinary medicine. The goal of the current experimental work was to compare the pharmacokinetic plasma behavior of FLBZ, and its metabolites, formulated as either an aqueous hydroxypropyl- β -cyclodextrin-solution (HPBCD, an aqueous carboxymethyl cellulose-suspension (CMC or a Tween 80-based formulation, in pigs. Animals were allocated into three groups and treated (2 mg/kg with FLBZ formulated as either a HPBCD-solution (oral, CMC-suspension (oral or Tween 80-based formulation (subcutaneous. Only trace amounts of FLBZ parent drug and its reduced metabolite were measured after administration of the different FLBZ formulations in pigs. The hydrolyzed FLBZ (H-FLBZ metabolite was the main analyte recovered in the bloodstream in pigs treated with the three experimental FLBZ formulations. The oral administration of the HPBCD-solution accounted for significantly higher (P < 0.05 Cmax and AUC (23.1 ± 4.4 μg h/mL values for the main metabolite (H-FLBZ, compared with those observed for the oral CMC-suspension (AUC = 3.5 ± 1.0 μg h/mL and injectable Tween 80-based formulation (AUC: 7.5 ± 1.7 μg h/mL. The oral administration of the HPBCD-solution significantly improved the poor absorption pattern (indirectly assessed as the H-FLBZ plasma concentrations observed after the oral administration of the FLBZ-CMC suspension or the subcutaneous injection of the

  8. Pharmacokinetics of vinyl chloride in the rat

    International Nuclear Information System (INIS)

    Bolt, H.M.; Laib, R.J.; Kappus, H.; Buchter, A.

    1977-01-01

    When rats are exposed to [ 14 C]vinyl chloride in a closed system, the vinyl chloride present in the atmosphere equilibrates with the animals' organism within 15 min. The course of equilibration could be determined using rats which had been given 6-nitro-1,2,3-benzothiadiazole. This compound completely blocks metabolism of vinyl chloride. The enzymes responsible for metabolism of vinyl chloride are saturated at an atmospheric concentration of vinyl chloride of 250 ppm. Pharmacokinetic analysis shows that no significant cumulation of vinyl chloride or its major metabolites is to be expected on repeated administration of vinyl chlorides. This may be consistent with the theory that a reactive, shortly living metabolite which occurs in low concentration only, may be responsible for the toxic effects of vinyl chloride

  9. Pharmacokinetic-pharmacodynamic modeling of diclofenac in normal and Freund's complete adjuvant-induced arthritic rats

    Science.gov (United States)

    Zhang, Jing; Li, Pei; Guo, Hai-fang; Liu, Li; Liu, Xiao-dong

    2012-01-01

    Aim: To characterize pharmacokinetic-pharmacodynamic modeling of diclofenac in Freund's complete adjuvant (FCA)-induced arthritic rats using prostaglandin E2 (PGE2) as a biomarker. Methods: The pharmacokinetics of diclofenac was investigated using 20-day-old arthritic rats. PGE2 level in the rats was measured using an enzyme immunoassay. A pharmacokinetic-pharmacodynamic (PK-PD) model was developed to illustrate the relationship between the plasma concentration of diclofenac and the inhibition of PGE2 production. The inhibition of diclofenac on lipopolysaccharide (LPS)-induced PGE2 production in blood cells was investigated in vitro. Results: Similar pharmacokinetic behavior of diclofenac was found both in normal and FCA-induced arthritic rats. Diclofenac significantly decreased the plasma levels of PGE2 in both normal and arthritic rats. The inhibitory effect on PGE2 levels in the plasma was in proportion to the plasma concentration of diclofenac. No delay in the onset of inhibition was observed, suggesting that the effect compartment was located in the central compartment. An inhibitory effect sigmoid Imax model was selected to characterize the relationship between the plasma concentration of diclofenac and the inhibition of PGE2 production in vivo. The Imax model was also used to illustrate the inhibition of diclofenac on LPS-induced PGE2 production in blood cells in vitro. Conclusion: Arthritis induced by FCA does not alter the pharmacokinetic behaviors of diclofenac in rats, but the pharmacodynamics of diclofenac is slightly affected. A PK-PD model characterizing an inhibitory effect sigmoid Imax can be used to fit the relationship between the plasma PGE2 and diclofenac levels in both normal rats and FCA-induced arthritic rats. PMID:22842736

  10. Mephedrone (4-Methylmethcathinone: Acute Behavioral Effects, Hyperthermic, and Pharmacokinetic Profile in Rats

    Directory of Open Access Journals (Sweden)

    Klára Šíchová

    2018-01-01

    Full Text Available Mephedrone (MEPH is a synthetic cathinone derivative with effects that mimic MDMA and/or cocaine. Our study in male Wistar rats provides detailed investigations of MEPH’s and its primary metabolite nor-mephedrone’s (nor-MEPH pharmacokinetics and bio-distribution to four different substrates (serum, brain, lungs, and liver, as well as comparative analysis of their effects on locomotion [open field test (OFT] and sensorimotor gating [prepulse inhibition of acoustic startle reaction (PPI ASR]. Furthermore, in order to mimic the crowded condition where MEPH is typically taken (e.g., clubs, the acute effect of MEPH on thermoregulation in singly- and group-housed rats was evaluated. Pharmacokinetics of MEPH and nor-MEPH after MEPH (5 mg/kg, sc. were analyzed over 8 h using liquid chromatography with mass spectrometry. MEPH (2.5, 5, or 20 mg/kg, sc. and nor-MEPH (5 mg/kg, sc. were administered 5 or 40 min before the behavioral testing in the OFT and PPI ASR; locomotion and its spatial distribution, ASR, habituation and PPI itself were quantified. The effect of MEPH on rectal temperature was measured after 5 and 20 mg/kg, sc. Both MEPH and nor-MEPH were detected in all substrates, with the highest levels detected in lungs. Mean brain: serum ratios were 1:1.19 (MEPH and 1:1.91 (nor-MEPH, maximum concentrations were observed at 30 min; at 2 and 4 h after administration, nor-MEPH concentrations were higher compared to the parent drug. While neither of the drugs disrupted PPI, both increased locomotion and affected its spatial distribution. The effects of MEPH were dose dependent, rapid, and short-lasting, and the intensity of locomotor stimulant effects was comparable between MEPH and nor-MEPH. Despite the disappearance of behavioral effects within 40 min after administration, MEPH induced rectal temperature elevations that persisted for 3 h even in singly housed rats. To conclude, we observed a robust, short-lasting, and most

  11. Pharmacokinetics and dosimetry of the anti-androgen vinclozolin after oral administration inthe rat

    Science.gov (United States)

    Vinclozolin (V) is a fungicide with antiandrogenic properties. To determine the pharmacokinetics and dosimetry of V, adult male rats were administered an oral dose of V (100 mg/kg) in corn oil and sacrificed over time after dosing. V and its metabolites were analyzed in serum and...

  12. Drug pharmacokinetics and pharmacodynamics: Technological considerations

    International Nuclear Information System (INIS)

    Fowler, J.S.; Volkow, N.D.; Wolf, A.P.

    1992-01-01

    Additionally, the use of PET to examine drug pharmacokinetics and pharmacadynamics and the relationship of these properties to the behavioral, therapeutic and toxic properties of drugs and substances of abuse is emerging as a powerful new scientific tool. The pharmacokinetic properties of a drug, which comprises all of the biological processes which determine the fraction of the drug available, can be measured using the labeled drug itself. For example, the labeled drug can be used to measure the absolute uptake, regional distribution and kinetics of a drug at its site of action in the body. Additionally the labeled drug and whole body its labeled metabolites and thus provide information an potential toxic effects as well as tissue half lives. On the other hand, different labeled tracers can be used to assess drug pharmacodynamics which include the biological Processes involved in the drug's effects. For example, with appropriate radiotracers, the effects of a drug on metabolism, neurotransmitter activity, blood flew, enzyme activity or other processes can be probed

  13. Pharmacokinetic studies of neuromuscular blocking agents: Good Clinical Research Practice (GCRP)

    DEFF Research Database (Denmark)

    Viby-Mogensen, J.; Østergaard, D.; Donati, F.

    2000-01-01

    Good Clinical Research Practice (GCRP), neuromuscular blocking agents, pharmacokinetics, pharmacokinetic/pharmacodynamic modeling, population pharmacokinetics, statistics, study design......Good Clinical Research Practice (GCRP), neuromuscular blocking agents, pharmacokinetics, pharmacokinetic/pharmacodynamic modeling, population pharmacokinetics, statistics, study design...

  14. Pharmacokinetics and metabolites of 10B-containing compounds in biological fluids

    International Nuclear Information System (INIS)

    Mauri, P.L.; Basilico, F.; Wittig, A.; Sauerwein, W.; Heimans, J.; Huiskamp, R.

    2006-01-01

    Mass spectrometry method has been applied for determining the pharmacokinetics profile of 10 B-containing compounds in urine and plasma of patients treated in the trials EORTC 11001 and 11011 with BSH or BPA. For these analyses a very small volume (1μl) of diluted samples (urine and plasma, diluted 10000 and 1000-fold, respectively) were used. These data were compared with those obtained using other analytical methods. (author)

  15. A Three-Pulse Release Tablet for Amoxicillin: Preparation, Pharmacokinetic Study and Physiologically Based Pharmacokinetic Modeling.

    Science.gov (United States)

    Li, Jin; Chai, Hongyu; Li, Yang; Chai, Xuyu; Zhao, Yan; Zhao, Yunfan; Tao, Tao; Xiang, Xiaoqiang

    2016-01-01

    Amoxicillin is a commonly used antibiotic which has a short half-life in human. The frequent administration of amoxicillin is often required to keep the plasma drug level in an effective range. The short dosing interval of amoxicillin could also cause some side effects and drug resistance, and impair its therapeutic efficacy and patients' compliance. Therefore, a three-pulse release tablet of amoxicillin is desired to generate sustained release in vivo, and thus to avoid the above mentioned disadvantages. The pulsatile release tablet consists of three pulsatile components: one immediate-release granule and two delayed release pellets, all containing amoxicillin. The preparation of a pulsatile release tablet of amoxicillin mainly includes wet granulation craft, extrusion/spheronization craft, pellet coating craft, mixing craft, tablet compression craft and film coating craft. Box-Behnken design, Scanning Electron Microscope and in vitro drug release test were used to help the optimization of formulations. A crossover pharmacokinetic study was performed to compare the pharmacokinetic profile of our in-house pulsatile tablet with that of commercial immediate release tablet. The pharmacokinetic profile of this pulse formulation was simulated by physiologically based pharmacokinetic (PBPK) model with the help of Simcyp®. Single factor experiments identify four important factors of the formulation, namely, coating weight of Eudragit L30 D-55 (X1), coating weight of AQOAT AS-HF (X2), the extrusion screen aperture (X3) and compression forces (X4). The interrelations of the four factors were uncovered by a Box-Behnken design to help to determine the optimal formulation. The immediate-release granule, two delayed release pellets, together with other excipients, namely, Avicel PH 102, colloidal silicon dioxide, polyplasdone and magnesium stearate were mixed, and compressed into tablets, which was subsequently coated with Opadry® film to produce pulsatile tablet of

  16. Alterations of urinary metabolite profile in model diabetic nephropathy

    Energy Technology Data Exchange (ETDEWEB)

    Stec, Donald F. [Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Wang, Suwan; Stothers, Cody [Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Avance, Josh [Berea College, 1916 CPO, Berea, KY 40404 (United States); Denson, Deon [Choctaw Central High School, Philadelphia, MS 39350 (United States); Harris, Raymond [Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Voziyan, Paul, E-mail: paul.voziyan@vanderbilt.edu [Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232 (United States)

    2015-01-09

    Highlights: • {sup 1}H NMR spectroscopy was employed to study urinary metabolite profile in diabetic mouse models. • Mouse urinary metabolome showed major changes that are also found in human diabetic nephropathy. • These models can be new tools to study urinary biomarkers that are relevant to human disease. - Abstract: Countering the diabetes pandemic and consequent complications, such as nephropathy, will require better understanding of disease mechanisms and development of new diagnostic methods. Animal models can be versatile tools in studies of diabetic renal disease when model pathology is relevant to human diabetic nephropathy (DN). Diabetic models using endothelial nitric oxide synthase (eNOS) knock-out mice develop major renal lesions characteristic of human disease. However, it is unknown whether they can also reproduce changes in urinary metabolites found in human DN. We employed Type 1 and Type 2 diabetic mouse models of DN, i.e. STZ-eNOS{sup −/−} C57BLKS and eNOS{sup −/−} C57BLKS db/db, with the goal of determining changes in urinary metabolite profile using proton nuclear magnetic resonance (NMR). Six urinary metabolites with significantly lower levels in diabetic compared to control mice have been identified. Specifically, major changes were found in metabolites from tricarboxylic acid (TCA) cycle and aromatic amino acid catabolism including 3-indoxyl sulfate, cis-aconitate, 2-oxoisocaproate, N-phenyl-acetylglycine, 4-hydroxyphenyl acetate, and hippurate. Levels of 4-hydroxyphenyl acetic acid and hippuric acid showed the strongest reverse correlation to albumin-to-creatinine ratio (ACR), which is an indicator of renal damage. Importantly, similar changes in urinary hydroxyphenyl acetate and hippurate were previously reported in human renal disease. We demonstrated that STZ-eNOS{sup −/−} C57BLKS and eNOS{sup −/−} C57BLKS db/db mouse models can recapitulate changes in urinary metabolome found in human DN and therefore can be

  17. Alterations of urinary metabolite profile in model diabetic nephropathy

    International Nuclear Information System (INIS)

    Stec, Donald F.; Wang, Suwan; Stothers, Cody; Avance, Josh; Denson, Deon; Harris, Raymond; Voziyan, Paul

    2015-01-01

    Highlights: • 1 H NMR spectroscopy was employed to study urinary metabolite profile in diabetic mouse models. • Mouse urinary metabolome showed major changes that are also found in human diabetic nephropathy. • These models can be new tools to study urinary biomarkers that are relevant to human disease. - Abstract: Countering the diabetes pandemic and consequent complications, such as nephropathy, will require better understanding of disease mechanisms and development of new diagnostic methods. Animal models can be versatile tools in studies of diabetic renal disease when model pathology is relevant to human diabetic nephropathy (DN). Diabetic models using endothelial nitric oxide synthase (eNOS) knock-out mice develop major renal lesions characteristic of human disease. However, it is unknown whether they can also reproduce changes in urinary metabolites found in human DN. We employed Type 1 and Type 2 diabetic mouse models of DN, i.e. STZ-eNOS −/− C57BLKS and eNOS −/− C57BLKS db/db, with the goal of determining changes in urinary metabolite profile using proton nuclear magnetic resonance (NMR). Six urinary metabolites with significantly lower levels in diabetic compared to control mice have been identified. Specifically, major changes were found in metabolites from tricarboxylic acid (TCA) cycle and aromatic amino acid catabolism including 3-indoxyl sulfate, cis-aconitate, 2-oxoisocaproate, N-phenyl-acetylglycine, 4-hydroxyphenyl acetate, and hippurate. Levels of 4-hydroxyphenyl acetic acid and hippuric acid showed the strongest reverse correlation to albumin-to-creatinine ratio (ACR), which is an indicator of renal damage. Importantly, similar changes in urinary hydroxyphenyl acetate and hippurate were previously reported in human renal disease. We demonstrated that STZ-eNOS −/− C57BLKS and eNOS −/− C57BLKS db/db mouse models can recapitulate changes in urinary metabolome found in human DN and therefore can be useful new tools in

  18. Pharmacokinetic modeling of gentamicin in treatment of infective endocarditis : Model development and validation of existing models

    NARCIS (Netherlands)

    Gomes, Anna; van der Wijk, Lars; Proost, Johannes H; Sinha, Bhanu; Touw, Daan J

    2017-01-01

    Gentamicin shows large variations in half-life and volume of distribution (Vd) within and between individuals. Thus, monitoring and accurately predicting serum levels are required to optimize effectiveness and minimize toxicity. Currently, two population pharmacokinetic models are applied for

  19. Perioperative pharmacokinetics of methadone in adolescents.

    Science.gov (United States)

    Sharma, Anshuman; Tallchief, Danielle; Blood, Jane; Kim, Thomas; London, Amy; Kharasch, Evan D

    2011-12-01

    Methadone is frequently administered to adults experiencing anesthesia and receiving pain treatment. Methadone pharmacokinetics in adults are well characterized, including the perioperative period. Methadone is also used in children. There is, however, no information on methadone pharmacokinetics in children of any age. The purpose of this investigation was to determine the pharmacokinetics of intravenous methadone in children undergoing surgery. Perioperative opioid-sparing effects were also assessed. Eligible subjects were children 5-18 yr undergoing general anesthesia and surgery, with an anticipated postoperative inpatient stay exceeding 3 days. Three groups of 10 to 11 patients each received intravenous methadone hydrochloride after anesthetic induction in ascending dose groups of 0.1, 0.2, and 0.3 mg/kg (up to 20 mg). Anesthetic care was not otherwise changed. Venous blood was obtained for 4 days, for stereoselective determination of methadone and metabolites. Pain assessments were made each morning. Daily and total opioid consumption was determined. Perioperative opioid consumption and pain was determined in a second cohort, which was matched to age, sex, race, ethnicity, surgical procedure, and length of stay, but not receiving methadone. The final methadone study cohort was 31 adolescents (14 ± 2 yr, range 10-18) undergoing major spine surgery for a diagnosis of scoliosis. Methadone pharmacokinetics were linear over the dose range 0.1-0.3 mg/kg. Disposition was stereoselective. Methadone administration did not dose-dependently affect postoperative pain scores, and did not dose-dependently decrease daily or total postoperative opioid consumption in spinal fusion patients. Methadone enantiomer disposition in adolescents undergoing surgery was similar to that in healthy adults.

  20. Vascular input function correction of inflow enhancement for improved pharmacokinetic modeling of liver DCE-MRI.

    Science.gov (United States)

    Ning, Jia; Schubert, Tilman; Johnson, Kevin M; Roldán-Alzate, Alejandro; Chen, Huijun; Yuan, Chun; Reeder, Scott B

    2018-06-01

    To propose a simple method to correct vascular input function (VIF) due to inflow effects and to test whether the proposed method can provide more accurate VIFs for improved pharmacokinetic modeling. A spoiled gradient echo sequence-based inflow quantification and contrast agent concentration correction method was proposed. Simulations were conducted to illustrate improvement in the accuracy of VIF estimation and pharmacokinetic fitting. Animal studies with dynamic contrast-enhanced MR scans were conducted before, 1 week after, and 2 weeks after portal vein embolization (PVE) was performed in the left portal circulation of pigs. The proposed method was applied to correct the VIFs for model fitting. Pharmacokinetic parameters fitted using corrected and uncorrected VIFs were compared between different lobes and visits. Simulation results demonstrated that the proposed method can improve accuracy of VIF estimation and pharmacokinetic fitting. In animal study results, pharmacokinetic fitting using corrected VIFs demonstrated changes in perfusion consistent with changes expected after PVE, whereas the perfusion estimates derived by uncorrected VIFs showed no significant changes. The proposed correction method improves accuracy of VIFs and therefore provides more precise pharmacokinetic fitting. This method may be promising in improving the reliability of perfusion quantification. Magn Reson Med 79:3093-3102, 2018. © 2017 International Society for Magnetic Resonance in Medicine. © 2017 International Society for Magnetic Resonance in Medicine.

  1. Prevention of irinotecan-induced diarrhea by oral sodium bicarbonate and influence on pharmacokinetics.

    Science.gov (United States)

    Tamura, Takao; Yasutake, Koichi; Nishisaki, Hogara; Nakashima, Takatoshi; Horita, Kazutugu; Hirohata, Sigeya; Ishii, Arata; Hamano, Kenichi; Aoyama, Nobuo; Shirasaka, Daisuke; Kamigaki, Takashi; Kasuga, Masato

    2004-01-01

    Alkalization of the intestinal tract by oral administration of sodium bicarbonate has been reported to be a promising method for preventing delayed diarrhea, a dose-limiting toxicity in patients receiving chemotherapy with irinotecan hydrochloride. However, it is feared that this method may adversely affect the pharmacokinetics of irinotecan by inhibiting its intestinal absorption and that of its active metabolites. We compared the pharmacokinetics and toxicity of irinotecan with and without oral alkalization in a cross-over study that enrolled 10 colorectal cancer patients. We found that alkalization did not decrease the blood levels of irinotecan and its active metabolite. In fact, the area under concentration versus time curves (AUCs) of irinotecan and 7-ethyl-10-hydroxycamptothecin glucuronide (SN-38G) were statistically equivalent both with and without oral alkalization. Also, the AUC of SN-38 with alkalization was statistically equivalent or larger than that without alkalization. Oral alkalization reduced the incidence of diarrhea and gastrointestinal symptoms, and these adverse effects were not worsened by long-term administration. These results suggest that oral alkalization can control diarrhea and gastrointestinal toxicity without decreasing the blood levels of irinotecan and its active metabolites, thus improving the tolerability of long-term chemotherapy without reducing efficacy. Copyright (c) 2004 S. Karger AG, Basel

  2. Rapid sensitive validated UPLC–MS method for determination of venlafaxine and its metabolite in rat plasma: Application to pharmacokinetic study

    Directory of Open Access Journals (Sweden)

    Sunil Kumar Dubey

    2013-12-01

    Full Text Available A new ultra-performance liquid chromatography–electrospray ionization mass spectrometry (UPLC–MS/ESI method for simultaneous determination of venlafaxine (VEN and its metabolite O-desmethylvenlafaxine (ODV in rat plasma has been developed and validated using Venlafaxine d6 as the internal standard. The compounds and internal standard were extracted from plasma by solid phase extraction. The UPLC separation of the analytes was performed on ACQUITY UPLC® BEH Shield RP18 (1.7 µm, 100 mm×2.1 mm column, using isocratic elution with mobile phase constituted of water (containing 2 mM ammonium acetate: acetonitrile (20:80, v/v at a flow rate of 0.3 mL/min. All of the analytes were eluted within 1.5 min. The compounds were ionized in the electrospray ionization (ESI ion source of the mass spectrometer, operating in multiple reaction monitoring (MRM and positive ion mode. The precursor to product ion transitions monitored for VEN, ODV and Venlafaxine d6 were m/z 278.3→121.08, 264.2→107.1 and 284.4→121.0, respectively. The developed and validated method was used for the pharmacokinetic study of VEN in rats. Keywords: Venlafaxine, O-desmethylvenlafaxine, Metabolite, UPLC–MS/ES

  3. Intracellular metabolites of mercaptopurine in children with lymphoblastic leukaemia: a possible indicator of non-compliance?

    OpenAIRE

    Lennard, L.; Welch, J.; Lilleyman, J. S.

    1995-01-01

    As part of a programme assessing the pharmacokinetics of oral thiopurines given for lymphoblastic leukaemia, we assayed intracellular metabolites of mercaptopurine in children from all over the United Kingdom who were given a standard dose of the drug. The metabolites we measured, thioguanine nucleotides and methylmercaptopurines, are products of two competing metabolic pathways and would be expected to show an inverse correlation. A total of 327 children from 17 centres in the UK were studie...

  4. Plant-Derived Polyphenols in Human Health: Biological Activity, Metabolites and Putative Molecular Targets.

    Science.gov (United States)

    Olivares-Vicente, Marilo; Barrajon-Catalan, Enrique; Herranz-Lopez, Maria; Segura-Carretero, Antonio; Joven, Jorge; Encinar, Jose Antonio; Micol, Vicente

    2018-01-01

    Hibiscus sabdariffa, Lippia citriodora, Rosmarinus officinalis and Olea europaea, are rich in bioactive compounds that represent most of the phenolic compounds' families and have exhibited potential benefits in human health. These plants have been used in folk medicine for their potential therapeutic properties in human chronic diseases. Recent evidence leads to postulate that polyphenols may account for such effects. Nevertheless, the compounds or metabolites that are responsible for reaching the molecular targets are unknown. data based on studies directly using complex extracts on cellular models, without considering metabolic aspects, have limited applicability. In contrast, studies exploring the absorption process, metabolites in the blood circulation and tissues have become essential to identify the intracellular final effectors that are responsible for extracts bioactivity. Once the cellular metabolites are identified using high-resolution mass spectrometry, docking techniques suppose a unique tool for virtually screening a large number of compounds on selected targets in order to elucidate their potential mechanisms. we provide an updated overview of the in vitro and in vivo studies on the toxicity, absorption, permeability, pharmacokinetics and cellular metabolism of bioactive compounds derived from the abovementioned plants to identify the potential compounds that are responsible for the observed health effects. we propose the use of targeted metabolomics followed by in silico studies to virtually screen identified metabolites on selected protein targets, in combination with the use of the candidate metabolites in cellular models, as the methods of choice for elucidating the molecular mechanisms of these compounds. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  5. Plasma and urine, pharmacokinetics of the dopamine agonist alpha-dihydroergocryptine in patients with hepatic dysfunction

    NARCIS (Netherlands)

    Althaus, M; de Mey, C; Ezan, E; Ciecko-Michalska, [No Value; Kostka-Trabkal, E; Goszcz, A; Retzow, A

    Objective: The aim of this study was to evaluate the pharmacokinetic behavior of unchanged alpha -dihydroergocryptine (DHEC, Almirid (R), Desitin Arzneimittel GmbH, Hamburg, Germany, under licence of Polichem S.A., Luxembourg) and total DHEC (unchanged DHEC and pooled metabolites) in plasma and

  6. Dispositions of enrofloxacin and its major metabolite ciprofloxacin in Thai swamp buffaloes

    Science.gov (United States)

    RUENNARONG, Nitwarat; WONGPANIT, Kannika; SAKULTHAEW, Chainarong; GIORGI, Mario; KUMAGAI, Susumu; POAPOLATHEP, Amnart; POAPOLATHEP, Saranya

    2015-01-01

    Given the limited information available in this species, the aim of this study was to investigate the pharmacokinetic characteristics of enrofloxacin (ER) and its major metabolite ciprofloxacin (CP) in buffaloes, Bubalus bubalis. ER was administered intravenously (i.v.) or subcutaneously (s.c.) to buffaloes at doses of 5.0 and 7.5 mg/kg BW, and plasma, urine and fecal samples were collected until 48 hr post-administration. The concentrations of ER and CP in the plasma, urine and feces were analyzed using high-performance liquid chromatography equipped with a fluorescence detector. The plasma concentrations of ER and CP could be determined up to 24 hr and 32 hr after i.v. and s.c. administrations at doses of 5.0 and 7.5 mg/kg BW, respectively. CP concentrations were always lower than those of parental drug. The s.c. bioavailability of ER was 52.36 ± 4.24% and 72.12 ± 5.39% at doses of 5.0 and 7.5 mg/kg BW, respectively. Both ER and CP were detectable in urine and feces up to 24 hr. ER and CP were mainly excreted via the urine. Based on the pharmacokinetic data and PK-PD indices, s.c. administration of ER at doses of 5.0 and 7.5 mg/kg BW might be appropriate for the treatment of susceptible bacterial diseases in Thai swamp buffaloes. PMID:26596287

  7. Disposition of allylic oxidation pathway metabolites of racemic hexobarbital in the rat

    NARCIS (Netherlands)

    Van der Graaff, M; Vermeulen, N P; Vinks, M H; Breimer, D D

    1986-01-01

    The pharmacokinetics in blood of the major metabolites of hexobarbital (HB), 3'-hydroxyhexobarbital (OH-HB) and 3'-ketohexobarbital (K-HB) were studied in rats. In addition urinary excretion of OH-HB and K-HB and 1,5-dimethylbarbituric acid (DMBA) was determined. Half-lives of OH-HB and K-HB were

  8. Pharmacokinetic/Pharmacodynamic Modeling of Renin-Angiotensin Aldosterone Biomarkers Following Angiotensin-Converting Enzyme (ACE) Inhibition Therapy with Benazepril in Dogs.

    Science.gov (United States)

    Mochel, Jonathan P; Fink, Martin; Peyrou, Mathieu; Soubret, Antoine; Giraudel, Jérôme M; Danhof, Meindert

    2015-06-01

    The objective of this research was to provide a comprehensive description of the effect of benazepril on the dynamics of the renin-angiotensin aldosterone system (RAAS) in dogs. Blood specimens for renin activity (RA), angiotensin II (AII), and aldosterone (ALD) quantitation in plasma were drawn from 12 healthy adult beagle dogs randomly allocated to 2 treatment groups: (i) benazepril 5 mg PO, q24 h (n: 6) and (ii) placebo (n: 6), in a cross-over design. A mechanism-based pharmacokinetic/pharmacodynamic model, which includes the periodic nature of RA, AII, and ALD during placebo treatment and the subsequent changes in dynamics following repeated dosing with benazepril, was developed. The disposition kinetics of benazepril active metabolite, benazeprilat, was characterized using a saturable binding model to the angiotensin converting enzyme. The modulatory effect of benazeprilat on the RAAS was described using a combination of immediate response models. Our data show that benazepril noticeably influences the dynamics of the renin cascade, resulting in a substantial decrease in AII and ALD, while increasing RA throughout the observation span. The model provides a quantitative framework for better understanding the effect of ACE inhibition on the dynamics of the systemic RAAS in dogs.

  9. Sequential updating of a new dynamic pharmacokinetic model for caffeine in premature neonates.

    Science.gov (United States)

    Micallef, Sandrine; Amzal, Billy; Bach, Véronique; Chardon, Karen; Tourneux, Pierre; Bois, Frédéric Y

    2007-01-01

    Caffeine treatment is widely used in nursing care to reduce the risk of apnoea in premature neonates. To check the therapeutic efficacy of the treatment against apnoea, caffeine concentration in blood is an important indicator. The present study was aimed at building a pharmacokinetic model as a basis for a medical decision support tool. In the proposed model, time dependence of physiological parameters is introduced to describe rapid growth of neonates. To take into account the large variability in the population, the pharmacokinetic model is embedded in a population structure. The whole model is inferred within a Bayesian framework. To update caffeine concentration predictions as data of an incoming patient are collected, we propose a fast method that can be used in a medical context. This involves the sequential updating of model parameters (at individual and population levels) via a stochastic particle algorithm. Our model provides better predictions than the ones obtained with models previously published. We show, through an example, that sequential updating improves predictions of caffeine concentration in blood (reduce bias and length of credibility intervals). The update of the pharmacokinetic model using body mass and caffeine concentration data is studied. It shows how informative caffeine concentration data are in contrast to body mass data. This study provides the methodological basis to predict caffeine concentration in blood, after a given treatment if data are collected on the treated neonate.

  10. Population Pharmacokinetic Model for Vancomycin Used in Open Heart Surgery: Model-Based Evaluation of Standard Dosing Regimens.

    Science.gov (United States)

    Alqahtani, Saeed A; Alsultan, Abdullah S; Alqattan, Hussain M; Eldemerdash, Ahmed; Albacker, Turki B

    2018-04-23

    The purpose of this study was to investigate the population pharmacokinetics of vancomycin in patients undergoing open heart surgery. In this observational pharmacokinetic study, multiple blood samples were drawn over a 48-h period of intravenous vancomycin in patients who were undergoing open heart surgery. Blood samples were analysed using the Architect i4000SR Immunoassay Analyzer. Population pharmacokinetic models were developed using Monolix 4.4 software. Pharmacokinetic-pharmacodynamic (PK-PD) simulations were performed to explore the ability of different dosage regimens to achieve the pharmacodynamic targets. One-hundred and sixty-eight blood samples were analysed from 28 patients. The pharmacokinetics of vancomycin was best described by a two-compartment model with between-subject variability in CL, V of the central compartment, and V of the peripheral compartment. CL and central compartment V of vancomycin were related to CL CR , body weight, and albumin concentration. Dosing simulations showed that standard dosing regimens of 1 and 1.5 g failed to achieve the PK-PD target of AUC 0--24 /MIC > 400 for an MIC of 1 mg/L, while high weight-based dosing regimens were able to achieve the PK-PD target. In summary, administration of standard doses of 1 and 1.5 g of vancomycin two times daily provided inadequate antibiotic prophylaxis in patients undergoing open heart surgery. The same findings were obtained when 15 mg/kg and 20 mg/kg doses of vancomycin were administered. Achieving the PK-PD target required higher doses (25 mg/kg and 30 mg/kg) of vancomycin. Copyright © 2018 American Society for Microbiology.

  11. Pharmacogenetics of taxanes: impact of gene polymorphisms of drug transporters on pharmacokinetics and toxicity.

    Science.gov (United States)

    Jabir, Rafid Salim; Naidu, Rakesh; Annuar, Muhammad Azrif Bin Ahmad; Ho, Gwo Fuang; Munisamy, Murali; Stanslas, Johnson

    2012-12-01

    Interindividual variability in drug response and the emergence of adverse drug effects are the main causes of treatment failure in cancer therapy. Functional membrane drug transporters play important roles in altering pharmacokinetic profile, resistance to treatment, toxicity and patient survival. Pharmacogenetic studies of these transporters are expected to provide new approaches for optimizing therapy. Taxanes are approved for the treatment of various cancers. Circulating taxanes are taken up by SLCO1B3 into hepatocytes. The CYP450 enzymes CYP3A4, CYP3A5 and CYP2C8 are responsible for the conversion of taxanes into their metabolites. Ultimately, ABCB1 and ABCC2 will dispose the metabolites into bile canaliculi. Polymorphisms of genes encoding for proteins involved in the transport and clearance of taxanes reduce excretion of the drugs, leading to development of toxicity in patients. This review addresses current knowledge on genetic variations of transporters affecting taxanes pharmacokinetics and toxicity, and provides insights into future direction for personalized medicine.

  12. Development of a paediatric population-based model of the pharmacokinetics of rivaroxaban.

    Science.gov (United States)

    Willmann, Stefan; Becker, Corina; Burghaus, Rolf; Coboeken, Katrin; Edginton, Andrea; Lippert, Jörg; Siegmund, Hans-Ulrich; Thelen, Kirstin; Mück, Wolfgang

    2014-01-01

    Venous thromboembolism has been increasingly recognised as a clinical problem in the paediatric population. Guideline recommendations for antithrombotic therapy in paediatric patients are based mainly on extrapolation from adult clinical trial data, owing to the limited number of clinical trials in paediatric populations. The oral, direct Factor Xa inhibitor rivaroxaban has been approved in adult patients for several thromboembolic disorders, and its well-defined pharmacokinetic and pharmacodynamic characteristics and efficacy and safety profiles in adults warrant further investigation of this agent in the paediatric population. The objective of this study was to develop and qualify a physiologically based pharmacokinetic (PBPK) model for rivaroxaban doses of 10 and 20 mg in adults and to scale this model to the paediatric population (0-18 years) to inform the dosing regimen for a clinical study of rivaroxaban in paediatric patients. Experimental data sets from phase I studies supported the development and qualification of an adult PBPK model. This adult PBPK model was then scaled to the paediatric population by including anthropometric and physiological information, age-dependent clearance and age-dependent protein binding. The pharmacokinetic properties of rivaroxaban in virtual populations of children were simulated for two body weight-related dosing regimens equivalent to 10 and 20 mg once daily in adults. The quality of the model was judged by means of a visual predictive check. Subsequently, paediatric simulations of the area under the plasma concentration-time curve (AUC), maximum (peak) plasma drug concentration (C max) and concentration in plasma after 24 h (C 24h) were compared with the adult reference simulations. Simulations for AUC, C max and C 24h throughout the investigated age range largely overlapped with values obtained for the corresponding dose in the adult reference simulation for both body weight-related dosing regimens. However

  13. Application of pharmacokinetic modeling to the radiation dosimetry of hepatobiliary agents

    International Nuclear Information System (INIS)

    Loberg, M.D.; Buddemeyer, E.U.

    1981-01-01

    Dosimetry calculations based on biodistribution data from lower animal species often inadequately approximate the true dosimetry in humans and seldom apply in the presence of human pathology. An alternative approach is to use animal data for the limited purpose of developing a pharmacokinetic model describing the various compartments and their interconnecting pathways. To the extent that components are similarly connected in man, the model can be used to compute cumulative concentrations (μCi-h/gm) in humans by using the compartment masses and rate constants appropriate for man. In this manner dose estimates can be obtained which are less dependent upon the species from which the model was derived. The altered radiation dose in certain disease states having a known relationship to the model can also be predicted with confidence. This work reports the development in dogs of a four-compartment model which accurately describes the in-vivo distribution of Tc/sup 99m/-HIDA. The pharmacokinetic model was used to predict the kinetics of the HIDA analog which would yield clinically useful information, while minimizing patient radiation exposure

  14. Physiologically-based pharmacokinetic model for Fentanyl in support of the development of Provisional Advisory Levels

    International Nuclear Information System (INIS)

    Shankaran, Harish; Adeshina, Femi; Teeguarden, Justin G.

    2013-01-01

    Provisional Advisory Levels (PALs) are tiered exposure limits for toxic chemicals in air and drinking water that are developed to assist in emergency responses. Physiologically-based pharmacokinetic (PBPK) modeling can support this process by enabling extrapolations across doses, and exposure routes, thereby addressing gaps in the available toxicity data. Here, we describe the development of a PBPK model for Fentanyl – a synthetic opioid used clinically for pain management – to support the establishment of PALs. Starting from an existing model for intravenous Fentanyl, we first optimized distribution and clearance parameters using several additional IV datasets. We then calibrated the model using pharmacokinetic data for various formulations, and determined the absorbed fraction, F, and time taken for the absorbed amount to reach 90% of its final value, t90. For aerosolized pulmonary Fentanyl, F = 1 and t90 50 human datasets. • Model predictions are in good agreement with the available pharmacokinetic data. • The model can be used for extrapolating across routes, doses and exposure durations. • We illustrate how the model can be used for developing Provisional Advisory Levels

  15. Pharmacokinetic-pharmacodynamic modeling of activity of ceftazidime during continuous and intermittent infusion

    NARCIS (Netherlands)

    J.W. Mouton (Johan); A.A. Vinks; N.C. Punt

    1997-01-01

    textabstractWe developed and applied pharmacokinetic-pharmacodynamic (PK-PD) models to characterize in vitro bacterial rate of killing as a function of ceftazidime concentrations over time. For PK-PD modeling, data obtained during continuous and intermittent infusion of

  16. Pharmacokinetic behavior of enrofloxacin and its metabolite ciprofloxacin in urutu pit vipers (Bothrops alternatus) after intramuscular administration.

    Science.gov (United States)

    Waxman, Samanta; Prados, Ana Paula; de Lucas, José Julio; San Andrés, Manuel Ignacion; Regner, Pablo; de Oliveira, Vanesa Costa; de Roodt, Adolfo; Rodríguez, Casilda

    2014-03-01

    Enrofloxacin is widely used in veterinary medicine and is an important alternative to treating bacterial infections, which play an important role as causes of disease and death in captive snakes. Its extralabel use in nontraditional species has been related to its excellent pharmacokinetic and antimicrobial characteristics. This can be demonstrated by its activity against gram-negative organisms implicated in serious infectious diseases of reptile species with a rapid and concentration-dependent bactericidal effect and a large volume of distribution. Pharmacokinetic parameters for enrofloxacin were investigated in seven urutu pit vipers (Bothrops alternatus), following intramuscular injections of 10 mg/kg. The plasma concentrations of enrofloxacin and its metabolite, ciprofloxacin, were measured using high-performance liquid chromatography. Blood samples were collected from the ventral coccygeal veins at 0.5, 1, 2, 4, 8, 12, 24, 36, 48, 72, 96, 108, and 168 hr. The kinetic behavior was characterized by a relatively slow absorption (time of maximal plasma concentration = 4.50 +/- 3.45 hr) with peak plasma concentration of 4.81 +/- 1.12 microg/ml. The long half-life during the terminal elimination phase (t1/2 lambda = 27.91 +/- 7.55 hr) of enrofloxacin after intramuscular administration, calculated in the present study, could suggest that the antibiotic is eliminated relatively slowly and/or the presence of a slow absorption in urutu pit vipers. Ciprofloxacin reached a peak plasma concentration of 0.35 microg/ml at 13.45 hr, and the fraction of enrofloxacin metabolized to ciprofloxacin was 13.06%. If enrofloxacin's minimum inhibitory concentration (MIC90) values of 0.5 microg/ml were used, the ratios AUC(e+c): MIC90 (276 +/- 67 hr) and Cmax(e+c): MIC90 (10 +/- 2) reach the proposed threshold values (125 hr and 10, respectively) for optimized efficacy and minimized resistance development when treating infections caused by Pseudomonas. The administration of 10 mg/kg of

  17. Development of a Physiologically-Based Pharmacokinetic Model of Trichloroethylene and Its Metabolites for Use in Risk Assessment

    Science.gov (United States)

    2004-09-01

    and free trichloroethanol. Toxicol. App!. Pharmacol., 152, 339-359, 1998. 10. Stenner , R.D., Merdink, J.L., Fisher, J.W., and Bull, R...M.V., Stevens, D.K., Stenner , R.D., Bonate, P.L., Tuman, D., and Bull, R.J., Factors affecting species differences in the kinetics of metabolites of

  18. Effects of dialysis on the pharmacokinetics of salazosulfapyridine.

    Science.gov (United States)

    Inami, Yuko; Yamaji, Ken; Sato, Michiko; Gohda, Tomohito; Io, Hiroaki; Nawata, Masuyuki; Hamada, Chieko; Takasaki, Yoshinari; Tomino, Yasuhiko

    2013-02-01

    There was no standard or report for the treatment of rheumatoid arthritis (RA) patients on hemodialysis with Salazosulfapyridine (SASP). We examined the pharmacokinetics of SASP and its metabolites in RA patient on hemodialysis. Hemodialysis was started 2 h after administration of SASP at a dose of 250 or 500 mg. Blood samples were took 8 times during the observation period. The concentration of SASP and its metabolites (SP, Ac-SP) in blood sample were measured. There was no difference for the concentration of SASP before and after hemodialysis. Results showed SASP was nondialyzable, but SP and AC-SP were dialyzable. At a dose of 500 mg, AUC0-∞ of SASP and SP were higher than healthy volunteer. Therapy with SASP for hemodialysis RA should be started at a lower dose for adverse event risk.

  19. Population pharmacokinetics of a three-day chloroquine treatment in patients with Plasmodium vivax infection on the Thai-Myanmar border.

    Science.gov (United States)

    Höglund, Richard; Moussavi, Younis; Ruengweerayut, Ronnatrai; Cheomung, Anurak; Äbelö, Angela; Na-Bangchang, Kesara

    2016-02-29

    A three-day course of chloroquine remains a standard treatment of Plasmodium vivax infection in Thailand with satisfactory clinical efficacy and tolerability although a continuous decline in in vitro parasite sensitivity has been reported. Information on the pharmacokinetics of chloroquine and its active metabolite desethylchloroquine are required for optimization of treatment to attain therapeutic exposure and thus prevent drug resistance development. The study was conducted at Mae Tao Clinic for migrant worker, Tak province, Thailand. Blood samples were collected from a total of 75 (8 Thais and 67 Burmeses; 36 males and 39 females; aged 17-52 years) patients with mono-infection with P. vivax malaria [median (95 % CI) admission parasitaemia 4898 (1206-29,480)/µL] following treatment with a three-day course of chloroquine (25 mg/kg body weight chloroquine phosphate over 3 days). Whole blood concentrations of chloroquine and desethylchloroquine were measured using high performance liquid chromatography with UV detection. Concentration-time profiles of both compounds were analysed using a population-based pharmacokinetic approach. All patients showed satisfactory response to standard treatment with a three-day course of chloroquine with 100 % cure rate within the follow-up period of 42 days. Neither recurrence of P. vivax parasitaemia nor appearance of P. falciparum occurred. A total of 1045 observations from 75 participants were included in the pharmacokinetic analysis. Chloroquine disposition was most adequately described by the two-compartment model with one transit compartment absorption model into the central compartment and a first-order transformation of chloroquine into desethylchloroquine with an additional peripheral compartment added to desethylchloroquine. First-order elimination from the central compartment of chloroquine and desethylchloroquine was assumed. The model exhibited a strong predictive ability and the pharmacokinetic parameters were

  20. Metoprolol Dose Equivalence in Adult Men and Women Based on Gender Differences: Pharmacokinetic Modeling and Simulations

    Directory of Open Access Journals (Sweden)

    Andy R. Eugene

    2016-11-01

    Full Text Available Recent meta-analyses and publications over the past 15 years have provided evidence showing there are considerable gender differences in the pharmacokinetics of metoprolol. Throughout this time, there have not been any research articles proposing a gender stratified dose-adjustment resulting in an equivalent total drug exposure. Metoprolol pharmacokinetic data was obtained from a previous publication. Data was modeled using nonlinear mixed effect modeling using the MONOLIX software package to quantify metoprolol concentration–time data. Gender-stratified dosing simulations were conducted to identify equivalent total drug exposure based on a 100 mg dose in adults. Based on the pharmacokinetic modeling and simulations, a 50 mg dose in adult women provides an approximately similar metoprolol drug exposure to a 100 mg dose in adult men.

  1. Population pharmacokinetics model of THC used by pulmonary route in occasional cannabis smokers.

    Science.gov (United States)

    Marsot, A; Audebert, C; Attolini, L; Lacarelle, B; Micallef, J; Blin, O

    Cannabis is the most widely used illegal drug in the world. Delta-9-tetrahydrocannabinol (THC) is the main source of the pharmacological effect. Some studies have been carried out and showed significant variability in the described models as the values of the estimated pharmacokinetic parameters. The objective of this study was to develop a population pharmacokinetic model for THC in occasional cannabis smokers. Twelve male volunteers (age: 20-28years, body weight: 62.5-91.0kg), tobacco (3-8 cigarette per day) and cannabis occasional smokers were recruited from the local community. After ad libitum smoking cannabis cigarette according a standardized procedure, 16 blood samples up to 72h were collected. Population pharmacokinetic analysis was performed using a non-linear mixed effects model, with NONMEM software. Demographic and biological data were investigated as covariates. A three-compartment model with first-order elimination fitted the data. The model was parameterized in terms of micro constants and central volume of distribution (V 1 ). Normal ALT concentration (6.0 to 45.0IU/l) demonstrated a statistically significant correlation with k 10 . The mean values (%Relative Standard Error (RSE)) for k 10 , k 12 , k 21 , k 23 , k 32 and V 1 were 0.408h -1 (48.8%), 4.070h -1 (21.4%), 0.022h -1 (27.0%), 1.070h -1 (14.3%), 1.060h -1 (16.7%) and 19.10L (39.7%), respectively. We have developed a population pharmacokinetic model able to describe the quantitative relationship between administration of inhaled doses of THC and the observed plasma concentrations after smoking cannabis. In addition, a linear relationship between ALT concentration and value of k 10 has been described and request further investigation. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. A computer-aided framework for development, identification andmanagement of physiologically-based pharmacokinetic models

    DEFF Research Database (Denmark)

    Heitzig, Martina; Linninger, Andreas; Sin, Gürkan

    2014-01-01

    The objective of this work is the development of a generic computer-aided modelling framework to support the development of physiologically-based pharmacokinetic models thereby increasing the efficiency and quality of the modelling process. In particular, the framework systematizes the modelling...

  3. Limited-sampling strategy models for estimating the pharmacokinetic parameters of 4-methylaminoantipyrine, an active metabolite of dipyrone

    Directory of Open Access Journals (Sweden)

    Suarez-Kurtz G.

    2001-01-01

    Full Text Available Bioanalytical data from a bioequivalence study were used to develop limited-sampling strategy (LSS models for estimating the area under the plasma concentration versus time curve (AUC and the peak plasma concentration (Cmax of 4-methylaminoantipyrine (MAA, an active metabolite of dipyrone. Twelve healthy adult male volunteers received single 600 mg oral doses of dipyrone in two formulations at a 7-day interval in a randomized, crossover protocol. Plasma concentrations of MAA (N = 336, measured by HPLC, were used to develop LSS models. Linear regression analysis and a "jack-knife" validation procedure revealed that the AUC0-¥ and the Cmax of MAA can be accurately predicted (R²>0.95, bias 0.85 of the AUC0-¥ or Cmax for the other formulation. LSS models based on three sampling points (1.5, 4 and 24 h, but using different coefficients for AUC0-¥ and Cmax, predicted the individual values of both parameters for the enrolled volunteers (R²>0.88, bias = -0.65 and -0.37%, precision = 4.3 and 7.4% as well as for plasma concentration data sets generated by simulation (R²>0.88, bias = -1.9 and 8.5%, precision = 5.2 and 8.7%. Bioequivalence assessment of the dipyrone formulations based on the 90% confidence interval of log-transformed AUC0-¥ and Cmax provided similar results when either the best-estimated or the LSS-derived metrics were used.

  4. Development of good modelling practice for phsiologically based pharmacokinetic models for use in risk assessment: The first steps

    Science.gov (United States)

    The increasing use of tissue dosimetry estimated using pharmacokinetic models in chemical risk assessments in multiple countries necessitates the need to develop internationally recognized good modelling practices. These practices would facilitate sharing of models and model eva...

  5. Mathematical modeling and simulation in animal health. Part I: Moving beyond pharmacokinetics.

    Science.gov (United States)

    Riviere, J E; Gabrielsson, J; Fink, M; Mochel, J

    2016-06-01

    The application of mathematical modeling to problems in animal health has a rich history in the form of pharmacokinetic modeling applied to problems in veterinary medicine. Advances in modeling and simulation beyond pharmacokinetics have the potential to streamline and speed-up drug research and development programs. To foster these goals, a series of manuscripts will be published with the following goals: (i) expand the application of modeling and simulation to issues in veterinary pharmacology; (ii) bridge the gap between the level of modeling and simulation practiced in human and veterinary pharmacology; (iii) explore how modeling and simulation concepts can be used to improve our understanding of common issues not readily addressed in human pharmacology (e.g. breed differences, tissue residue depletion, vast weight ranges among adults within a single species, interspecies differences, small animal species research where data collection is limited to sparse sampling, availability of different sampling matrices); and (iv) describe how quantitative pharmacology approaches could help understanding key pharmacokinetic and pharmacodynamic characteristics of a drug candidate, with the goal of providing explicit, reproducible, and predictive evidence for optimizing drug development plans, enabling critical decision making, and eventually bringing safe and effective medicines to patients. This study introduces these concepts and introduces new approaches to modeling and simulation as well as clearly articulate basic assumptions and good practices. The driving force behind these activities is to create predictive models that are based on solid physiological and pharmacological principles as well as adhering to the limitations that are fundamental to applying mathematical and statistical models to biological systems. © 2015 John Wiley & Sons Ltd.

  6. Impact of Cytochrome P450 2D6 Function on the Chiral Blood Plasma Pharmacokinetics of 3,4-Methylenedioxymethamphetamine (MDMA) and Its Phase I and II Metabolites in Humans.

    Science.gov (United States)

    Steuer, Andrea E; Schmidhauser, Corina; Tingelhoff, Eva H; Schmid, Yasmin; Rickli, Anna; Kraemer, Thomas; Liechti, Matthias E

    2016-01-01

    3,4-methylenedioxymethamphetamine (MDMA; ecstasy) metabolism is known to be stereoselective, with preference for S-stereoisomers. Its major metabolic step involves CYP2D6-catalyzed demethylenation to 3,4-dihydroxymethamphetamine (DHMA), followed by methylation and conjugation. Alterations in CYP2D6 genotype and/or phenotype have been associated with higher toxicity. Therefore, the impact of CYP2D6 function on the plasma pharmacokinetics of MDMA and its phase I and II metabolites was tested by comparing extensive metabolizers (EMs), intermediate metabolizers (IMs), and EMs that were pretreated with bupropion as a metabolic inhibitor in a controlled MDMA administration study. Blood plasma samples were collected from 16 healthy participants (13 EMs and three IMs) up to 24 h after MDMA administration in a double-blind, placebo-controlled, four-period, cross-over design, with subjects receiving 1 week placebo or bupropion pretreatment followed by a single placebo or MDMA (125 mg) dose. Bupropion pretreatment increased the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from 0 to 24 h (AUC24) of R-MDMA (9% and 25%, respectively) and S-MDMA (16% and 38%, respectively). Bupropion reduced the Cmax and AUC24 of the CYP2D6-dependently formed metabolite stereoisomers of DHMA 3-sulfate, DHMA 4-sulfate, and 4-hydroxy-3-methoxymethamphetamine (HMMA sulfate and HMMA glucuronide) by approximately 40%. The changes that were observed in IMs were generally comparable to bupropion-pretreated EMs. Although changes in stereoselectivity based on CYP2D6 activity were observed, these likely have low clinical relevance. Bupropion and hydroxybupropion stereoisomer pharmacokinetics were unaltered by MDMA co-administration. The present data might aid further interpretations of toxicity based on CYP2D6-dependent MDMA metabolism.

  7. Impact of Cytochrome P450 2D6 Function on the Chiral Blood Plasma Pharmacokinetics of 3,4-Methylenedioxymethamphetamine (MDMA and Its Phase I and II Metabolites in Humans.

    Directory of Open Access Journals (Sweden)

    Andrea E Steuer

    Full Text Available 3,4-methylenedioxymethamphetamine (MDMA; ecstasy metabolism is known to be stereoselective, with preference for S-stereoisomers. Its major metabolic step involves CYP2D6-catalyzed demethylenation to 3,4-dihydroxymethamphetamine (DHMA, followed by methylation and conjugation. Alterations in CYP2D6 genotype and/or phenotype have been associated with higher toxicity. Therefore, the impact of CYP2D6 function on the plasma pharmacokinetics of MDMA and its phase I and II metabolites was tested by comparing extensive metabolizers (EMs, intermediate metabolizers (IMs, and EMs that were pretreated with bupropion as a metabolic inhibitor in a controlled MDMA administration study. Blood plasma samples were collected from 16 healthy participants (13 EMs and three IMs up to 24 h after MDMA administration in a double-blind, placebo-controlled, four-period, cross-over design, with subjects receiving 1 week placebo or bupropion pretreatment followed by a single placebo or MDMA (125 mg dose. Bupropion pretreatment increased the maximum plasma concentration (Cmax and area under the plasma concentration-time curve from 0 to 24 h (AUC24 of R-MDMA (9% and 25%, respectively and S-MDMA (16% and 38%, respectively. Bupropion reduced the Cmax and AUC24 of the CYP2D6-dependently formed metabolite stereoisomers of DHMA 3-sulfate, DHMA 4-sulfate, and 4-hydroxy-3-methoxymethamphetamine (HMMA sulfate and HMMA glucuronide by approximately 40%. The changes that were observed in IMs were generally comparable to bupropion-pretreated EMs. Although changes in stereoselectivity based on CYP2D6 activity were observed, these likely have low clinical relevance. Bupropion and hydroxybupropion stereoisomer pharmacokinetics were unaltered by MDMA co-administration. The present data might aid further interpretations of toxicity based on CYP2D6-dependent MDMA metabolism.

  8. Effect of methamphetamine on the pharmacokinetics of dextromethorphan and midazolam in rats.

    Science.gov (United States)

    Dostalek, M; Hadasova, E; Hanesova, M; Pistovcakova, J; Sulcova, A; Jurica, J; Tomandl, J; Linhart, I

    2005-01-01

    Methamphetamine is the fourth most frequently reported compound associated with drug abuse on admission of patients to treatment centres after cocaine, heroin and marijuana. It is metabolized in the organism with a reaction that is catalyzed by cytochrome P450, mainly by the CYP2D and CYP3A subfamily, 4-hydroxyamphetamine and amphetamine being dominant metabolites. The present pharmacokinetic study was undertaken to investigate the possible influence of methamphetamine (10 mg/kg, i.p., once daily for six days) on the pharmacokinetics of dextromethorphane as a model substrate for rat cytochrome P-4502D2 and midazolam as a model substrate for CYP3A1/2. Animals received a single injection of dextromethorphane (10 mg/kg) or midazolam (5 mg/kg) in the tail vein 24 h after the last dose of methamphetamine or administration of placebo. The results of pharmacokinetic analysis showed a significantly increased rate of dextrorphane and 3-hydroxymorphinan formation, and a marked stimulatory effect of methamphetamine on CYP2D2 metabolic activity. Similarly, the kinetics of midazolam's metabolic conversion to hydroxy derivates of midazolam indicated a significant increase in CYP3A1/2 activity. The results showed that the administration of methamphetamine significantly stimulated the metabolic activity of CYP2D2 as well as that of CYP3A1/2. With regard to the high level of homology between human and rat CYP isoforms studied, the results may have a clinical impact on future pharmacotherapy for methamphetamine abuse.

  9. Development and validation of bioanalytical UHPLC-UV method for simultaneous analysis of unchanged fenofibrate and its metabolite fenofibric acid in rat plasma: Application to pharmacokinetics

    Directory of Open Access Journals (Sweden)

    Rayan G. Alamri

    2017-01-01

    Full Text Available A simple, precise, selective and fast ultra-high performance liquid chromatography (UHPLC-UV method has been developed and validated for the simultaneous determination of a lipid regulating agent fenofibrate and its metabolite fenofibric acid in rat plasma. The chromatographic separation was carried out on a reversed-phase Acquity® BEH C18 column using methanol–water (65:35, v/v as the mobile phase. The isocratic flow was 0.3 ml/min with rapid run time of 2.5 min and UV detection was at 284 nm. The method was validated over a concentration range of 100–10000 ng/ml (r2 ⩾ 0.9993. The selectivity, specificity, recovery, accuracy and precision were validated for determination of fenofibrate/fenofibric acid in rat plasma. The lower limits of detection and quantitation of the method were 30 and 90 ng/ml for fenofibrate and 40 and 100 ng/ml for fenofibric acid, respectively. The within and between-day coefficients of variation were less than 5%. The validated method has been successfully applied to measure the plasma concentrations in pharmacokinetics study of fenofibrate in an animal model to illustrate the scope and application of the method.

  10. Development of a Physiologically-Based Pharmacokinetic Model of the Rat Central Nervous System

    Directory of Open Access Journals (Sweden)

    Raj K. Singh Badhan

    2014-03-01

    Full Text Available Central nervous system (CNS drug disposition is dictated by a drug’s physicochemical properties and its ability to permeate physiological barriers. The blood–brain barrier (BBB, blood-cerebrospinal fluid barrier and centrally located drug transporter proteins influence drug disposition within the central nervous system. Attainment of adequate brain-to-plasma and cerebrospinal fluid-to-plasma partitioning is important in determining the efficacy of centrally acting therapeutics. We have developed a physiologically-based pharmacokinetic model of the rat CNS which incorporates brain interstitial fluid (ISF, choroidal epithelial and total cerebrospinal fluid (CSF compartments and accurately predicts CNS pharmacokinetics. The model yielded reasonable predictions of unbound brain-to-plasma partition ratio (Kpuu,brain and CSF:plasma ratio (CSF:Plasmau using a series of in vitro permeability and unbound fraction parameters. When using in vitro permeability data obtained from L-mdr1a cells to estimate rat in vivo permeability, the model successfully predicted, to within 4-fold, Kpuu,brain and CSF:Plasmau for 81.5% of compounds simulated. The model presented allows for simultaneous simulation and analysis of both brain biophase and CSF to accurately predict CNS pharmacokinetics from preclinical drug parameters routinely available during discovery and development pathways.

  11. The Influence of Normalization Weight in Population Pharmacokinetic Covariate Models.

    Science.gov (United States)

    Goulooze, Sebastiaan C; Völler, Swantje; Välitalo, Pyry A J; Calvier, Elisa A M; Aarons, Leon; Krekels, Elke H J; Knibbe, Catherijne A J

    2018-03-23

    In covariate (sub)models of population pharmacokinetic models, most covariates are normalized to the median value; however, for body weight, normalization to 70 kg or 1 kg is often applied. In this article, we illustrate the impact of normalization weight on the precision of population clearance (CL pop ) parameter estimates. The influence of normalization weight (70, 1 kg or median weight) on the precision of the CL pop estimate, expressed as relative standard error (RSE), was illustrated using data from a pharmacokinetic study in neonates with a median weight of 2.7 kg. In addition, a simulation study was performed to show the impact of normalization to 70 kg in pharmacokinetic studies with paediatric or obese patients. The RSE of the CL pop parameter estimate in the neonatal dataset was lowest with normalization to median weight (8.1%), compared with normalization to 1 kg (10.5%) or 70 kg (48.8%). Typical clearance (CL) predictions were independent of the normalization weight used. Simulations showed that the increase in RSE of the CL pop estimate with 70 kg normalization was highest in studies with a narrow weight range and a geometric mean weight away from 70 kg. When, instead of normalizing with median weight, a weight outside the observed range is used, the RSE of the CL pop estimate will be inflated, and should therefore not be used for model selection. Instead, established mathematical principles can be used to calculate the RSE of the typical CL (CL TV ) at a relevant weight to evaluate the precision of CL predictions.

  12. Quantitative and qualitative analysis of the novel antitumor 1,3,4-oxadiazole derivative (GLB) and its metabolites using HPLC-UV and UPLC-QTOF-MS

    Science.gov (United States)

    Li, Pu; Wang, Xin; Li, Jian; Meng, Zhi-Yun; Li, Shu-Chun; Li, Zhong-Jun; Lu, Ying-Yuan; Ren, Hong; Lou, Ya-Qing; Lu, Chuang; Dou, Gui-Fang; Zhang, Guo-Liang

    2015-01-01

    Fructose-based 3-acetyl-2,3-dihydro-1,3,4-oxadiazole (GLB) is a novel antitumor agent and belongs to glycosylated spiro-heterocyclic oxadiazole scaffold derivative. This research first reported a simple, specific, sensitive and stable high performance liquid chromatography -ultraviolet detector (HPLC-UV) method for the quantitative determination of GLB in plasma. In this method, the chromatographic separation was achieved with a reversed phase C18 column. The calibration curve for GLB was linear at 300 nm. The lower limit of quantification was 10 ng/mL. The precision, accuracy and stability of the method were validated adequately. This method was successfully applied to the pharmacokinetic study in rats for detection of GLB after oral administration. Moreover, the structures of parent compound GLB and its two major metabolites M1 and M2 were identified in plasma using an ultra performance liquid chromatography- electrospray ionization-quadrupole-time of flight- mass spectrometry (UPLC-ESI-QTOF-MS) method. Our results indicated that the di-hydroxylation (M1) and hydroxylation (M2) of GLB are the major metabolites. In conclusion, the present study provided valuable information on an analytical method for the determination of GLB and its metabolites in rats, can be used to support further developing of this antitumor agent. PMID:26148672

  13. Pharmacokinetic drug interactions of morphine, codeine, and their derivatives: theory and clinical reality, part I.

    Science.gov (United States)

    Armstrong, Scott C; Cozza, Kelly L

    2003-01-01

    Pharmacokinetic drug-drug interactions with morphine, hydromorphone, and oxymorphone are reviewed in this column. Morphine is a naturally occurring opiate that is metabolized chiefly through glucuronidation by uridine diphosphate glucuronosyl transferase (UGT) enzymes in the liver. These enzymes produce an active analgesic metabolite and a potentially toxic metabolite. In vivo drug-drug interaction studies with morphine are few, but they do suggest that inhibition or induction of UGT enzymes could alter morphine and its metabolite levels. These interactions could change analgesic efficacy. Hydromorphone and oxymorphone, close synthetic derivatives of morphine, are also metabolized primarily by UGT enzymes. Hydromorphone may have a toxic metabolite similar to morphine. In vivo drug-drug interaction studies with hydromorphone and oxymorphone have not been done, so it is difficult to make conclusions with these drugs.

  14. Simultaneous quantitation of hydroxychloroquine and its metabolites in mouse blood and tissues using LC-ESI-MS/MS: An application for pharmacokinetic studies.

    Science.gov (United States)

    Chhonker, Yashpal S; Sleightholm, Richard L; Li, Jing; Oupický, David; Murry, Daryl J

    2018-01-01

    Hydroxychloroquine (HCQ) has been shown to disrupt autophagy and sensitize cancer cells to radiation and chemotherapeutic agents. However, the optimal delivery method, dose, and tumor concentrations required for these effects are not known. This is in part due to a lack of sensitive and reproducible analytical methods for HCQ quantitation in small animals. As such, we developed and validated a selective and sensitive liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method for simultaneous quantitation of hydroxychloroquine and its metabolites in mouse blood and tissues. The chromatographic separation and detection of analytes were achieved on a reversed phase Thermo Aquasil C 18 (50×4.6mm, 3μ) column, with gradient elution using 0.2% formic acid and 0.1% formic acid in methanol as mobile phase at a flow rate of 0.5mL/min. Simple protein precipitation was utilized for extraction of analytes from the desired matrix. Analytes were separated and quantitated using MS/MS with an electrospray ionization source in positive multiple reaction monitoring (MRM) mode. The MS/MS response was linear over the concentration range from 1 to 2000ng/mL for all analytes with a correlation coefficient (R 2 ) of 0.998 or better. The within- and between-day precision (relative standard deviation, % RSD) and accuracy were within the acceptable limits per FDA guidelines. The validated method was successfully applied to a preclinical pharmacokinetic mouse study involving low volume blood and tissue samples for hydroxychloroquine and metabolites. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. MetRxn: a knowledgebase of metabolites and reactions spanning metabolic models and databases

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    Kumar Akhil

    2012-01-01

    Full Text Available Abstract Background Increasingly, metabolite and reaction information is organized in the form of genome-scale metabolic reconstructions that describe the reaction stoichiometry, directionality, and gene to protein to reaction associations. A key bottleneck in the pace of reconstruction of new, high-quality metabolic models is the inability to directly make use of metabolite/reaction information from biological databases or other models due to incompatibilities in content representation (i.e., metabolites with multiple names across databases and models, stoichiometric errors such as elemental or charge imbalances, and incomplete atomistic detail (e.g., use of generic R-group or non-explicit specification of stereo-specificity. Description MetRxn is a knowledgebase that includes standardized metabolite and reaction descriptions by integrating information from BRENDA, KEGG, MetaCyc, Reactome.org and 44 metabolic models into a single unified data set. All metabolite entries have matched synonyms, resolved protonation states, and are linked to unique structures. All reaction entries are elementally and charge balanced. This is accomplished through the use of a workflow of lexicographic, phonetic, and structural comparison algorithms. MetRxn allows for the download of standardized versions of existing genome-scale metabolic models and the use of metabolic information for the rapid reconstruction of new ones. Conclusions The standardization in description allows for the direct comparison of the metabolite and reaction content between metabolic models and databases and the exhaustive prospecting of pathways for biotechnological production. This ever-growing dataset currently consists of over 76,000 metabolites participating in more than 72,000 reactions (including unresolved entries. MetRxn is hosted on a web-based platform that uses relational database models (MySQL.

  16. Comparative Pharmacokinetic Analysis of Thiamine and Its Phosphorylated Metabolites Administered as Multivitamin Preparations.

    Science.gov (United States)

    Park, Wan-Su; Lee, Jongtae; Hong, Taegon; Park, Gabjin; Youn, Sunil; Seo, Youngwhan; Lee, Sanghun; Han, Seunghoon

    2016-10-01

    Fursultiamine and benfotiamine are lipophilic thiamine derivatives used as oral sources of thiamine. Although there are many publications on the pharmacokinetic (PK) properties of thiamine-containing products, no direct comparisons between these agents . We aimed to compare the PK profiles of these lipophilic thiamine derivatives and to compare the extent of the increase in bioavailability to that of naïve thiamine. Two randomized, single-dose, 2-way crossover, full PK studies were conducted in healthy Korean male subjects (n = 24 per group). Among the test compounds, fursultiamine was compared with benfotiamine (reference A in study A) and thiamine nitrate (reference B in study B). All formulations were multivitamin preparations containing the test or reference formulation as the major thiamine source. In study A, the plasma and hemolysate concentrations of thiamine and its metabolites were measured, while only the plasma thiamine concentration was assayed in study B. The systemic thiamine exposure of the test compound was slightly greater than that of reference A, based on the geometric mean ratio (%) of the AUC last value for plasma (116.6%) and hemolysate (137.5%). The thiamine diphosphate (TDP) distribution between plasma and hemolysate showed clear differences according to the formulations, in that more TDP was present in the hemolysate when thiamine was given as the test formulation. The AUC last value of plasma thiamine showed a >300% increase when thiamine was given as the test formulation in study B. The summed total exposure to thiamine (thiamine + TDP in both plasma and hemolysate) observed as a point estimate after the administration of fursultiamine was slightly greater than that with benfotiamine; however, the 90% CI was within the conventional bioequivalence range. These findings support clear benefits of lipophilic thiamine derivatives in the absorption of thiamine in healthy volunteers. Clinical Research Information Service identifiers: KCT

  17. Pharmacokinetics of lansoprazole and its main metabolites after single intravenous doses in healthy Chinese subjects.

    Science.gov (United States)

    Zhang, Dan; Yang, Man; Liu, Man; Zhang, Yanan; Wang, Xiaolin; Xiao, Xue; Liu, Huichen

    2012-11-01

    The aim of the study was to evaluate the pharmacokinetics (PK) of lansoprazole (LPZ) and its main metabolites 5'-hydroxy lansoprazole (HLPZ) and lansoprazole sulphone (LPZS) after single intravenous (i.v.) doses of LPZ in healthy Chinese subjects, and the relationship between the cytochrome P450 (CYP) 2C19 phenotypes and the plasma concentrations of LPZS at the time-points in the elimination phase of LPZ. Twelve subjects were given lansoprazole by i.v. infusion. Blood samples were collected at designated time points up to 24 h. Plasma concentrations of LPZ, HLPZ and LPZS were quantified by a selective and sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) method. After single i.v. doses of 15, 30 and 60 mg LPZ, C(max) and area under the plasma concentration-time curve (AUC(0-t)) of LPZ were 725 ± 151, 1480 ± 190, 3130 ± 480 µg · L(-1) and 1690 ± 1210, 3630 ± 2530, 8080 ± 4550 µg · h · L(-1), respectively. LPZ was generally well tolerated in healthy Chinese subjects, and displayed linear PK in the range of 15-60 mg. There were significant differences in the elimination of LPZ and the formation of LPZS between the single CYP2C19 poor metabolizer (PM) and the CYP2C19 extensive metabolizers (EM). The concentration of LPZS at the time-points in the elimination phase of LPZ could be monitored for CYP2C19 phenotyping. As a probe drug for CYP2C19 phenotyping, LPZ for injection might be more suitable than LPZ oral formulations.

  18. Development of a physiologically based pharmacokinetic model for assessment of human exposure to bisphenol A

    International Nuclear Information System (INIS)

    Yang, Xiaoxia; Doerge, Daniel R.; Teeguarden, Justin G.; Fisher, Jeffrey W.

    2015-01-01

    A previously developed physiologically based pharmacokinetic (PBPK) model for bisphenol A (BPA) in adult rhesus monkeys was modified to characterize the pharmacokinetics of BPA and its phase II conjugates in adult humans following oral ingestion. Coupled with in vitro studies on BPA metabolism in the liver and the small intestine, the PBPK model was parameterized using oral pharmacokinetic data with deuterated-BPA (d 6 -BPA) delivered in cookies to adult humans after overnight fasting. The availability of the serum concentration time course of unconjugated d 6 -BPA offered direct empirical evidence for the calibration of BPA model parameters. The recalibrated PBPK adult human model for BPA was then evaluated against published human pharmacokinetic studies with BPA. A hypothesis of decreased oral uptake was needed to account for the reduced peak levels observed in adult humans, where d 6 -BPA was delivered in soup and food was provided prior to BPA ingestion, suggesting the potential impact of dosing vehicles and/or fasting on BPA disposition. With the incorporation of Monte Carlo analysis, the recalibrated adult human model was used to address the inter-individual variability in the internal dose metrics of BPA for the U.S. general population. Model-predicted peak BPA serum levels were in the range of pM, with 95% of human variability falling within an order of magnitude. This recalibrated PBPK model for BPA in adult humans provides a scientific basis for assessing human exposure to BPA that can serve to minimize uncertainties incurred during extrapolations across doses and species. - Highlights: • A PBPK model predicts the kinetics of bisphenol A (BPA) in adult humans. • Serum concentrations of aglycone BPA are available for model calibration. • Model predicted peak BPA serum levels for adult humans were in the range of pM. • Model predicted 95% of human variability fell within an order of magnitude.

  19. Fisetin disposition and metabolism in mice: Identification of geraldol as an active metabolite. : Fisetin disposition and metabolism in mice

    OpenAIRE

    Touil, Yasmine,; Auzeil, Nicolas; Boulinguez, François; Saighi, Hanane; Regazzetti, Anne; Scherman, Daniel; Chabot, Guy,

    2011-01-01

    International audience; Although the natural flavonoid fisetin (3,3',4',7-tetrahydroxyflavone) has been recently identified as an anticancer agent with antiangiogenic properties in mice, its in vivo pharmacokinetics and metabolism are presently not characterized. Our purpose was to determine the pharmacokinetics and metabolism of fisetin in mice and determine the biological activity of a detected fisetin metabolite. After fisetin administration of an efficacious dose of 223 mg/kg i.p. in mice...

  20. Development of a physiologically based pharmacokinetic model for inhalation of jet fuels in the rat.

    Science.gov (United States)

    Martin, Sheppard A; Campbell, Jerry L; Tremblay, Raphael T; Fisher, Jeffrey W

    2012-01-01

    The pharmacokinetic behavior of the majority of jet fuel constituents has not been previously described in the framework of a physiologically based pharmacokinetic (PBPK) model for inhalation exposure. Toxic effects have been reported in multiple organ systems, though exposure methods varied across studies, utilizing either vaporized or aerosolized fuels. The purpose of this work was to assess the pharmacokinetics of aerosolized and vaporized fuels, and develop a PBPK model capable of describing both types of exposures. To support model development, n-tetradecane and n-octane exposures were conducted at 89 mg/m(3) aerosol+vapor and 1000-5000 ppm vapor, respectively. Exposures to JP-8 and S-8 were conducted at ~900-1000 mg/m(3), and ~200 mg/m(3) to a 50:50 blend of both fuels. Sub-models were developed to assess the behavior of representative constituents and grouped unquantified constituents, termed "lumps", accounting for the remaining fuel mass. The sub-models were combined into the first PBPK model for petroleum and synthetic jet fuels. Inhalation of hydrocarbon vapors was described with simple gas-exchange assumptions for uptake and exhalation. For aerosol droplets systemic uptake occurred in the thoracic region. Visceral tissues were described using perfusion and diffusion-limited equations. The model described kinetics at multiple fuel concentrations, utilizing a chemical "lumping" strategy to estimate parameters for fractions of speciated and unspeciated hydrocarbons and gauge metabolic interactions. The model more accurately simulated aromatic and lower molecular weight (MW) n-alkanes than some higher MW chemicals. Metabolic interactions were more pronounced at high (~2700-1000 mg/m(3)) concentrations. This research represents the most detailed assessment of fuel pharmacokinetics to date.

  1. Widespread occurrence of neuro-active pharmaceuticals and metabolites in 24 Minnesota rivers and wastewaters

    Science.gov (United States)

    Writer, Jeffrey; Ferrer, Imma; Barber, Larry B.; Thurman, E. Michael

    2013-01-01

    Concentrations of 17 neuro-active pharmaceuticals and their major metabolites (bupropion, hydroxy-bupropion, erythro-hydrobupropion, threo-hydrobupropion, carbamazepine, 10,11,-dihydro-10,11,-dihydroxycarbamazepine, 10-hydroxy-carbamazepine, citalopram, N-desmethyl-citalopram, fluoxetine, norfluoxetine, gabapentin, lamotrigine, 2-N-glucuronide-lamotrigine, oxcarbazepine, venlafaxine and O-desmethyl-venlafaxine), were measured in treated wastewater and receiving surface waters from 24 locations across Minnesota, USA. The analysis of upstream and downstream sampling sites indicated that the wastewater treatment plants were the major source of the neuro-active pharmaceuticals and associated metabolites in surface waters of Minnesota. Concentrations of parent compound and the associated metabolite varied substantially between treatment plants (concentrations ± standard deviation of the parent compound relative to its major metabolite) as illustrated by the following examples; bupropion and hydrobupropion 700 ± 1000 ng L−1, 2100 ± 1700 ng L−1, carbamazepine and 10-hydroxy-carbamazepine 480 ± 380 ng L−1, 360 ± 400 ng L−1, venlafaxine and O-desmethyl-venlafaxine 1400 ± 1300 ng L−1, 1800 ± 2300 ng L−1. Metabolites of the neuro-active compounds were commonly found at higher or comparable concentrations to the parent compounds in wastewater effluent and the receiving surface water. Neuro-active pharmaceuticals and associated metabolites were detected only sporadically in samples upstream from the effluent outfall. Metabolite to parent ratios were used to evaluate transformation, and we determined that ratios in wastewater were much lower than those reported in urine, indicating that the metabolites are relatively more labile than the parent compounds in the treatment plants and in receiving waters. The widespread occurrence of neuro-active pharmaceuticals and metabolites in Minnesota effluents and surface waters indicate that

  2. Application of Pharmacokinetics Modelling to Predict Human Exposure of a Cationic Liposomal Subunit Antigen Vaccine System

    Directory of Open Access Journals (Sweden)

    Raj K. S. Badhan

    2017-12-01

    Full Text Available The pharmacokinetics of a liposomal subunit antigen vaccine system composed of the cationic lipid dimethyldioctadecylammonium bromide (DDA and the immunostimulatory agent trehalose 6,6-dibehenate (TDB (8:1 molar ratio combined with the Ag85B-ESAT-6 (H1 antigen were modelled using mouse in-vivo data. Compartment modelling and physiologically based pharmacokinetics (PBPK were used to predict the administration site (muscle and target site (lymph temporal concentration profiles and factors governing these. Initial estimates using compartmental modelling established that quadriceps pharmacokinetics for the liposome demonstrated a long half-life (22.6 days compared to the associated antigen (2.62 days. A mouse minimal-PBPK model was developed and successfully predicted quadriceps liposome and antigen pharmacokinetics. Predictions for the popliteal lymph node (PLN aligned well at earlier time-points. A local sensitivity analysis highlighted that the predicted AUCmuscle was sensitive to the antigen degradation constant kdeg (resulting in a 3-log change more so than the fraction escaping the quadriceps (fe (resulting in a 10-fold change, and the predicted AUCPLN was highly sensitive to fe. A global sensitivity analysis of the antigen in the muscle demonstrated that model predictions were within the 50th percentile for predictions and showed acceptable fits. To further translate in-vitro data previously generated by our group, the mouse minimal-PBPK model was extrapolated to humans and predictions made for antigen pharmacokinetics in muscle and PLN. Global analysis demonstrated that both kdeg and fe had a minimal impact on the resulting simulations in the muscle but a greater impact in the PLN. In summary, this study has predicted the in-vivo fate of DDA:TDB:H1 in humans and demonstrated the roles that formulation degradation and fraction escaping the depot site can play upon the overall depot effect within the site of administration.

  3. Rapid identification of herbal compounds derived metabolites using zebrafish larvae as the biotransformation system.

    Science.gov (United States)

    Wang, Chen; Yin, Ying-Hao; Wei, Ying-Jie; Shi, Zi-Qi; Liu, Jian-Qun; Liu, Li-Fang; Xin, Gui-Zhong

    2017-09-15

    Metabolites derived from herbal compounds are becoming promising sources for discovering new drugs. However, the rapid identification of metabolites from biological matrixes is limited by massive endogenous interference and low abundance of metabolites. Thus, by using zebrafish larvae as the biotransformation system, we herein proposed and validated an integrated strategy for rapid identification of metabolites derived from herbal compounds. Two pivotal steps involved in this strategy are to differentiate metabolites from herbal compounds and match metabolites with their parent compounds. The differentiation step was achieved by cross orthogonal partial least-squares discriminant analysis. Automatic matching analysis was performed on R Project based on a self-developed program, of which the number of matched ionic clusters and its corresponding percentage between metabolite and parent compound were taken into account to assess their similarity. Using this strategy, 46 metabolites screened from incubation water samples of zebrafish treated with total Epimedium flavonoids (EFs) could be matched with their corresponding parent compounds, 37 of them were identified and validated by the known metabolic pathways and fragmentation patterns. Finally, 75% of the identified EFs metabolites were successfully detected in urine samples of rats treated with EFs. These experimental results indicate that the proposed strategy using zebrafish larvae as the biotransformation system will facilitate the rapid identification of metabolites derived from herbal compounds, which shows promising perspectives in providing additional resources for pharmaceutical developments from natural products. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Tissue distribution of berberine and its metabolites after oral administration in rats.

    Directory of Open Access Journals (Sweden)

    Xiang-Shan Tan

    Full Text Available Berberine (BBR has been confirmed to have multiple bioactivities in clinic, such as cholesterol-lowering, anti-diabetes, cardiovascular protection and anti- inflammation. However, BBR's plasma level is very low; it cannot explain its pharmacological effects in patients. We consider that the in vivo distribution of BBR as well as of its bioactive metabolites might provide part of the explanation for this question. In this study, liquid chromatography coupled to ion trap time-of-flight mass spectrometry (LC/MS(n-IT-TOF as well as liquid chromatography that coupled with tandem mass spectrometry (LC-MS/MS was used for the study of tissue distribution and pharmacokinetics of BBR in rats after oral administration (200 mg/kg. The results indicated that BBR was quickly distributed in the liver, kidneys, muscle, lungs, brain, heart, pancreas and fat in a descending order of its amount. The pharmacokinetic profile indicated that BBR's level in most of studied tissues was higher (or much higher than that in plasma 4 h after administration. BBR remained relatively stable in the tissues like liver, heart, brain, muscle, pancreas etc. Organ distribution of BBR's metabolites was also investigated paralleled with that of BBR. Thalifendine (M1, berberrubine (M2 and jatrorrhizine (M4, which the metabolites with moderate bioactivity, were easily detected in organs like the liver and kidney. For instance, M1, M2 and M4 were the major metabolites in the liver, among which the percentage of M2 was up to 65.1%; the level of AUC (0-t (area under the concentration-time curve for BBR or the metabolites in the liver was 10-fold or 30-fold higher than that in plasma, respectively. In summary, the organ concentration of BBR (as well as its bioactive metabolites was higher than its concentration in the blood after oral administration. It might explain BBR's pharmacological effects on human diseases in clinic.

  5. Effects of the CYP2D6*10 allele on the pharmacokinetics of atomoxetine and its metabolites.

    Science.gov (United States)

    Byeon, Ji-Yeong; Kim, Young-Hoon; Na, Han-Sung; Jang, Jong-Hwa; Kim, Se-Hyung; Lee, Yun-Jeong; Bae, Jung-Woo; Kim, In Su; Jang, Choon-Gon; Chung, Myeon-Woo; Lee, Seok-Yong

    2015-11-01

    To investigate the effect of the variant CYP2D6*10 allele on the pharmacokinetics of atomoxetine and its metabolites, 4-hydroxyatomoxetine (4-HAT) and N-desmethylatomoxetine (NAT), in healthy subjects, a single oral dose of atomoxetine was administered to 62 subjects with a CYP2D6*wt/*wt (*wt = *1 or *2, n = 22), CYP2D6*wt/*10 (n = 22) or CYP2D6*10/*10 (n = 18) genotype. Plasma samples were then collected for 24 h after atomoxetine administration. The concentrations of atomoxetine and its metabolites were assayed using LC-MS/MS. For atomoxetine, the Cmax, AUC0-∞, t1/2 and CL/F showed genotype-dependent differences. The CYP2D6*10/*10 and CYP2D6*wt/*10 groups showed 1.74- and 1.15-fold higher Cmax, 3.40- and 1.33-fold higher AUC0-∞, and 69.7 and 24.6 % lower CL/F, compared to those of the CYP2D6*wt/*wt group, respectively. The Cmax and t1/2 for 4-HAT were lower and longer in the CYP2D6*10/*10 group than those in the CYP2D6*wt/*wt group, but the AUC0-∞ was not different between these groups. The Cmax, AUC0-∞ and t1/2 for NAT were profoundly greater in the CYP2D6*10/*10 group than they were in the CYP2D6*wt/*wt group. The concentration of active moieties of atomoxetine (atomoxetine + 4-HAT) in the CYP2D6*10/*10 group was 3.32-fold higher than that in the CYP2D6*wt/*wt group. The mean exposure to active moieties of atomoxetine was markedly higher in subjects with the CYP2D6*10/*10 genotype compared to that in those with the CYP2D6*wt/*wt genotype. The higher systemic exposure of the active atomoxetine moieties in CYP2D6*10/*10 individuals may increase the risk of concentration-related adverse events of atomoxetine, although this has not yet been clinically confirmed.

  6. Proposal of 5-methoxy-N-methyl-N-isopropyltryptamine consumption biomarkers through identification of in vivo metabolites from mice.

    Science.gov (United States)

    Fabregat-Safont, D; Barneo-Muñoz, M; Martinez-Garcia, F; Sancho, J V; Hernández, F; Ibáñez, M

    2017-07-28

    New psychoactive substances (NPS) are a new breed of synthetically produced substances designed to mimic the effects of traditional illegal drugs. Synthetic cannabinoids and synthetic cathinones are the two most common groups, which try to mimic the effects of the natural compounds 9 Δ-tetrahydrocannabinol and cathinone, respectively. Similarly, synthetic tryptamines are designer compounds which are based on the compounds psilocin, N,N-dimethyltryptamine and 5-methoxy-N,N-dimethyltryptamine found in some mushrooms. One of the most important tryptamine compounds found in seizures is 5-methoxy-N,N-diisopropyltryptamine, which has been placed as controlled substance in USA and some European countries. The control of this compound has promoted the rising of another tryptamine, the 5-methoxy-N-methyl-N-isopropyltryptamine, which at the time of writing this article has not been banned yet. So, it is undeniable that this new substance should be monitored. 5-methoxy-N-methyl-N-isopropyltryptamine has been reported by the Spanish Early Warning System and detected in our laboratory in two pill samples purchased in a local smart shop. This has promoted the need of stablishing consumption markers for this compound in consumers' urine. In the present work, the metabolism and pharmacokinetic of 5-methoxy-N-methyl-N-isopropyltryptamine has been studied by an in vivo approach, using adult male mice of the inbred strain C57BLJ/6. The use of ultra-high performance liquid chromatography coupled to high resolution mass spectrometry allowed the identification of four metabolites. After the pharmacokinetic study in serum and urine, the O-demethylated metabolite and the non-metabolised parent compound are proposed as consumption markers in hydrolysed urine. Data reported in this work will help hospitals and forensic laboratories to monitor the consumption and potential intoxication cases related to this tryptamine. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Influence of Erroneous Patient Records on Population Pharmacokinetic Modeling and Individual Bayesian Estimation

    NARCIS (Netherlands)

    van der Meer, Aize Franciscus; Touw, Daniel J.; Marcus, Marco A. E.; Neef, Cornelis; Proost, Johannes H.

    2012-01-01

    Background: Observational data sets can be used for population pharmacokinetic (PK) modeling. However, these data sets are generally less precisely recorded than experimental data sets. This article aims to investigate the influence of erroneous records on population PK modeling and individual

  8. Challenges Associated With Applying Physiologically Based Pharmacokinetic Modeling for Public Health Decision-Making

    Science.gov (United States)

    The development and application of physiologically based pharmacokinetic (PBPK) models in chemical toxicology have grown steadily since their emergence in the 1980s. However, critical evaluation of PBPK models to support public health decision-making across federal agencies has t...

  9. Fenproporex and amphetamine pharmacokinetics in oral fluid after controlled oral administration of fenproporex.

    Science.gov (United States)

    Comiran, Eloisa; Souza, Daniele Zago; Boehl, Paula Otero; Cássia Mariotti, Kristiane de; Pechansky, Flavio; Duarte, Paulina do Carmo Arruda Vieira; De Boni, Raquel Brandini; Fröehlich, Pedro Eduardo; Limberger, Renata Pereira

    2012-10-01

    Fenproporex hydrochloride (FEN) is an anorectic drug used in the treatment of obesity, and its major metabolite is amphetamine (AMP), another central nervous system stimulant. The concentration versus time profile of FEN and its metabolite AMP has been described in classic biological matrices such as plasma and urine; however, there are no reports of such data in oral fluid. The aim of this study is to describe the pharmacokinetics of FEN and AMP in oral fluid after intake of FEN. Twenty-five milligrams of FEN (1 capsule of Desobesi-m) was orally administered to 6 male volunteers, and oral fluid samples were collected with a Quantisal device during 24.00 hours after drug ingestion. These samples were submitted to solid-phase microextraction before analysis by gas chromatography-mass spectrometry in the selected-ion-monitoring mode, using deuterium-labeled AMP as internal standard. After FEN administration, both analytes could be detected in oral fluid of all volunteers with an initial detection time varying from 0.50 to 1.00 hour. FEN peak concentrations occurred between 1.00 and 1.50 hours after administration and were between 70.7 and 227.5 μg/L. For AMP, peak concentration occurred between 1.50 and 4.00 hours, reaching 33.0-150.9 μg/L. The authors observed that oral administration of FEN resulted in significant amounts of FEN and AMP in oral fluid, showing that oral fluid could be a biological matrix suitable for pharmacokinetic studies for both analytes. Using a compartmental approach, FEN data were best fitted by 1-compartment model with first-order input and output, whereas AMP followed a 2-compartment model with first-order input and output.

  10. Gender differences in cocaine pharmacokinetics in CF-1 mice.

    Science.gov (United States)

    Visalli, Thomas; Turkall, Rita; Abdel-Rahman, Mohamed S

    2005-01-15

    Hepatocellular damage is thought to occur as a result of cytochrome P450-mediated oxidation of cocaine to norcocaine (NC), a precursor of the hepatotoxic nitrosonium ion. However, this damage occurs only in male mice, with females exhibiting minimal biochemical and histological signs of hepatocellular stress. The objective of this study was to determine the plasma time course and tissue disposition of cocaine and its metabolites to further investigate the role that metabolism may play in the gender difference observed. Male and female CF-1 mice were orally administered 20mg/kg cocaine hydrochloride once daily for 7 days. Blood samples were withdrawn at various time points post-injection and analyzed for cocaine and its metabolites benzoylecgonine (BE), norcocaine, ecgonine methyl ester (EME), and ecgonine (E). In addition, tissue concentrations of cocaine and its metabolites were determined in liver, heart, brain, and kidney tissue. The results demonstrated that the plasma elimination half-life of cocaine is nearly three times longer in males versus females. Non-hepatotoxic hydrolysis metabolites BE, EME, and E were higher in female tissues while norcocaine was detected in tissues of male animals only. This study revealed that differences in cocaine pharmacokinetics and the resultant differences in the biodisposition of cocaine and its metabolites in tissues contribute to the mechanism of gender difference seen in cocaine hepatotoxicity.

  11. Pharmacokinetic properties and in silico ADME modeling in drug discovery.

    Science.gov (United States)

    Honório, Kathia M; Moda, Tiago L; Andricopulo, Adriano D

    2013-03-01

    The discovery and development of a new drug are time-consuming, difficult and expensive. This complex process has evolved from classical methods into an integration of modern technologies and innovative strategies addressed to the design of new chemical entities to treat a variety of diseases. The development of new drug candidates is often limited by initial compounds lacking reasonable chemical and biological properties for further lead optimization. Huge libraries of compounds are frequently selected for biological screening using a variety of techniques and standard models to assess potency, affinity and selectivity. In this context, it is very important to study the pharmacokinetic profile of the compounds under investigation. Recent advances have been made in the collection of data and the development of models to assess and predict pharmacokinetic properties (ADME--absorption, distribution, metabolism and excretion) of bioactive compounds in the early stages of drug discovery projects. This paper provides a brief perspective on the evolution of in silico ADME tools, addressing challenges, limitations, and opportunities in medicinal chemistry.

  12. A Physiologically Based Pharmacokinetic Model to Predict the Pharmacokinetics of Highly Protein-Bound Drugs and Impact of Errors in Plasma Protein Binding

    Science.gov (United States)

    Ye, Min; Nagar, Swati; Korzekwa, Ken

    2015-01-01

    Predicting the pharmacokinetics of highly protein-bound drugs is difficult. Also, since historical plasma protein binding data was often collected using unbuffered plasma, the resulting inaccurate binding data could contribute to incorrect predictions. This study uses a generic physiologically based pharmacokinetic (PBPK) model to predict human plasma concentration-time profiles for 22 highly protein-bound drugs. Tissue distribution was estimated from in vitro drug lipophilicity data, plasma protein binding, and blood: plasma ratio. Clearance was predicted with a well-stirred liver model. Underestimated hepatic clearance for acidic and neutral compounds was corrected by an empirical scaling factor. Predicted values (pharmacokinetic parameters, plasma concentration-time profile) were compared with observed data to evaluate model accuracy. Of the 22 drugs, less than a 2-fold error was obtained for terminal elimination half-life (t1/2, 100% of drugs), peak plasma concentration (Cmax, 100%), area under the plasma concentration-time curve (AUC0–t, 95.4%), clearance (CLh, 95.4%), mean retention time (MRT, 95.4%), and steady state volume (Vss, 90.9%). The impact of fup errors on CLh and Vss prediction was evaluated. Errors in fup resulted in proportional errors in clearance prediction for low-clearance compounds, and in Vss prediction for high-volume neutral drugs. For high-volume basic drugs, errors in fup did not propagate to errors in Vss prediction. This is due to the cancellation of errors in the calculations for tissue partitioning of basic drugs. Overall, plasma profiles were well simulated with the present PBPK model. PMID:26531057

  13. Comparison of tiletamine and zolazepam pharmacokinetics in tigers (Panthera tigris) and leopards (Panthera pardus): do species differences account for adverse effects in tigers?

    Science.gov (United States)

    Lewis, J C M; Teale, P; Webber, G; Sear, J W; Taylor, P M

    2014-09-01

    Serious post-operative neurological complications of unknown aetiology are reported in tigers after immobilisation using tiletamine and zolazepam. These complications may arise from the persistent effects of tiletamine or active metabolites of tiletamine or zolazepam. Concentrations of tiletamine, zolazepam and some metabolites were measured using high performance liquid chromatography-mass spectrometry in plasma from captive tigers (n = 8) and leopards (n = 9; an unaffected species, for comparison) during anaesthesia for routine clinical procedures. The zolazepam:tiletamine (Z:T) ratio was calculated. Peak concentrations occurred at 9-33 min and ranged from 83.5 to 379.2 ng/mL for tiletamine and 301.1 to 1239.3 ng/mL for zolazepam after correction for dose by weight. There were no significant differences between tigers and leopards. The Z:T ratio was generally leopards, zolazepam metabolism appeared to be primarily via demethylation. There was evidence for hydroxylation in leopards, but much less in tigers than leopards. No major differences between the species in parent pharmacokinetics were identified. The metabolism of tiletamine could not be defined with any degree of certainty for either species. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. Evaluation of pharmacokinetics underlies the collaborated usage of lamivudine and oxymatrine in beagle dogs

    Directory of Open Access Journals (Sweden)

    Zhenbao Li

    2016-10-01

    Full Text Available Combinational therapy of lamivudine and oxymatrine has been employed in the battle against hepatitis B virus in clinical setting. However, the pharmacokinetic behavior of the drug or active metabolism in intravenous/oral co-administration regime is poorly investigated. Herein, we evaluated the pharmacokinetic characteristic through a tailor-designed 3 way crossover-Latin square experiment in adult male beagle dogs. Six dogs were randomly treated by intravenous administration of lamivudine (2.5 mg/kg, oxymatrine (15 mg/kg and combinational dosage, named as intravenous regime. Meanwhile the other six dogs were orally administrated with lamivudine (2.5 mg/kg, oxymatrine (15 mg/kg and combinational dosage, named as oral regime. The pharmacokinetic feature in simultaneous oral treatment appeared to have no significant difference when compared with individual administration, even including matrine, the active metabolite of oxymatrine. In intravenous regime, the main pharmacokinetic parameters of simultaneous administration were nearly consistent with intravenous regime remedy. The collaborated application of lamivudine and oxymatrine contributed to non-distinctive pharmacokinetic fluctuations of beagle dogs in intravenous/oral regime, compared with individual employment, which established a vital base for the clinical co-administration against hepatitis B. Furthermore, the present study demonstrated that the determination of pharmacokinetics between combinational and individual therapy might assist in the development of drug compatibility in clinical therapy.

  15. Virtual pharmacokinetic model of human eye.

    Science.gov (United States)

    Kotha, Sreevani; Murtomäki, Lasse

    2014-07-01

    A virtual pharmacokinetic 3D model of the human eye is built using Comsol Multiphysics® software, which is based on the Finite Element Method (FEM). The model considers drug release from a polymer patch placed on sclera. The model concentrates on the posterior part of the eye, retina being the target tissue, and comprises the choroidal blood flow, partitioning of the drug between different tissues and active transport at the retina pigment epithelium (RPE)-choroid boundary. Although most straightforward, in order to check the mass balance, no protein binding or metabolism is yet included. It appeared that the most important issue in obtaining reliable simulation results is the finite element mesh, while time stepping has hardly any significance. Simulations were extended to 100,000 s. The concentration of a drug is shown as a function of time at various points of retina, as well as its average value, varying several parameters in the model. This work demonstrates how anybody with basic knowledge of calculus is able to build physically meaningful models of quite complex biological systems. Copyright © 2014 Elsevier Inc. All rights reserved.

  16. Dose Assessment of Cefquinome by Pharmacokinetic/Pharmacodynamic Modeling in Mouse Model of Staphylococcus aureus Mastitis

    Directory of Open Access Journals (Sweden)

    Yang Yu

    2016-10-01

    Full Text Available This work aimed to characterize the mammary gland pharmacokinetics of cefquinome after an intramammary administration and integrate pharmacokinetic/pharmacodynamic model. The pharmacokinetic profiles of cefquinome in gland tissue were measured using high performance liquid chromatograph. Therapeutic regimens covered various dosages ranging from 25 to 800 μg/gland and multiple dosing intervals of 8, 12, and 24 h. The in vivo bacterial killing activity elevated when dosage increased or when dosing intervals were shortened. The best antibacterial effect was demonstrated by a mean 1.5 log10CFU/gland visible count reduction. On the other hand, the results showed that the percentage of time duration of drug concentration exceeding the MIC during a dose interval (%T > MIC was generally 100% because of the influence of drug distribution caused by the blood-milk barrier. Therefore, pharmacokinetic/pharmacodynamic parameter of the ratio of area under the concentration-time curve over 24 h to the MIC (AUC0-24/MIC was used to describe the efficacy of cefquinome instead of %T > MIC. When the magnitude of AUC0-24/MIC exceeding 16571.55 h•mL/g, considerable activity of about 1.5 log10CFU/g gland bacterial count reduction was observed in vivo. Based on the Monte Carlo simulation, the clinical recommended regimen of three infusions of 75 mg per quarter every 12 h can achieve a 76.67% cure rate in clinical treatment of bovine mastitis caused by Staphylococcus aureus infection.

  17. WORKSHOP ON APPLICATION OF STATISTICAL METHODS TO BIOLOGICALLY-BASED PHARMACOKINETIC MODELING FOR RISK ASSESSMENT

    Science.gov (United States)

    Biologically-based pharmacokinetic models are being increasingly used in the risk assessment of environmental chemicals. These models are based on biological, mathematical, statistical and engineering principles. Their potential uses in risk assessment include extrapolation betwe...

  18. Population pharmacokinetic-pharmacodynamic modeling of ketamine-induced pain relief of chronic pain.

    Science.gov (United States)

    Dahan, Albert; Olofsen, Erik; Sigtermans, Marnix; Noppers, Ingeborg; Niesters, Marieke; Aarts, Leon; Bauer, Martin; Sarton, Elise

    2011-03-01

    Pharmacological treatment of chronic (neuropathic) pain is often disappointing. In order to enhance our insight in the complex interaction between analgesic drug and chronic pain relief, we performed a pharmacokinetic-pharmacodynamic (PK-PD) modeling study on the effect of S(+)-ketamine on pain scores in Complex Regional Pain Syndrome type 1 (CRPS-1) patients. Sixty CRPS-1 patients were randomly allocated to received a 100-h infusion of S(+)-ketamine or placebo. The drug infusion rate was slowly increased from 5 mg/h (per 70 kg) to 20 mg/h based upon the effect/side effect profile. Pain scores and drug blood samples were obtained during the treatment phase and pain scores were further obtained weekly for another 11 weeks. A population PK-PD model was developed to analyze the S(+)-ketamine-pain data. Plasma concentrations of S(+)-ketamine and its metabolite decreased rapidly upon the termination of S(+)-ketamine infusion. The chance for an analgesic effect from ketamine and placebo treatment was 67±10% and 23±9% (population value±SE), respectively. The pain data were well described by the PK-PD model with parameters C(50)=10.5±4.8 ng/ml (95% ci 4.37-21.2 ng/ml) and t½ for onset/offset=10.9±4.0 days (5.3-20.5 days). Long-term S(+)-ketamine treatment is effective in causing pain relief in CRPS-1 patients with analgesia outlasting the treatment period by 50 days. These data suggest that ketamine initiated a cascade of events, including desensitization of excitatory receptor systems in the central nervous system, which persisted but slowly abated when ketamine molecules were no longer present. Copyright © 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.

  19. Pharmacokinetics and pharmacodynamic effects of amiodarone in plasma of ponies after single intravenous administration

    International Nuclear Information System (INIS)

    Trachsel, D.; Tschudi, P.; Portier, C.J.; Kuhn, M.; Thormann, W.; Scholtysik, G.; Mevissen, M.

    2004-01-01

    Atrial fibrillation is a well-known heart disease in horses. The common therapy consists of administration of quinidine. More potent antiarrhythmic drugs have become available for human therapy and the use of these as alternatives to quinidine for equine antiarrhythmic therapy is a matter of interest. Amiodarone (AMD) is used in human medicine for treatment of many arrhythmias, including atrial fibrillation. Its disposition in horses has not yet been investigated. The purpose of this study was to measure the effect of single intravenous doses of amiodarone (5 and 7 mg/kg) on the surface electrocardiogram (ECG) of healthy minishetland ponies during the first 2 days after drug administration and to calculate pharmacokinetic parameters with a physiologically based pharmacokinetic model (PBPK) using amiodarone and desethylamiodarone (DAMD) plasma levels that were determined by high-performance liquid chromatography (HPLC). As expected for a K + -channel-blocker, the main effect on the measured ECG could be seen on the ventricular complex, as the QT interval and the T wave showed statistically significant alterations. The doses investigated were well tolerated clinically. Results from the pharmacokinetic model were found to compare well with literature data of rats, dogs, and humans. It showed a rapid distribution in the tissue, beginning with the rapidly perfused tissue, like the heart, followed by slowly perfused tissues, and finally an accumulation in fat. The half-life for total elimination was calculated to be 16.3 days with 99% eliminated by 97 days. The model predicts that approximately 96% of amiodarone is eliminated as desethylamiodarone in urine, 2% eliminated as desethylamiodarone in bile, and 2% as other metabolites

  20. The Effect of Route, Vehicle, and Divided Doses on the Pharmacokinetics of Chlorpyrifos and its Metabolite Trichloropyridinol in Neonatal Sprague-Dawley Rats

    Energy Technology Data Exchange (ETDEWEB)

    Marty, M. S.; Domoradzki, J. Y.; Hansen, S. C.; Timchalk, Chuck; Bartels, M. J.; Mattsson, Joel L.

    2007-12-01

    There is a paucity of data on neonatal systemic exposure using different dosing paradigms. Male CD (Sprague-Dawley derived) rats at postnatal day (PND) 5 were dosed with chlorpyrifos (CPF, 1 mg/kg) using different routes of exposure, vehicles, and single vs. divided doses. Blood concentrations of CPF and its primary metabolite, trichloropyridinol (TCP), were measured at multiple times through 24 h. Groups included: single gavage bolus vs. divided gavage doses in corn oil (1 vs 3 times in 24 h), single gavage bolus vs. divided gavage doses in rat milk, and subcutaneous administration in DMSO. These data were compared with lactational exposure of PND 5 pups from dams exposed to CPF in the diet at 5 mg/kg/day for four weeks or published data from dams exposed to daily gavage with CPF at 5 mg/kg/day. Maternal blood CPF levels were an order of magnitude lower from dietary exposure than gavage (1.1 vs 14.8 ng/g), and blood CPF levels in PND 5 pups that nursed dietary-exposed or gavage-exposed dams were below the limit of detection. Single gavage doses of 1 mg/kg CPF in corn oil vehicle in pups resulted in CPF blood levels of 49 ng/g, and in milk vehicle about 9 ng/g. Divided doses led to lower peak CPF levels. A bolus dose of 1 mg/kg CPF in DMSO administered sc appeared to have substantially altered pharmacokinetics from orally administered chlorpyrifos. To be meaningful for risk assessment, neonatal studies require attention to the exposure scenario, since route, vehicle, dose and frequency of administration result in different systemic exposure to the test chemical and its metabolites.

  1. Microsomal metabolism of trenbolone acetate metabolites ...

    Science.gov (United States)

    Trenbolone acetate (TBA) is a synthetic growth promoter widely used in animal agriculture, and its metabolites are suspected endocrine disrupting compounds in agriculturally impacted receiving waters. However, beyond the three widely recognized TBA metabolites (17-trenbolone, 17-trenbolone and trendione), little is known about other metabolites formed in vivo and subsequently discharged into the environment, with some evidence suggesting these unknown metabolites comprise a majority of the TBA mass dosed to the animal. Here, we explored the metabolism of the three known TBA metabolites using rat liver microsome studies. All TBA metabolites are transformed into a complex mixture of monohydroxylated products. Based on product characterization, the majority are more polar than the parent metabolites but maintain their characteristic trienone backbone. A minor degree of interconversion between known metabolites was also observed, as were higher order hydroxylated products with a greater extent of reaction. Notably, the distribution and yield of products were generally comparable across a series of variably induced rat liver microsomes, as well as during additional studies with human and bovine liver microsomes. Bioassays conducted with mixtures of these transformation products suggest that androgen receptor (AR) binding activity is diminished as a result of the microsomal treatment, suggesting that the transformation products are generally less potent than

  2. Physiologically based pharmacokinetic and pharmacodynamic modeling of an antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in a mouse xenograft model of human breast cancer.

    Science.gov (United States)

    Zhang, Tao; Li, Yanyan; Zou, Peng; Yu, Jing-yu; McEachern, Donna; Wang, Shaomeng; Sun, Duxin

    2013-09-01

    The inhibitors of apoptosis proteins (IAPs) are a class of key apoptosis regulators overexpressed or dysregulated in cancer. SM-406/AT-406 is a potent and selective small molecule mimetic of Smac that antagonizes the inhibitor of apoptosis proteins (IAPs). A physiologically based pharmacokinetic and pharmacodynamic (PBPK-PD) model was developed to predict the tissue concentration-time profiles of SM-406, the related onco-protein levels in tumor, and the tumor growth inhibition in a mouse model bearing human breast cancer xenograft. In the whole body physiologically based pharmacokinetic (PBPK) model for pharmacokinetics characterization, a well stirred (perfusion rate-limited) model was used to describe SM-406 pharmacokinetics in the lung, heart, kidney, intestine, liver and spleen, and a diffusion rate-limited (permeability limited) model was used for tumor. Pharmacodynamic (PD) models were developed to correlate the SM-406 concentration in tumor to the cIAP1 degradation, pro-caspase 8 decrease, CL-PARP accumulation and tumor growth inhibition. The PBPK-PD model well described the experimental pharmacokinetic data, the pharmacodynamic biomarker responses and tumor growth. This model may be helpful to predict tumor and plasma SM-406 concentrations in the clinic. Copyright © 2013 John Wiley & Sons, Ltd.

  3. Association of CYP2B6, CYP3A5, and CYP2C19 genetic polymorphisms with sibutramine pharmacokinetics in healthy Korean subjects.

    Science.gov (United States)

    Kim, K A; Song, W K; Park, J Y

    2009-11-01

    We assessed the association of CYP2B6, CYP3A5, and CYP2C19 polymorphisms with sibutramine pharmacokinetics. Forty six healthy male subjects were enrolled, and their CYP2B6 (*4 and *6), CYP3A5 (*3), and CYP2C19 (*2, and *3) genotypes were analyzed. After a single 15-mg dose of sibutramine was administered, plasma concentrations of sibutramine and its metabolites, M1 and M2, were measured. CYP2B6 and CYP3A5 polymorphisms did not affect the pharmacokinetics of sibutramine and its metabolites. However, the CYP2C19 genotype substantially influenced plasma levels of sibutramine and its metabolites. The mean area under the curve (AUC) of sibutramine in CYP2C19 intermediate metabolizers (IMs; *1/*2 or *1/*3) and poor metabolizers (PMs; *2/*2, *2/*3)) was 18.5 and 252.2% higher, respectively, than the AUC in extensive metabolizers (EMs, *1/*1) (P sibutramine.

  4. Investigating pulmonary and systemic pharmacokinetics of inhaled olodaterol in healthy volunteers using a population pharmacokinetic approach.

    Science.gov (United States)

    Borghardt, Jens Markus; Weber, Benjamin; Staab, Alexander; Kunz, Christina; Formella, Stephan; Kloft, Charlotte

    2016-03-01

    Olodaterol, a novel β2-adrenergic receptor agonist, is a long-acting, once-daily inhaled bronchodilator approved for the treatment of chronic obstructive pulmonary disease. The aim of the present study was to describe the plasma and urine pharmacokinetics of olodaterol after intravenous administration and oral inhalation in healthy volunteers by population pharmacokinetic modelling and thereby to infer its pulmonary fate. Plasma and urine data after intravenous administration (0.5-25 μg) and oral inhalation (2.5-70 μg via the Respimat® inhaler) were available from a total of 148 healthy volunteers (single and multiple dosing). A stepwise model building approach was applied, using population pharmacokinetic modelling. Systemic disposition parameters were fixed to estimates obtained from intravenous data when modelling data after inhalation. A pharmacokinetic model, including three depot compartments with associated parallel first-order absorption processes (pulmonary model) on top of a four-compartment body model (systemic disposition model), was found to describe the data the best. The dose reaching the lung (pulmonary bioavailable fraction) was estimated to be 49.4% [95% confidence interval (CI) 46.1, 52.7%] of the dose released from the device. A large proportion of the pulmonary bioavailable fraction [70.1% (95% CI 66.8, 73.3%)] was absorbed with a half-life of 21.8 h (95% CI 19.7, 24.4 h). The plasma and urine pharmacokinetics of olodaterol after intravenous administration and oral inhalation in healthy volunteers were adequately described. The key finding was that a high proportion of the pulmonary bioavailable fraction had an extended pulmonary residence time. This finding was not expected based on the physicochemical properties of olodaterol. © 2015 The British Pharmacological Society.

  5. Development of a physiologically based pharmacokinetic model for assessment of human exposure to bisphenol A

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Xiaoxia, E-mail: xiaoxia.yang@fda.hhs.gov [Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079 (United States); Doerge, Daniel R. [Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079 (United States); Teeguarden, Justin G. [Health Effects and Exposure Science, Pacific Northwest National Laboratory, Richland, WA 99352 (United States); Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331 (United States); Fisher, Jeffrey W. [Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079 (United States)

    2015-12-15

    A previously developed physiologically based pharmacokinetic (PBPK) model for bisphenol A (BPA) in adult rhesus monkeys was modified to characterize the pharmacokinetics of BPA and its phase II conjugates in adult humans following oral ingestion. Coupled with in vitro studies on BPA metabolism in the liver and the small intestine, the PBPK model was parameterized using oral pharmacokinetic data with deuterated-BPA (d{sub 6}-BPA) delivered in cookies to adult humans after overnight fasting. The availability of the serum concentration time course of unconjugated d{sub 6}-BPA offered direct empirical evidence for the calibration of BPA model parameters. The recalibrated PBPK adult human model for BPA was then evaluated against published human pharmacokinetic studies with BPA. A hypothesis of decreased oral uptake was needed to account for the reduced peak levels observed in adult humans, where d{sub 6}-BPA was delivered in soup and food was provided prior to BPA ingestion, suggesting the potential impact of dosing vehicles and/or fasting on BPA disposition. With the incorporation of Monte Carlo analysis, the recalibrated adult human model was used to address the inter-individual variability in the internal dose metrics of BPA for the U.S. general population. Model-predicted peak BPA serum levels were in the range of pM, with 95% of human variability falling within an order of magnitude. This recalibrated PBPK model for BPA in adult humans provides a scientific basis for assessing human exposure to BPA that can serve to minimize uncertainties incurred during extrapolations across doses and species. - Highlights: • A PBPK model predicts the kinetics of bisphenol A (BPA) in adult humans. • Serum concentrations of aglycone BPA are available for model calibration. • Model predicted peak BPA serum levels for adult humans were in the range of pM. • Model predicted 95% of human variability fell within an order of magnitude.

  6. Modeling Pharmacokinetics and Pharmacodynamics of Glucagon for Simulation of the Glucoregulatory System in Patients with Type 1 Diabetes

    DEFF Research Database (Denmark)

    Wendt, Sabrina Lyngbye

    The goal of this thesis was to develop a pharmacokinetics/pharmacodynamics (PK/PD) model for glucagon. The proposed PD model included multiplication of the stimulating glucagon effect and inhibiting insulin effect on the endogenous glucose production (EGP). Moreover, the concentration-response re......The goal of this thesis was to develop a pharmacokinetics/pharmacodynamics (PK/PD) model for glucagon. The proposed PD model included multiplication of the stimulating glucagon effect and inhibiting insulin effect on the endogenous glucose production (EGP). Moreover, the concentration...

  7. A validated LC–MS/MS method for the determination of tolterodine and its metabolite in rat plasma and application to pharmacokinetic study

    Directory of Open Access Journals (Sweden)

    Rihana Parveen Shaik

    2013-12-01

    Full Text Available Liquid chromatography–tandem mass spectrometry (LC–MS/MS method was used for simultaneous quantification of tolterodine and its metabolite 5-hydroxy methyl tolterodine in rat plasma. Tolterodine-d6 and 5-hydroxy methyl tolterodine-d14 were used as internal standards (IS. Chromatographic separation was performed on Ascentis Express RP amide (50 mm×4.6 mm, 2.7 μm column with an isocratic mobile phase composed of 10 mM ammonium acetate and acetonitrile in the ratio of 20:80 (v/v, at a flow-rate of 0.5 mL/min. Tolterodine, tolterodine-d6, 5-hydroxy methyl tolterodine and 5-hydroxy methyl tolterodine-d14 were detected with proton adducts at m/z 326.1→147.1, 332.3→153.1, 342.2→223.1 and 356.2→223.1 in multiple reaction monitoring (MRM positive mode respectively. The drug, metabolite and internal standards were extracted by liquid–liquid extraction method. The method was validated over a linear concentration range of 20.00–5000.00 pg/mL for tolterodine and 20.00–5000.00 pg/mL for 5-hydroxy methyl tolterodine. This method demonstrated intra- and inter-day precision of 0.62–6.36% and 1.73–4.84% for tolterodine, 1.38–4.22% and 1.62–4.25% for 5-hydroxy methyl tolterodine respectively. This method also demonstrated intra- and inter-day accuracy of 98.75–103.56% and 99.20–104.40% for tolterodine, 98.08–104.67% and 98.73–103.06% for 5-hydroxy methyl tolterodine respectively. Both analytes were found to be stable throughout freeze–thaw cycles, bench top and postoperative stability studies. This method was successfully applied for the pharmacokinetic analysis of rat plasma samples following i.v. administration. Keywords: LC–MS/MS, Tolterodine, 5-Hydroxy methyl tolterodine, Pharmacokinetics

  8. Lansoprazole-sulfide, pharmacokinetics of this promising anti-tuberculous agent.

    Science.gov (United States)

    Mdanda, Sipho; Baijnath, Sooraj; Shobo, Adeola; Singh, Sanil D; Maguire, Glenn E M; Kruger, Hendrik G; Arvidsson, Per I; Naicker, Tricia; Govender, Thavendran

    2017-12-01

    Lansoprazole (LPZ) is a commercially available proton-pump inhibitor whose primary metabolite, lansoprazole sulfide (LPZS) was recently reported to have in vitro and in vivo activity against Mycobacterium tuberculosis. It was also reported that a 300 mg kg -1 oral administration of LPZS was necessary to reach therapeutic levels in the lung, with the equivalent human dose being unrealistic. A validated liquid chromatography-tandem mass spectrometric method (LC-MS/MS) for the simultaneous quantification LPZ and LPZS in rat plasma and lung homogenates was developed. We administered 15 mg kg -1 oral doses of LPZ to a healthy rat model to determine the pharmacokinetics of its active metabolite, LPZS, in plasma and lung tissue. We found that the LPZS was present in amounts that were below the limit of quantification. This prompted us to administer the same dose of LPZS to the experimental animals intraperitoneally (i.p.). Using this approach, we found high concentrations of LPZS in plasma and lung, 7841.1 and 9761.2 ng mL -1 , respectively, which were significantly greater than the minimum inhibitory concentration (MIC) for Mycobacterium tuberculosis. While oral and i.p. administration of LPZ resulted in significant concentrations in the lung, it did not undergo sufficient cellular conversion to its anti-TB metabolite. However, when LPZS itself was administered i.p., significant amounts penetrated the tissue. These results have implications for future in vivo studies exploring the potential of LPZS as an anti-TB compound. Copyright © 2017 John Wiley & Sons, Ltd.

  9. Antipyrine metabolite formation and excretion in patients with chronic renal failure

    NARCIS (Netherlands)

    Teunissen, M W; Kampf, D; Roots, I; Vermeulen, N P; Breimer, D D

    1985-01-01

    In the present study the influence of chronic renal insufficiency on antipyrine clearance, metabolite formation and excretion was investigated in 8 patients. After oral administration of antipyrine, the parent compound, its metabolites and their conjugates were assayed in plasma and urine. Besides

  10. Application of in Vitro Biotransformation Data and Pharmacokinetic Modeling to Risk Assessment

    Science.gov (United States)

    The adverse biological effects of toxic substances are dependent upon the exposure concentration and the duration of exposure. Pharmacokinetic models can quantitatively relate the external concentration of a toxicant in the environment to the internal dose of the toxicant in the ...

  11. PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL FOR HUMAN EXPOSURES TO METHYL TERTIARY-BUTYL ETHER

    Science.gov (United States)

    Humans can be exposed by inhalation, ingestion, or dermal absorption to methyl tertiary-butyl ether (MTBE), an oxygenated fuel additive, from contaminated water sources. The purpose of this research was to develop a physiologically based pharmacokinetic model describing in human...

  12. Evaluating Pharmacokinetic and Pharmacodynamic Interactions with Computational Models in Supporting Cumulative Risk Assessment

    Science.gov (United States)

    Tan, Yu-Mei; Clewell, Harvey; Campbell, Jerry; Andersen, Melvin

    2011-01-01

    Simultaneous or sequential exposure to multiple chemicals may cause interactions in the pharmacokinetics (PK) and/or pharmacodynamics (PD) of the individual chemicals. Such interactions can cause modification of the internal or target dose/response of one chemical in the mixture by other chemical(s), resulting in a change in the toxicity from that predicted from the summation of the effects of the single chemicals using dose additivity. In such cases, conducting quantitative cumulative risk assessment for chemicals present as a mixture is difficult. The uncertainties that arise from PK interactions can be addressed by developing physiologically based pharmacokinetic (PBPK) models to describe the disposition of chemical mixtures. Further, PK models can be developed to describe mechanisms of action and tissue responses. In this article, PBPK/PD modeling efforts conducted to investigate chemical interactions at the PK and PD levels are reviewed to demonstrate the use of this predictive modeling framework in assessing health risks associated with exposures to complex chemical mixtures. PMID:21655141

  13. Human plasma concentrations of tolbutamide and acetaminophen extrapolated from in vivo animal pharmacokinetics using in vitro human hepatic clearances and simple physiologically based pharmacokinetic modeling for radio-labeled microdose clinical studies

    International Nuclear Information System (INIS)

    Yamazaki, Hiroshi; Kunikane, Eriko; Nishiyama, Sayako; Murayama, Norie; Shimizu, Makiko; Sugiyama, Yuichi; Chiba, Koji; Ikeda, Toshihiko

    2015-01-01

    The aim of the current study was to extrapolate the pharmacokinetics of drug substances orally administered in humans from rat pharmacokinetic data using tolbutamide and acetaminophen as model compounds. Adjusted animal biomonitoring equivalents from rat studies based on reported plasma concentrations were scaled to human biomonitoring equivalents using known species allometric scaling factors. In this extrapolation, in vitro metabolic clearance data were obtained using liver preparations. Rates of tolbutamide elimination were roughly similar in rat and human liver microsome experiments, but acetaminophen elimination by rat liver microsomes and cytosolic preparations showed a tendency to be faster than those in humans. Using a simple physiologically based pharmacokinetic (PBPK) model, estimated human plasma concentrations of tolbutamide and acetaminophen were consistent with reported concentrations. Tolbutamide cleared in a roughly similar manner in humans and rats, but medical-dose levels of acetaminophen cleared (dependent on liver metabolism) more slowly from plasma in humans than it did in rats. The data presented here illustrate how pharmacokinetic data in combination with a simple PBPK model can be used to assist evaluations of the pharmacological/toxicological potential of new drug substances and for estimating human radiation exposures from radio-labeled drugs when planning human studies. (author)

  14. Population pharmacokinetics of olprinone in healthy male volunteers

    Directory of Open Access Journals (Sweden)

    Kunisawa T

    2014-03-01

    Full Text Available Takayuki Kunisawa,1 Hidefumi Kasai,2 Makoto Suda,2 Manabu Yoshimura,3 Ami Sugawara,3 Yuki Izumi,3 Takafumi Iida,3 Atsushi Kurosawa,3 Hiroshi Iwasaki3 1Surgical Operation Department, Asahikawa Medical University Hospital, Hokkaido, Japan; 2Clinical Study Management Division, Bell Medical Solutions Inc, Tokyo, Japan; 3Department of Anesthesiology and Critical Care Medicine, Asahikawa Medical University, Hokkaido, Japan Background: Olprinone decreases the cardiac preload and/or afterload because of its vasodilatory effect and increases myocardial contractility by inhibiting phosphodiesterase III. Purpose: The objective of this study was to characterize the population pharmacokinetics of olprinone after a single continuous infusion in healthy male volunteers. Methods: We used 500 plasma concentration data points collected from nine healthy male volunteers for the study. The population pharmacokinetic analysis was performed using the nonlinear mixed effect model (NONMEM® software. Results: The time course of plasma concentration of olprinone was best described using a two-compartment model. The final pharmacokinetic parameters were total clearance (7.37 mL/minute/kg, distribution volume of the central compartment (134 mL/kg, intercompartmental clearance (7.75 mL/minute/kg, and distribution volume of the peripheral compartment (275 mL/kg. The interindividual variability in the total clearance was 12.4%, and the residual error variability (exponential and additive were 22.2% and 0.129 (standard deviation. The final pharmacokinetic model was assessed using a bootstrap method and visual predictive check. Conclusion: We developed a population pharmacokinetic model of olprinone in healthy male adults. The bootstrap method and visual predictive check showed that this model was appropriate. Our results might be used to develop the population pharmacokinetic model in patients. Keywords: phosphodiesterase III inhibitor, men, pharmacokinetic model

  15. Pharmacokinetic models relevant to toxicity and metabolism for uranium in humans and animals

    International Nuclear Information System (INIS)

    Wrenn, M.E.; Lipsztein, J.; Bertelli, L.

    1988-01-01

    The aim of this paper is to summarize pharmacokinetic models of uranium metabolism. Fortunately, others have recently reviewed metabolic models of all types, not just pharmacokinetic models. Their papers should be consulted for greater biological detail than is possible here. Improvements in the models since these other papers are noted. Models for assessing the biological consequences of exposure should account for the kinetics of intake by ingestion, inhalation, and injection, and the chemical form of uranium; predict the time dependent concentration in red blood cells, plasma, urine, kidney, bone and other organs (or compartments); and be adaptable to calculating these concentrations for varying regimens of intake. The biological parameters in the models come from metabolic data in humans and animals. Some of these parameters are reasonably well defined. For example, the cumulative urinary excretion at 24 hours post injection of soluble uranium in man is about 70%, the absorbed fraction for soluble uranium ingested by man in drinking water during normal dietary conditions is about 1%, and the half time in the mammalian kidney is several days. 17 refs., 8 figs

  16. Nitro-fatty acid pharmacokinetics in the adipose tissue compartment.

    Science.gov (United States)

    Fazzari, Marco; Khoo, Nicholas K H; Woodcock, Steven R; Jorkasky, Diane K; Li, Lihua; Schopfer, Francisco J; Freeman, Bruce A

    2017-02-01

    Electrophilic nitro-FAs (NO 2 -FAs) promote adaptive and anti-inflammatory cell signaling responses as a result of an electrophilic character that supports posttranslational protein modifications. A unique pharmacokinetic profile is expected for NO 2 -FAs because of an ability to undergo reversible reactions including Michael addition with cysteine-containing proteins and esterification into complex lipids. Herein, we report via quantitative whole-body autoradiography analysis of rats gavaged with radiolabeled 10-nitro-[ 14 C]oleic acid, preferential accumulation in adipose tissue over 2 weeks. To better define the metabolism and incorporation of NO 2 -FAs and their metabolites in adipose tissue lipids, adipocyte cultures were supplemented with 10-nitro-oleic acid (10-NO 2 -OA), nitro-stearic acid, nitro-conjugated linoleic acid, and nitro-linolenic acid. Then, quantitative HPLC-MS/MS analysis was performed on adipocyte neutral and polar lipid fractions, both before and after acid hydrolysis of esterified FAs. NO 2 -FAs preferentially incorporated in monoacyl- and diacylglycerides, while reduced metabolites were highly enriched in triacylglycerides. This differential distribution profile was confirmed in vivo in the adipose tissue of NO 2 -OA-treated mice. This pattern of NO 2 -FA deposition lends new insight into the unique pharmacokinetics and pharmacologic actions that could be expected for this chemically-reactive class of endogenous signaling mediators and synthetic drug candidates. Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

  17. [Pharmacokinetics of salazosulfapyridine in a hemodialysis patient].

    Science.gov (United States)

    Akiyama, Yuji; Fujimaki, Toshihisa; Sakurai, Yusei

    2003-06-01

    The patient was a 62-year-old female. Total gastrectomy was performed due to gastric ulcer in 1969. She was diagnosed as rheumatoid arthritis (RA) in 1985 and was developed to amyloidosis in 1991. She was started on hemodialysis (HD) for chronic renal failure in 1996. In 1998, her arthralgia was aggravated, and 100 mg/day of bucillamine was administered on the day of HD. Her arthralgia persisted, and switching to salazosulfapyridine (SASP) was considered. As there were no standards and no reports for the use of SASP in HD patients, we examined the pharmacokinetics of SASP and its metabolites, and compared our patient with the results of phase one study in normal subjects in Japan. In this case, the blood concentration of SASP was similar to that in healthy controls after single administration of 500 mg of SASP on the day of non-HD, while the concentration of sulfapyridine (SP) was higher than that in healthy donors. However, the blood concentrations of SASP, SP, and N4-acetyl-SP (AcSP) at 24 hours after administration were similar to those obtained in healthy men. SASP was not dialyzed, while about half of SP and AcSP, were dialyzed. In a five-day consecutive administration study also, the blood concentrations of these compounds on Day 5 were similar to those of phase one study, suggesting no accumulation. No adverse drug reaction was observed. As this case had the past history of total gastrectomy and amyloidosis, it is possible that this result is influenced by the factors. Therefore it is necessary to examine pharmacokinetics of SASP and its metabolites beforehand when administering this agent to other HD/RA patients.

  18. Application of Physiologically-Based Pharmacokinetic Modeling for the Prediction of Tofacitinib Exposure in Japanese.

    Science.gov (United States)

    Suzuki, Misaki; Tse, Susanna; Hirai, Midori; Kurebayashi, Yoichi

    2017-05-09

    Tofacitinib (3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3 -oxopropanenitrile) is an oral Janus kinase inhibitor that is approved in countries including Japan and the United States for the treatment of rheumatoid arthritis, and is being developed across the globe for the treatment of inflammatory diseases. In the present study, a physiologically-based pharmacokinetic model was applied to compare the pharmacokinetics of tofacitinib in Japanese and Caucasians to assess the potential impact of ethnicity on the dosing regimen in the two populations. Simulated plasma concentration profiles and pharmacokinetic parameters, i.e. maximum concentration and area under plasma concentration-time curve, in Japanese and Caucasian populations after single or multiple doses of 1 to 30 mg tofacitinib were in agreement with clinically observed data. The similarity in simulated exposure between Japanese and Caucasian populations supports the currently approved dosing regimen in Japan and the United States, where there is no recommendation for dose adjustment according to race. Simulated results for single (1 to 100 mg) or multiple doses (5 mg twice daily) of tofacitinib in extensive and poor metabolizers of CYP2C19, an enzyme which has been shown to contribute in part to tofacitinib elimination and is known to exhibit higher frequency in Japanese compared to Caucasians, were also in support of no recommendation for dose adjustment in CYP2C19 poor metabolizers. This study demonstrated a successful application of physiologically-based pharmacokinetic modeling in evaluating ethnic sensitivity in pharmacokinetics at early stages of development, presenting its potential value as an efficient and scientific method for optimal dose setting in the Japanese population.

  19. Pharmacokinetic analysis of trichloroethylene metabolism in male B6C3F1 mice: Formation and disposition of trichloroacetic acid, dichloroacetic acid, S-(1,2-dichlorovinyl)glutathione and S-(1,2-dichlorovinyl)-L-cysteine

    Science.gov (United States)

    Kim, Sungkyoon; Kim, David; Pollack, Gary M.; Collins, Leonard B.; Rusyn, Ivan

    2009-01-01

    Trichloroethylene (TCE) is a well-known carcinogen in rodents and concerns exist regarding its potential carcinogenicity in humans. Oxidative metabolites of TCE, such as dichloroacetic acid (DCA) and trichloroacetic acid (TCA), are thought to be hepatotoxic and carcinogenic in mice. The reactive products of glutathione conjugation, such as S-(1,2-dichlorovinyl)-L-cysteine (DCVC), and S-(1,2-dichlorovinyl) glutathione (DCVG), are associated with renal toxicity in rats. Recently, we developed a new analytical method for simultaneous assessment of these TCE metabolites in small-volume biological samples. Since important gaps remain in our understanding of the pharmacokinetics of TCE and its metabolites, we studied a time-course of DCA, TCA, DCVG and DCVG formation and elimination after a single oral dose of 2100 mg/kg TCE in male B6C3F1 mice. Based on systemic concentration-time data, we constructed multi-compartment models to explore the kinetic properties of the formation and disposition of TCE metabolites, as well as the source of DCA formation. We conclude that TCE-oxide is the most likely source of DCA. According to the best-fit model, bioavailability of oral TCE was ~74%, and the half-life and clearance of each metabolite in the mouse were as follows: DCA: 0.6 hr, 0.081 ml/hr; TCA: 12 hr, 3.80 ml/hr; DCVG: 1.4 hr, 16.8 ml/hr; DCVC: 1.2 hr, 176 ml/hr. In B6C3F1 mice, oxidative metabolites are formed in much greater quantities (~3600 fold difference) than glutathione-conjugative metabolites. In addition, DCA is produced to a very limited extent relative to TCA, while most of DCVG is converted into DCVC. These pharmacokinetic studies provide insight into the kinetic properties of four key biomarkers of TCE toxicity in the mouse, representing novel information that can be used in risk assessment. PMID:19409406

  20. Pharmacokinetic analysis of trichloroethylene metabolism in male B6C3F1 mice: Formation and disposition of trichloroacetic acid, dichloroacetic acid, S-(1,2-dichlorovinyl)glutathione and S-(1,2-dichlorovinyl)-L-cysteine

    International Nuclear Information System (INIS)

    Kim, Sungkyoon; Kim, David; Pollack, Gary M.; Collins, Leonard B.; Rusyn, Ivan

    2009-01-01

    Trichloroethylene (TCE) is a well-known carcinogen in rodents and concerns exist regarding its potential carcinogenicity in humans. Oxidative metabolites of TCE, such as dichloroacetic acid (DCA) and trichloroacetic acid (TCA), are thought to be hepatotoxic and carcinogenic in mice. The reactive products of glutathione conjugation, such as S-(1,2-dichlorovinyl)-L-cysteine (DCVC), and S-(1,2-dichlorovinyl) glutathione (DCVG), are associated with renal toxicity in rats. Recently, we developed a new analytical method for simultaneous assessment of these TCE metabolites in small-volume biological samples. Since important gaps remain in our understanding of the pharmacokinetics of TCE and its metabolites, we studied a time-course of DCA, TCA, DCVG and DCVG formation and elimination after a single oral dose of 2100 mg/kg TCE in male B6C3F1 mice. Based on systemic concentration-time data, we constructed multi-compartment models to explore the kinetic properties of the formation and disposition of TCE metabolites, as well as the source of DCA formation. We conclude that TCE-oxide is the most likely source of DCA. According to the best-fit model, bioavailability of oral TCE was ∼ 74%, and the half-life and clearance of each metabolite in the mouse were as follows: DCA: 0.6 h, 0.081 ml/h; TCA: 12 h, 3.80 ml/h; DCVG: 1.4 h, 16.8 ml/h; DCVC: 1.2 h, 176 ml/h. In B6C3F1 mice, oxidative metabolites are formed in much greater quantities (∼ 3600 fold difference) than glutathione-conjugative metabolites. In addition, DCA is produced to a very limited extent relative to TCA, while most of DCVG is converted into DCVC. These pharmacokinetic studies provide insight into the kinetic properties of four key biomarkers of TCE toxicity in the mouse, representing novel information that can be used in risk assessment.

  1. Ecotoxicity and genotoxicity of cyclophosphamide, ifosfamide, their metabolites/transformation products and their mixtures

    International Nuclear Information System (INIS)

    Česen, Marjeta; Eleršek, Tina; Novak, Matjaž; Žegura, Bojana; Kosjek, Tina; Filipič, Metka; Heath, Ester

    2016-01-01

    Cyclophosphamide (CP) and ifosfamide (IF) are commonly used cytostatic drugs that repress cell division by interaction with DNA. The present study investigates the ecotoxicity and genotoxicity of CP, IF, their human metabolites/transformation products (TPs) carboxy-cyclophosphamide (CPCOOH), keto-cyclophosphamide (ketoCP) and N-dechloroethyl-cyclophosphamide (NdCP) as individual compounds and as mixture. The two parent compounds (CP and IF), at concentrations up to 320 mg L −1 , were non-toxic towards the alga Pseudokirchneriella subcapitata and cyanobacterium Synecococcus leopoliensis. Further ecotoxicity studies of metabolites/TPs and a mixture of parent compounds and metabolites/TPs performed in cyanobacteria S. leopoliensis, showed that only CPCOOH (EC 50  = 17.1 mg L −1 ) was toxic. The measured toxicity (EC 50  = 11.5 mg L −1 ) of the mixture was lower from the toxicity predicted by concentration addition model (EC 50  = 21.1 mg L −1 ) indicating potentiating effects of the CPCOOH toxicity. The SOS/umuC assay with Salmonella typhimurium revealed genotoxic activity of CP, CPCOOH and the mixture in the presence of S9 metabolic activation. Only CPCOOH was genotoxic also in the absence of metabolic activation indicating that this compound is a direct acting genotoxin. This finding is of particular importance as in the environment such compounds can directly affect DNA of non-target organisms and also explains toxicity of CPCOOH against cyanobacteria S. leopoliensis. The degradation study with UV irradiation of samples containing CP and IF showed efficient degradation of both compounds and remained non-toxic towards S. leopoliensis, suggesting that no stable TPs with adverse effects were formed. To our knowledge, this is the first study describing the ecotoxicity and genotoxicity of the commonly used cytostatics CP and IF, their known metabolites/TPs and their mixture. The results indicate the importance of toxicological evaluation and

  2. Instruments for radiation measurement in life sciences (4). VI. Use of Accelerator mass spectrometry in studies on drug metabolism and pharmacokinetics

    International Nuclear Information System (INIS)

    Ikeda, Toshihiko

    2005-01-01

    Non-clinical and clinical uses of accelerator mass spectrometry (AMS) are described mainly on studies of drug metabolism and pharmacokinetics from a view of new drug development. AMS is applicable as a highly sensitive method to measure plasma drug concentrations. Measurement of 14 C-labeled compounds less than 1 dpm/sample or of parathyroid hormone-related protein (PTHrP), in combination of AMS and radioimmunoassay without radioactive waste release is described as an example. Cases of measuring DNA-adduct are also described involving human studies using 14 C-mutagen (a quinoxaline derivative derived from burned amino acid, given in a microdose of 304 ng/kg, 4.3 μCi/body). Plasma concentration measurement, mass balance study and metabolite identification of 14 C-GI1817771 (a drug candidate) are a typical AMS application for a pharmacokinetic study in human in a microdose (121 Bq/body). Metabolites of 14 C-compound A in rat platelet are identified by the author. As above, AMS makes it possible to conduct the pharmacokinetic study in human at a microdose with no significant radiation exposure, which will promote the efficient new drug development. (N.I.)

  3. Pharmacokinetics and Concentration-Effect Relationship of Oral LSD in Humans.

    Science.gov (United States)

    Dolder, Patrick C; Schmid, Yasmin; Haschke, Manuel; Rentsch, Katharina M; Liechti, Matthias E

    2015-06-24

    The pharmacokinetics of oral lysergic acid diethylamide are unknown despite its common recreational use and renewed interest in its use in psychiatric research and practice. We characterized the pharmacokinetic profile, pharmacokinetic-pharmacodynamic relationship, and urine recovery of lysergic acid diethylamide and its main metabolite after administration of a single oral dose of lysergic acid diethylamide (200 μg) in 8 male and 8 female healthy subjects. Plasma lysergic acid diethylamide concentrations were quantifiable (>0.1 ng/mL) in all the subjects up to 12 hours after administration. Maximal concentrations of lysergic acid diethylamide (mean±SD: 4.5±1.4 ng/mL) were reached (median, range) 1.5 (0.5-4) hours after administration. Concentrations then decreased following first-order kinetics with a half-life of 3.6±0.9 hours up to 12 hours and slower elimination thereafter with a terminal half-life of 8.9±5.9 hours. One percent of the orally administered lysergic acid diethylamide was eliminated in urine as lysergic acid diethylamide, and 13% was eliminated as 2-oxo-3-hydroxy-lysergic acid diethylamide within 24 hours. No sex differences were observed in the pharmacokinetic profiles of lysergic acid diethylamide. The acute subjective and sympathomimetic responses to lysergic acid diethylamide lasted up to 12 hours and were closely associated with the concentrations in plasma over time and exhibited no acute tolerance. These first data on the pharmacokinetics and concentration-effect relationship of oral lysergic acid diethylamide are relevant for further clinical studies and serve as a reference for the assessment of intoxication with lysergic acid diethylamide. © The Author 2015. Published by Oxford University Press on behalf of CINP.

  4. Simultaneous LC-MS/MS determination of JWH-210, RCS-4, ∆(9)-tetrahydrocannabinol, and their main metabolites in pig and human serum, whole blood, and urine for comparing pharmacokinetic data.

    Science.gov (United States)

    Schaefer, Nadine; Kettner, Mattias; Laschke, Matthias W; Schlote, Julia; Peters, Benjamin; Bregel, Dietmar; Menger, Michael D; Maurer, Hans H; Ewald, Andreas H; Schmidt, Peter H

    2015-05-01

    A series of new synthetic cannabinoids (SC) has been consumed without any toxicological testing. For example, pharmacokinetic data have to be collected from forensic toxicological case work and/or animal studies. To develop a corresponding model for assessing such data, samples of controlled pig studies with two selected SC (JWH-210, RCS-4) and, as reference, ∆(9)-tetrahydrocannabinol (THC) should be analyzed as well as those of human cases. Therefore, a method for determination of JWH-210, RCS-4, THC, and their main metabolites in pig and human serum, whole blood, and urine samples is presented. Specimens were analyzed by liquid-chromatography tandem mass spectrometry and multiple-reaction monitoring with three transitions per compound. Full validation was carried out for the pig specimens and cross-validation for the human specimens concerning precision and bias. For the pig studies, the limits of detection were between 0.05 and 0.50 ng/mL in serum and whole blood and between 0.05 and 1.0 ng/mL in urine, the lower limits of quantification between 0.25 and 1.0 ng/mL in serum and 0.50 and 2.0 ng/mL in whole blood and urine, and the intra- and interday precision values lower than 15% and bias values within ±15%. The applicability was tested with samples taken from a pharmacokinetic pilot study with pigs following intravenous administration of a mixture of 200 μg/kg body mass dose each of JWH-210, RCS-4, and THC. The cross-validation data for human serum, whole blood, and urine showed that this approach should also be suitable for human specimens, e.g., of clinical or forensic cases.

  5. Pharmacokinetics of S-Allyl-l-cysteine in Rats Is Characterized by High Oral Absorption and Extensive Renal Reabsorption.

    Science.gov (United States)

    Amano, Hirotaka; Kazamori, Daichi; Itoh, Kenji

    2016-02-01

    S-Allylcysteine (SAC) is a key component of aged garlic extract, one of many garlic products. However, information on its pharmacokinetics has been scant except for data from a few animal studies. We designed this study to determine the overall pharmacokinetics of SAC in rats. After oral or intravenous administration of SAC to rats at a dose of 5 mg/kg, the plasma concentration-time profile of SAC and its metabolites, as well as the amounts excreted in bile and urine, were analyzed by using liquid chromatography tandem mass spectrometry. After oral administration, SAC was well absorbed with a bioavailability of 98%. Two major metabolites of SAC, N-acetyl-S-allylcysteine (NAc-SAC) and N-acetyl-S-allylcysteine sulfoxide (NAc-SACS), were detected in plasma, but their concentrations were markedly lower than those of SAC. SAC was metabolized to a limited extent, but most of the orally absorbed SAC was excreted into urine in the form of its N-acetylated metabolites. The amounts of SAC, NAc-SAC, and NAc-SACS excreted in urine over 24 h were 2.9%, 80%, and 11% of the orally administered SAC, respectively. The very low renal clearance (0.016 L ⋅ h(-1) ⋅ kg(-1)) of SAC indicated that it undergoes extensive renal reabsorption. These results collectively suggested that SAC was ultimately metabolized to NAc-SAC and NAc-SACS through the cycles of urinary excretion, renal reabsorption, and systemic recirculation. The pharmacokinetics of SAC in rats were characterized by high oral absorption, limited metabolism, and extensive renal reabsorption, all of which potentially contribute to its high and relatively long-lasting plasma concentrations. © 2016 American Society for Nutrition.

  6. Ethnic comparison of pharmacokinetics of {sup 18}F-florbetaben, a PET tracer for beta-amyloid imaging, in healthy Caucasian and Japanese subjects

    Energy Technology Data Exchange (ETDEWEB)

    Senda, Michio; Sasaki, Masahiro; Yamane, Tomohiko; Shimizu, Keiji [Institute of Biomedical Research and Innovation, Division of Molecular Imaging, 2-2 Minatojima-Minamimachi, Chuo-ku, Kobe (Japan); Patt, Marianne; Barthel, Henryk; Sattler, Bernhard; Sabri, Osama [University of Leipzig, Department of Nuclear Medicine, Leipzig (Germany); Nagasawa, Toshiki; Aitoku, Yasuko [Bayer Yakuhin Ltd, Osaka (Japan); Schultze-Mosgau, Marcus [Bayer HealthCare AG, Berlin (Germany); Dinkelborg, Ludger [Piramal Imaging GmbH, Berlin (Germany)

    2015-01-15

    {sup 18}F-Florbetaben is a positron emission tomography (PET) tracer indicated for imaging cerebral beta-amyloid deposition in adult patients with cognitive impairment who are being evaluated for Alzheimer's disease and other causes of cognitive decline. The present study examined ethnic comparability of the plasma pharmacokinetics, which is the input to the brain, between Caucasian and Japanese subjects. Two identical phase I trials were performed in 18 German and 18 Japanese healthy volunteers to evaluate the plasma pharmacokinetics of a single dose of 300 MBq {sup 18}F-florbetaben, either of low (≤5 μg, LD) or high (50-55 μg, HD) mass dose. Pharmacokinetic parameters were evaluated based on the total {sup 18}F radioactivity measurements in plasma followed by metabolite analysis using radio-HPLC. The pharmacokinetics of {sup 18}F-florbetaben was characterized by a rapid elimination from plasma. The dose-normalized areas under the curve of {sup 18}F-florbetaben in plasma as an indicator of the input to the brain were comparable between Germans (LD: 0.38 min/l, HD: 0.55 min/l) and Japanese (LD: 0.35 min/l, HD: 0.45 min/l) suggesting ethnic similarity, and the mass dose effect was minimal. A polar metabolite fraction was the main radiolabelled degradation product in plasma and was also similar between the doses and the ethnic groups. Absence of a difference in the pharmacokinetics of {sup 18}F-florbetaben in Germans and Japanese has warranted further global development of the PET imaging agent. (orig.)

  7. A physiologically based pharmacokinetic model to predict the pharmacokinetics of highly protein-bound drugs and the impact of errors in plasma protein binding.

    Science.gov (United States)

    Ye, Min; Nagar, Swati; Korzekwa, Ken

    2016-04-01

    Predicting the pharmacokinetics of highly protein-bound drugs is difficult. Also, since historical plasma protein binding data were often collected using unbuffered plasma, the resulting inaccurate binding data could contribute to incorrect predictions. This study uses a generic physiologically based pharmacokinetic (PBPK) model to predict human plasma concentration-time profiles for 22 highly protein-bound drugs. Tissue distribution was estimated from in vitro drug lipophilicity data, plasma protein binding and the blood: plasma ratio. Clearance was predicted with a well-stirred liver model. Underestimated hepatic clearance for acidic and neutral compounds was corrected by an empirical scaling factor. Predicted values (pharmacokinetic parameters, plasma concentration-time profile) were compared with observed data to evaluate the model accuracy. Of the 22 drugs, less than a 2-fold error was obtained for the terminal elimination half-life (t1/2 , 100% of drugs), peak plasma concentration (Cmax , 100%), area under the plasma concentration-time curve (AUC0-t , 95.4%), clearance (CLh , 95.4%), mean residence time (MRT, 95.4%) and steady state volume (Vss , 90.9%). The impact of fup errors on CLh and Vss prediction was evaluated. Errors in fup resulted in proportional errors in clearance prediction for low-clearance compounds, and in Vss prediction for high-volume neutral drugs. For high-volume basic drugs, errors in fup did not propagate to errors in Vss prediction. This is due to the cancellation of errors in the calculations for tissue partitioning of basic drugs. Overall, plasma profiles were well simulated with the present PBPK model. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  8. Metabolic Pathway of Icotinib In Vitro: The Differential Roles of CYP3A4, CYP3A5, and CYP1A2 on Potential Pharmacokinetic Drug-Drug Interaction.

    Science.gov (United States)

    Zhang, TianHong; Zhang, KeRong; Ma, Li; Li, Zheng; Wang, Juan; Zhang, YunXia; Lu, Chuang; Zhu, Mingshe; Zhuang, XiaoMei

    2018-04-01

    Icotinib is the first self-developed small molecule drug in China for targeted therapy of non-small cell lung cancer. To date, systematic studies on the pharmacokinetic drug-drug interaction of icotinib were limited. By identifying metabolite generated in human liver microsomes and revealing the contributions of major cytochromes P450 (CYPs) in the formation of major metabolites, the aim of the present work was to understand the mechanisms underlying pharmacokinetic and pharmacological variability in clinic. A liquid chromatography/UV/high-resolution mass spectrometer method was developed to characterize the icotinib metabolites. The formation of 6 major metabolites was studied in recombinant CYP isozymes and human liver microsomes with specific inhibitors to identify the CYPs responsible for icotinib metabolism. The metabolic pathways observed in vitro are consistent with those observed in human. Results demonstrated that the metabolites are predominantly catalyzed by CYP3A4 (77%∼87%), with a moderate contribution from CYP3A5 (5%∼15%) and CYP1A2 (3.7%∼7.5%). The contribution of CYP2C8, 2C9, 2C19, and 2D6 is insignificant. Based on our observations, to minimize drug-drug interaction risk in clinic, coprescription of icotinib with strong CYP3A inhibitors or inducers must be weighed. CYP1A2, a highly inducible enzyme in the smoking population, may also represent a determinant of pharmacokinetic and pharmacological variability of icotinib, especially in lung cancer patients with smoking history. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  9. Determinants of Organophosphorus Pesticide Urinary Metabolite Levels in Young Children Living in an Agricultural Community

    Directory of Open Access Journals (Sweden)

    Brenda Eskenazi

    2011-04-01

    Full Text Available Organophosphorus (OP pesticides are used in agriculture and several are registered for home use. As young children age they may experience different pesticide exposures due to varying diet, behavior, and other factors. We measured six OP dialkylphosphate (DAP metabolites (three dimethyl alkylphosphates (DMAP and three diethyl alkylphosphates (DEAP in urine samples collected from ~400 children living in an agricultural community when they were 6, 12, and 24 months old. We examined bivariate associations between DAP metabolite levels and determinants such as age, diet, season, and parent occupation. To evaluate independent impacts, we then used generalized linear mixed multivariable models including interaction terms with age. The final models indicated that DMAP metabolite levels increased with age. DMAP levels were also positively associated with daily servings of produce at 6- and 24-months. Among the 6-month olds, DMAP metabolite levels were higher when samples were collected during the summer/spring versus the winter/fall months. Among the 12-month olds, DMAP and DEAP metabolites were higher when children lived ≤60 meters from an agricultural field. Among the 24-month-olds, DEAP metabolite levels were higher during the summer/spring months. Our findings suggest that there are multiple determinants of OP pesticide exposures, notably dietary intake and temporal and spatial proximity to agricultural use. The impact of these determinants varied by age and class of DAP metabolite.

  10. Pharmacokinetics of enrofloxacin and marbofloxacin in Japanese quails and common pheasants.

    Science.gov (United States)

    Lashev, L D; Dimitrova, D J; Milanova, A; Moutafchieva, R G

    2015-04-01

    The pharmacokinetics of enrofloxacin and marbofloxacin was studied in Japanese quails and common pheasants. Healthy mature birds from both species and both genders were treated intravenously and orally with enrofloxacin (10 mg/kg) and marbofloxacin (5 mg/kg). After intravenous administration enrofloxacin was extensively metabolised to ciprofloxacin. Metabolites of marbofloxacin were not detected. Values of volume of distribution were respectively 4.63 l/kg and 3.67 l/kg for enrofloxacin and 1.56 l/kg and 1.43 l/kg for marbofloxacin. In quails, total body clearance values were higher than those in pheasants and other avian species. After oral application enrofloxacin was rapidly absorbed in quails, more rapidly than marbofloxacin. Pheasants absorbed both antimicrobials at a lower rate. Higher bioavailability was observed for marbofloxacin (118%). Relatively low bioavailability was established in quails for enrofloxacin (26.4%), accompanied by extensive conversion to ciprofloxacin. Generally, quails absorbed and eliminated both fluoroquinolones more rapidly than pheasants; the latter showed pharmacokinetics similar to poultry. Because of favourable pharmacokinetic properties, marbofloxacin should be preferred for oral administration in Japanese quails and pheasants for treatment of infections caused by equally susceptible pathogens.

  11. Clinical applications of fast liquid chromatography: a review on the analysis of cardiovascular drugs and their metabolites.

    Science.gov (United States)

    Baranowska, Irena; Magiera, Sylwia; Baranowski, Jacek

    2013-05-15

    One of the major challenges facing the medicine today is developing new therapies that enhance human health. To help address these challenges the utilization of analytical technologies and high-throughput automated platforms has been employed; in order to perform more experiments in a shorter time frame with increased data quality. In the last decade various analytical strategies have been established to enhance separation speed and efficiency in liquid chromatography applications. Liquid chromatography is an increasingly important tool for monitoring drugs and their metabolites. Furthermore, liquid chromatography has played an important role in pharmacokinetics and metabolism studies at these drug development stages since its introduction. This paper provides an overview of current trends in fast chromatography for the analysis of cardiovascular drugs and their metabolites in clinical applications. Current trends in fast liquid chromatographic separations involve monolith technologies, fused-core columns, high-temperature liquid chromatography (HTLC) and ultra-high performance liquid chromatography (UHPLC). The high specificity in combination with high sensitivity makes it an attractive complementary method to traditional methodology used for routine applications. The practical aspects of, recent developments in and the present status of fast chromatography for the analysis of biological fluids for therapeutic drug and metabolite monitoring, pharmacokinetic studies and bioequivalence studies are presented. Copyright © 2013 Elsevier B.V. All rights reserved.

  12. Corneal pharmacokinetics of the 2% diacerein eye drops between multiple administration and single administration

    Directory of Open Access Journals (Sweden)

    Ke Yang

    2018-04-01

    Full Text Available AIM: To compare the pharmacokinetic differences of the 2% diacerein eye drops between conjunctival sac multiple administration and single administration in the cornea, and to provide the experimental basis for clinicians to use the conjunctival sac multiple administration.METHODS: Male Kunming mice were randomly divided into the multiple administration group and the single administration group. The multiple administration group were given diacerein eye drop every 2min(3 times in total. The concentrations of the metabolites of diacerein in the cornea were measured by high performance liquid chromatography after given eye drop 5, 15, 30, 60, 120, and 180min. The pharmacokinetic parameters were calculated by pharmacokinetic software(DAS2.1.1. RESULTS: The metabolites of diacerein, rhein, was detected in the cornea at each time point. The concentration of the metabolite of diacerein in the cornea was 318.678±40.88, 210.02±25.66, 188.83±31.74, 112.24±11.70, 90.28±22.01 and 57.67±13.71μg/g after given eye drop 5, 15, 30, 60, 120, and 180min in the multiple administration group. The concentration in the single administration group was 145.17±19.29, 97.95±10.49, 71.18±18.70, 39.11±2.44, 18.10±2.34 and 9.08±2.04μg/g respectively. The concentration of rhein in the cornea was the highest at 5min after the administration in the two groups. The concentration of the multiple administration group was higher than that in the single administration group at 5, 15, 30, 60, 120, and 180min(PCONCLUSION: Compared with the single administration, the conjunctival sac multiple administration has the advantages of high drug concentration and long duration. Therefor the conjunctival sac multiple administration is a more effective method to treat acute infectious corneal diseases.

  13. Population Pharmacokinetics of Intranasal Scopolamine

    Science.gov (United States)

    Wu, L.; Chow, D. S. L.; Putcha, L.

    2013-01-01

    Introduction: An intranasal gel dosage formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness (SMS).The bioavailability and pharmacokinetics (PK) was evaluated using data collected in Phase II IND protocols. We reported earlier statistically significant gender differences in PK parameters of INSCOP at a dose level of 0.4 mg. To identify covariates that influence PK parameters of INSCOP, we examined population covariates of INSCOP PK model for 0.4 mg dose. Methods: Plasma scopolamine concentrations versus time data were collected from 20 normal healthy human subjects (11 male/9 female) after a 0.4 mg dose. Phoenix NLME was employed for PK analysis of these data using gender, body weight and age as covariates for model selection. Model selection was based on a likelihood ratio test on the difference of criteria (-2LL). Statistical significance for base model building and individual covariate analysis was set at P less than 0.05{delta(-2LL)=3.84}. Results: A one-compartment pharmacokinetic model with first-order elimination best described INSCOP concentration ]time profiles. Inclusion of gender, body weight and age as covariates individually significantly reduced -2LL by the cut-off value of 3.84(P less than 0.05) when tested against the base model. After the forward stepwise selection and backward elimination steps, gender was selected to add to the final model which had significant influence on absorption rate constant (ka) and the volume of distribution (V) of INSCOP. Conclusion: A population pharmacokinetic model for INSCOP has been identified and gender was a significant contributing covariate for the final model. The volume of distribution and Ka were significantly higher in males than in females which confirm gender-dependent pharmacokinetics of scopolamine after administration of a 0.4 mg dose.

  14. Neuropharmacology of 3,4-Methylenedioxypyrovalerone (MDPV), Its Metabolites, and Related Analogs.

    Science.gov (United States)

    Baumann, Michael H; Bukhari, Mohammad O; Lehner, Kurt R; Anizan, Sebastien; Rice, Kenner C; Concheiro, Marta; Huestis, Marilyn A

    2017-01-01

    3,4-Methylenedioxypyrovalerone (MDPV) is a psychoactive component of so-called bath salts products that has caused serious medical consequences in humans. In this chapter, we review the neuropharmacology of MDPV and related analogs, and supplement the discussion with new results from our preclinical experiments. MDPV acts as a potent uptake inhibitor at plasma membrane transporters for dopamine (DAT) and norepinephrine (NET) in nervous tissue. The MDPV formulation in bath salts is a racemic mixture, and the S isomer is much more potent than the R isomer at blocking DAT and producing abuse-related effects. Elevations in brain extracellular dopamine produced by MDPV are likely to underlie its locomotor stimulant and addictive properties. MDPV displays rapid pharmacokinetics when injected into rats (0.5-2.0 mg/kg), with peak plasma concentrations achieved by 10-20 min and declining quickly thereafter. MDPV is metabolized to 3,4-dihydroxypyrovalerone (3,4-catechol-PV) and 4-hydroxy-3-methoxypyrovalerone (4-OH-3-MeO-PV) in vivo, but motor activation produced by the drug is positively correlated with plasma concentrations of parent drug and not its metabolites. 3,4-Catechol-PV is a potent uptake blocker at DAT in vitro but has little activity after administration in vivo. 4-OH-3-MeO-PV is the main MDPV metabolite but is weak at DAT and NET. MDPV analogs, such as α-pyrrolidinovalerophenone (α-PVP), display similar ability to inhibit DAT and increase extracellular dopamine concentrations. Taken together, these findings demonstrate that MDPV and its analogs represent a unique class of transporter inhibitors with a high propensity for abuse and addiction.

  15. Non-equilibrium method for the radioimmunoassay of clozapine in the presence of metabolites

    International Nuclear Information System (INIS)

    Rosenthaler, J.; Nimmerfall, F.; Sigrist, R.; Munzer, H.

    1977-01-01

    Cross-reactions with metabolites are an ever-recurring problem encountered in the use of radioimmunoassay techniques to determine active compounds in biological material. Metabolites may interfere with the assay of the parent drug to a variable extent. Taking 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine (clozapine) as an example, it was shown that the extent to which the antiserum produced interacts with the parent drug and the metabolites can be estimated by determining the equilibrium constants and the kinetics. In the present case, therefore, it was advantageous to carry out the radioimmunoassay in disequilibrium, i.e. in order to differentiate the metabolites from the parent drug, the sample was incubated with the antiserum for 10 min, after which the labelled antigen was added and the reaction mixture again incubated for a brief, exactly timed interval. It was shown that cross-reactions did not occur in mixtures of clozapine and its N-demethyl and N-oxide metabolites in the proportions 1 : 1 : 2 over a range of concentration of 1.5-48 ng clozapine per 100 μl human plasma. The equilibrium constants measured with the clozapine goat antiserum were as follows: clozapine 1.2 x 10 8 M -1 , the N-demethyl metabolite 4.6 x 10 7 M -1 and the N-oxide 3.7 x 10 7 M -1 (pH 7.5 and 20 0 C). (orig.) [de

  16. Development and validation of a high performance liquid chromatography quantification method of levo-tetrahydropalmatine and its metabolites in plasma and brain tissues: application to a pharmacokinetic study.

    Science.gov (United States)

    Abdallah, Inas A; Huang, Peng; Liu, Jing; Lee, David Y; Liu-Chen, Lee-Yuan; Hassan, Hazem E

    2017-04-01

    Levo-tetrahydropalmatine (l-THP) is an alkaloid isolated from Chinese medicinal herbs of the Corydalis and Stephania genera. It has been used in China for more than 40 years mainly as an analgesic with sedative/hypnotic effects. Despite its extensive use, its metabolism has not been quantitatively studied, nor there a sensitive reliable bioanalytical method for its quantification simultaneously with its metabolites. As such, the objective of this study was to develop and validate a sensitive and selective HPLC method for simultaneous quantification of l-THP and its desmethyl metabolites l-corydalmine (l-CD) and l-corypalmine (l-CP) in rat plasma and brain tissues. Rat plasma and brain samples were processed by liquid-liquid extraction using ethyl acetate. Chromatographic separation was achieved on a reversed-phase Symmetry® C 18 column (4.6 × 150 mm, 5 μm) at 25°C. The mobile phase consisted of acetonitrile-methanol-10 mm ammonium phosphate (pH 3) (10:30:60, v/v) and was used at a flow rate of 0.8 mL/min. The column eluent was monitored at excitation and emission wavelengths of 230 and 315 nm, respectively. The calibration curves were linear over the concentration range of 1-10,000 ng/mL. The intra- and interday reproducibility studies demonstrated accuracy and precision within the acceptance criteria of bioanalytical guidelines. The validated HPLC method was successfully applied to analyze samples from a pharmacokinetic study of l-THP in rats. Taken together, the developed method can be applied for bioanalysis of l-THP and its metabolites in rodents and potentially can be transferred for bioanalysis of human samples. Copyright © 2016 John Wiley & Sons, Ltd.

  17. Influence of Differing Analgesic Formulations of Aspirin on Pharmacokinetic Parameters

    Directory of Open Access Journals (Sweden)

    Kunal Kanani

    2015-08-01

    Full Text Available Aspirin has been used therapeutically for over 100 years. As the originator and an important marketer of aspirin-containing products, Bayer’s clinical trial database contains numerous reports of the pharmacokinetics of various aspirin formulations. These include evaluations of plain tablets, effervescent tablets, granules, chewable tablets, and fast-release tablets. This publication seeks to expand upon the available pharmacokinetic information concerning aspirin formulations. In the pre-systemic circulation, acetylsalicylic acid (ASA is rapidly converted into its main active metabolite, salicylic acid (SA. Therefore, both substances are measured in plasma and reported in the results. The 500 mg strength of each formulation was chosen for analysis as this is the most commonly used for analgesia. A total of 22 studies were included in the analysis. All formulations of 500 mg aspirin result in comparable plasma exposure to ASA and SA as evidenced by AUC. Tablets and dry granules provide a consistently lower Cmax compared to effervescent, granules in suspension and fast release tablets. Effervescent tablets, fast release tablets, and granules in suspension provide a consistently lower median Tmax compared to dry granules and tablets for both ASA and SA. This report reinforces the importance of formulation differences and their impact on pharmacokinetic parameters.

  18. Pharmacokinetics, Pharmacodynamics and Clinical Use of SGLT2 Inhibitors in Patients with Type 2 Diabetes Mellitus and Chronic Kidney Disease.

    Science.gov (United States)

    Scheen, André J

    2015-07-01

    Inhibitors of sodium-glucose cotransporters type 2 (SGLT2) are proposed as a novel approach for the management of type 2 diabetes mellitus. SGLT2 cotransporters are responsible for reabsorption of 90 % of the glucose filtered by the kidney. The glucuretic effect resulting from SGLT2 inhibition contributes to reduce hyperglycaemia and also assists weight loss and blood pressure reduction. Several SGLT2 inhibitors are already available in many countries (dapagliflozin, canagliflozin, empagliflozin) and in Japan (ipragliflozin, tofogliflozin). These SGLT2 inhibitors share similar pharmacokinetic characteristics with a rapid oral absorption, a long elimination half-life allowing once-daily administration, an extensive hepatic metabolism mainly via glucuronidation to inactive metabolites and a low renal elimination as a parent drug. Pharmacokinetic parameters are slightly altered in the case of chronic kidney disease (CKD). While no dose adjustment is required in the case of mild CKD, SGLT2 inhibitors may not be used or only at a lower daily dose in patients with moderate CKD. Furthermore, the pharmacodynamic response to SGLT2 inhibitors as assessed by urinary glucose excretion declines with increasing severity of renal impairment as assessed by a reduction in the estimated glomerular filtration rate. Nevertheless, the glucose-lowering efficacy and safety of SGLT2 inhibitors are almost comparable in patients with mild CKD as in patients with normal kidney function. In patients with moderate CKD, the efficacy tends to be dampened and safety concerns may occur. In patients with severe CKD, the use of SGLT2 inhibitors is contraindicated. Thus, prescribing information should be consulted regarding dosage adjustments or restrictions in the case of renal dysfunction for each SGLT2 inhibitor. The clinical impact of SGLT2 inhibitors on renal function and their potential to influence the course of diabetic nephropathy deserve attention because of preliminary favourable results

  19. Physiologically Based Pharmacokinetic Modeling of Therapeutic Proteins.

    Science.gov (United States)

    Wong, Harvey; Chow, Timothy W

    2017-09-01

    Biologics or therapeutic proteins are becoming increasingly important as treatments for disease. The most common class of biologics are monoclonal antibodies (mAbs). Recently, there has been an increase in the use of physiologically based pharmacokinetic (PBPK) modeling in the pharmaceutical industry in drug development. We review PBPK models for therapeutic proteins with an emphasis on mAbs. Due to their size and similarity to endogenous antibodies, there are distinct differences between PBPK models for small molecules and mAbs. The high-level organization of a typical mAb PBPK model consists of a whole-body PBPK model with organ compartments interconnected by both blood and lymph flows. The whole-body PBPK model is coupled with tissue-level submodels used to describe key mechanisms governing mAb disposition including tissue efflux via the lymphatic system, elimination by catabolism, protection from catabolism binding to the neonatal Fc (FcRn) receptor, and nonlinear binding to specific pharmacological targets of interest. The use of PBPK modeling in the development of therapeutic proteins is still in its infancy. Further application of PBPK modeling for therapeutic proteins will help to define its developing role in drug discovery and development. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  20. Physiologically Based Pharmacokinetic Model for Terbinafine in Rats and Humans

    Science.gov (United States)

    Hosseini-Yeganeh, Mahboubeh; McLachlan, Andrew J.

    2002-01-01

    The aim of this study was to develop a physiologically based pharmacokinetic (PB-PK) model capable of describing and predicting terbinafine concentrations in plasma and tissues in rats and humans. A PB-PK model consisting of 12 tissue and 2 blood compartments was developed using concentration-time data for tissues from rats (n = 33) after intravenous bolus administration of terbinafine (6 mg/kg of body weight). It was assumed that all tissues except skin and testis tissues were well-stirred compartments with perfusion rate limitations. The uptake of terbinafine into skin and testis tissues was described by a PB-PK model which incorporates a membrane permeability rate limitation. The concentration-time data for terbinafine in human plasma and tissues were predicted by use of a scaled-up PB-PK model, which took oral absorption into consideration. The predictions obtained from the global PB-PK model for the concentration-time profile of terbinafine in human plasma and tissues were in close agreement with the observed concentration data for rats. The scaled-up PB-PK model provided an excellent prediction of published terbinafine concentration-time data obtained after the administration of single and multiple oral doses in humans. The estimated volume of distribution at steady state (Vss) obtained from the PB-PK model agreed with the reported value of 11 liters/kg. The apparent volume of distribution of terbinafine in skin and adipose tissues accounted for 41 and 52%, respectively, of the Vss for humans, indicating that uptake into and redistribution from these tissues dominate the pharmacokinetic profile of terbinafine. The PB-PK model developed in this study was capable of accurately predicting the plasma and tissue terbinafine concentrations in both rats and humans and provides insight into the physiological factors that determine terbinafine disposition. PMID:12069977

  1. A general method to determine sampling windows for nonlinear mixed effects models with an application to population pharmacokinetic studies.

    Science.gov (United States)

    Foo, Lee Kien; McGree, James; Duffull, Stephen

    2012-01-01

    Optimal design methods have been proposed to determine the best sampling times when sparse blood sampling is required in clinical pharmacokinetic studies. However, the optimal blood sampling time points may not be feasible in clinical practice. Sampling windows, a time interval for blood sample collection, have been proposed to provide flexibility in blood sampling times while preserving efficient parameter estimation. Because of the complexity of the population pharmacokinetic models, which are generally nonlinear mixed effects models, there is no analytical solution available to determine sampling windows. We propose a method for determination of sampling windows based on MCMC sampling techniques. The proposed method attains a stationary distribution rapidly and provides time-sensitive windows around the optimal design points. The proposed method is applicable to determine sampling windows for any nonlinear mixed effects model although our work focuses on an application to population pharmacokinetic models. Copyright © 2012 John Wiley & Sons, Ltd.

  2. Biological assessment of neonicotinoids imidacloprid and its major metabolites for potentially human health using globular proteins as a model.

    Science.gov (United States)

    Ding, Fei; Peng, Wei

    2015-06-01

    The assessment of biological activities of imidacloprid and its two major metabolites, namely 6-chloronicotinic acid and 2-imidazolidone for nontarget organism, by employing essentially functional biomacromolecules, albumin and hemoglobin as a potentially model with the use of circular dichroism (CD), fluorescence, extrinsic 8-anilino-1-naphthalenesulfonic acid (ANS) fluorescence as well as molecular modeling is the theme of this work. By dint of CD spectra and synchronous fluorescence, it was clear that the orderly weak interactions between amino acid residues within globular proteins were disturbed by imidacloprid, and this event led to marginally alterations or self-regulations of protein conformation so as to lodge imidacloprid more tightly. Both steady state and time-resolved fluorescence suggested that the fluorescence of Trp residues in proteins was quenched after the presence of imidacloprid, corresponding to noncovalent protein-imidacloprid complexes formation and, the reaction belongs to moderate association (K=1.888/1.614×10(4)M(-1) for albumin/hemoglobin-imidacloprid, respectively), hydrogen bonds and π stacking performed a vital role in stabilizing the complexes, as derived from thermodynamic analysis and molecular modeling. With the aid of hydrophobic ANS experiments, subdomain IIA and α1β2 interface of albumin and hemoglobin, respectively, were found to be preserved high-affinity for imidacloprid. These results ties in with the subsequently molecular modeling laying imidacloprid in the Sudlow's site I and close to Trp-213 residue on albumin, while settling down B/Trp-37 residue nearby in hemoglobin, and these conclusions further confirmed by site-directed mutagenesis and molecular dynamics simulation. But, at the same time, several crucial noncovalent bonds came from other amino acid residues, e.g. Arg-194 and Arg-198 (albumin) and B/Arg-40, B/Asp-99 and B/Asn-102 (hemoglobin) cannot be ignored completely. Based on the comparative studies of

  3. Pharmacokinetics of subcutaneous versus intramuscular administration of ceftiofur crystalline-free acid to bearded dragons (Pogona vitticeps).

    Science.gov (United States)

    Churgin, Sarah M; Musgrave, Kari E; Cox, Sherry K; Sladky, Kurt K

    2014-05-01

    To compare pharmacokinetics after a single IM or SC injection of ceftiofur crystalline-free acid (CCFA) to bearded dragons (Pogona vitticeps). 8 adult male bearded dragons. In a preliminary experiment, doses of 15 and 30 mg/kg, SC, were compared in 2 animals, and 30 mg/kg resulted in a more desirable pharmacokinetic profile. Then, in a randomized, complete crossover experimental design, each bearded dragon (n = 6) received a single dose of 30 mg of CCFA/kg IM or SC; the experiment was repeated after a 28-day washout period with the other route of administration. Blood samples were collected at 10 time points for 288 hours after injection. Plasma concentrations of ceftiofur and desfuroylceftiofur metabolites were measured via reverse-phase high-performance liquid chromatography. Data were analyzed with a noncompartmental model. No adverse effects were observed. Plasma concentrations greater than a target minimum inhibitory concentration of 1 μg/mL were achieved by 4 hours after administration by both routes. Mean plasma concentrations remained > 1 μg/mL for > 288 hours for both routes of administration. A single dose of CCFA (30 mg/kg) administered IM or SC to bearded dragons yielded plasma concentrations of ceftiofur and its metabolites > 1 μg/mL for > 288 hours. The SC route would be preferred because of less variability in plasma concentrations and greater ease of administration than the IM route. Future studies should include efficacy data as well as evaluation of the administration of multiple doses.

  4. A physiologically-based pharmacokinetic(PB-PK) model for ethylene dibromide : relevance of extrahepatic metabolism

    NARCIS (Netherlands)

    Hissink, A M; Wormhoudt, L.W.; Sherratt, P.J.; Hayes, D.J.; Commandeur, J N; Vermeulen, N P; van Bladeren, P.J.

    A physiologically-based pharmacokinetic (PB-PK) model was developed for ethylene dibromide (1,2-dibromoethane, EDB) for rats and humans, partly based on previously published in vitro data (Ploemen et al., 1997). In the present study, this PB-PK model has been validated for the rat. In addition, new

  5. A physiologically-based pharmacokinetic (PB-PK) model for ethylene dibromide : relevance of extrahepatic metabolism

    NARCIS (Netherlands)

    Hissink, A.M.; Wormhoudt, L.W.; Sherratt, P.J.; Hayes, J.D.; Commandeur, J.N.M.; Vermeulen, N.P.E.; Bladeren, P.J. van

    2000-01-01

    A physiologically-based pharmacokinetic (PB-PK) model was developed for ethylene dibromide (1,2-dibromoethane, EDB) for rats and humans, partly based on previously published in vitro data (Ploemen et al., 1997). In the present study, this PB-PK model has been validated for the rat. In addition, new

  6. Clinical pharmacokinetics of nisoldipine coat-core.

    Science.gov (United States)

    Heinig, R

    1998-09-01

    Nisoldipine, a calcium antagonist of the dihydropyridine type, is the active ingredient of the controlled release nisoldipine coat-core (CC) formulation. In humans, the absorption from nisoldipine CC occurs across the entire gastrointestinal tract with an increase in bioavailability in the colon because of the lower concentrations of metabolising enzymes in the distal gut wall. Although nisoldipine is almost completely absorbed, its absolute bioavailability from the CC tablet is only 5.5%, as a result of significant first-pass metabolism in the gut and liver. Nisoldipine is a high-clearance drug with substantial interindividual and relatively lower intraindividual variability in pharmacokinetics, dependent on liver blood flow. Nisoldipine is highly (> 99%) protein bound. Its elimination is almost exclusively via the metabolic route and renal excretion of metabolites dominates over excretion in the faeces. Although nisoldipine is administered as a racemic mixture, its plasma concentrations are almost entirely caused by the eutomer as a result of highly stereoselective intrinsic clearance. Nisoldipine CC demonstrates linear pharmacokinetics in the therapeutic dose range and its steady-state pharmacokinetics are predictable from single dose data. Steady-state is reached with the second dose when the drug is given once daily and the peak-trough fluctuations in plasma concentration is minimal. Plasma-concentrations of nisoldipine increase with age. Careful dose titration according to individual clinical response is recommended in the elderly. Nisoldipine CC should not be used in patients with liver cirrhosis, though dosage adjustments in patients with renal impairment are not necessary. Inter-ethnic differences in its pharmacokinetics are not evident. Owing to inhibition of metabolising enzymes, a small dosage adjustment decrement for nisoldipine CC may be required when it is given in combination with cimetidine. Concomitant ingestion of nisoldipine with grapefruit

  7. A quick review of carbamazepine pharmacokinetics in epilepsy from 1953 to 2012.

    Science.gov (United States)

    Tolou-Ghamari, Zahra; Zare, Mohammad; Habibabadi, Jafar Mehvari; Najafi, Mohammad Reza

    2013-03-01

    Carbamazepine has been used as AEDs since 1965, and is most effective against partial seizures. Two basic mechanisms of action have been proposed: 1) enhancement of sodium channel inactivation by reducing high-frequency repetitive firing of action potentials, 2) and action on synaptic transmission. The aim of this study was to provide a review of carbamazepine pharmacokinetics and its management guidelines in Iranian epileptic population. Directory of Open Access Journals (DOAJ), Google Scholar, Pubmed (NLM), LISTA (EBSCO), Web of Science were searched; 1600, 722 and 167 research and review articles relevant to the topics; carbamazepine pharmacokinetics, carbamazepine pharmacokinetics in epilepsy and review on carbamazepine pharmacokinetics in epilepsy were found, respectively. Carbamazepine is highly bound to plasma proteins. In patients the protein-bound fraction ranged from 75-80% of the total plasma concentration. Bioavailability ranges from 75-85%. The rate or extent of absorption was not be affected by food. It is completely metabolized and the main metabolite is carbamazepine-epoxide (CBZ-E). Carbamazepine induces its own metabolism, leading to increased clearance, shortened serum half-life, and progressive decrease in serum levels. Increases in daily dosage are necessary to maintain plasma concentration. Severe liver dysfunction may cause disordered pharmacokinetics. In cardiac failure, congestion of major vital organs, including kidneys, may result in abnormally slow absorption and metabolism. Carbamazepine shows variability due to its narrow therapeutic window. Therefore clinical management in a3n Iranian epileptic population should focus on results derived from therapeutic drug monitoring in order to reduce inter and intra- individual variability in plasma drug concentrations.

  8. Pharmacokinetics and brain distribution in non human primate of R(-)[123I]DOI, A 5HT2A/2C serotonin agonist

    International Nuclear Information System (INIS)

    Zea-Ponce, Yolanda; Kegeles, Lawrence S.; Guo, Ningning; Raskin, Leonid; Bakthavachalam, Venkatesalu; Laruelle, Marc

    2002-01-01

    Our goal was to synthesize with high specific activity R(-)-1-(2,5-Dimethoxy-4-[ 123 I]iodophenyl)-2-aminopropane [R(-)[ 123 I]DOI], an in vitro potent and selective 5-HT 2A/2C serotonin agonist, and study in vivo its plasma pharmacokinetics and brain distribution in baboon by SPECT. The purpose was to evaluate this radiotracer as a potential tool in discerning the role of the agonist high affinity state of 5-HT 2 receptors in depression and other neurological disorders. The radiotracer was prepared by electrophilic radioiodination of the N-trifluoroacetyl precursor of R(-)-1-(2,5-Dimethoxyphenyl)-2-aminopropane [R(-)DMA-TFA] with high-purity sodium [ 123 I]iodide in the presence of chloramine-T, followed by amino deprotection with KOH in isopropanol (labeling yield: 73%, radiochemical yield: 62%, radiochemical purity: 99%). In vivo studies in baboon showed high accumulation of radioactivity in thalamus, the frontoparietal cortex, temporal, occipital and the striatum regions, with slightly lower accumulation in the midbrain and cerebellum. Ketanserin did not displaced the radioactivity in any of these brain regions. Plasma metabolite analysis was performed using methanol protein precipitation, the methanol fractions contained from 68% to 92% of the mixture of a labeled metabolite and parent compound. The recovery coefficient of unmetabolized R(-)[ 123 I]DOI was 68%. The percent parent compound present in the extracted fraction, measured by HPLC, decreased gradually with time from 99.8% to 0.3% still present after 4.7 hours post injection whereas the percentage of the only one detected metabolite increased conversely. Free fraction determination (f 1 ), was 31±0.9% (n=3). For comparison purposes, ex-vivo brain distribution, displacement and metabolite analysis was also carried out in rodents. Although R(-)[ 123 I]DOI displayed good brain uptake and localized in serotonergic areas of the brain, its target to non target ratio and its insensitivity to ketanserin

  9. Pharmacokinetic Modeling of Voriconazole To Develop an Alternative Dosing Regimen in Children.

    Science.gov (United States)

    Gastine, Silke; Lehrnbecher, Thomas; Müller, Carsten; Farowski, Fedja; Bader, Peter; Ullmann-Moskovits, Judith; Cornely, Oliver A; Groll, Andreas H; Hempel, Georg

    2018-01-01

    The pharmacokinetic variability of voriconazole (VCZ) in immunocompromised children is high, and adequate exposure, particularly in the first days of therapy, is uncertain. A population pharmacokinetic model was developed to explore VCZ exposure in plasma after alternative dosing regimens. Concentration data were obtained from a pediatric phase II study. Nonlinear mixed effects modeling was used to develop the model. Monte Carlo simulations were performed to test an array of three-times-daily (TID) intravenous dosing regimens in children 2 to 12 years of age. A two-compartment model with first-order absorption, nonlinear Michaelis-Menten elimination, and allometric scaling best described the data (maximal kinetic velocity for nonlinear Michaelis-Menten clearance [ V max ] = 51.5 mg/h/70 kg, central volume of distribution [ V 1 ] = 228 liters/70 kg, intercompartmental clearance [ Q ] = 21.9 liters/h/70 kg, peripheral volume of distribution [ V 2 ] = 1,430 liters/70 kg, bioavailability [ F ] = 59.4%, K m = fixed value of 1.15 mg/liter, absorption rate constant = fixed value of 1.19 h -1 ). Interindividual variabilities for V max , V 1 , Q , and F were 63.6%, 45.4%, 67%, and 1.34% on a logit scale, respectively, and residual variability was 37.8% (proportional error) and 0.0049 mg/liter (additive error). Monte Carlo simulations of a regimen of 9 mg/kg of body weight TID simulated for 24, 48, and 72 h followed by 8 mg/kg two times daily (BID) resulted in improved early target attainment relative to that with the currently recommended BID dosing regimen but no increased rate of accumulation thereafter. Pharmacokinetic modeling suggests that intravenous TID dosing at 9 mg/kg per dose for up to 3 days may result in a substantially higher percentage of children 2 to 12 years of age with adequate exposure to VCZ early during treatment. Before implementation of this regimen in patients, however, validation of exposure, safety, and tolerability in a carefully designed

  10. Pharmacokinetic profile of dextromethorphan hydrobromide in a syrup formulation in children and adolescents.

    Science.gov (United States)

    Guenin, Eric; Armogida, Marianna; Riff, Dennis

    2014-09-01

    Dextromethorphan hydrobromide (DM) is a widely used antitussive. This study determined, for the first time, the basic pharmacokinetic profile of DM and its active metabolite, dextrorphan (DP) in children and adolescents. Thirty-eight male and female subjects at risk for developing an upper respiratory tract infection (URTI), or symptomatic with cough due to URTI, were enrolled in this single-dose, open-label study: ages 2-5 years (Group A, n = 8), 6-11 years (Group B, n = 17), 12-17 years (Group C, n = 13). Subjects were genotyped for cytochrome P450 (CYP) 2D6 polymorphisms and characterized as poor (PM) or non-poor metabolizers (non-PM). Groups A and B were dosed using an age-weight dosing schedule (DM range 7.5-24.75 mg); a 30-mg dose was used for Group C. Average exposures to total DP increased as age group increased, and average exposure to DM was highest in the adolescent group. One subject in that group was a PM. The terminal half-life (t ½) values were longer in the adolescent group due in part to the single PM subject. No relationship between body weight and pharmacokinetic parameters was noted. This is the first evaluation of the pharmacokinetic characteristics of DM in children and adolescents. A single dose of DM in this population was safe, and well tolerated at all doses tested. The data are used to model and compare pediatric DM exposures with those of adults.

  11. Pharmacokinetic modeling of gentamicin in treatment of infective endocarditis: Model development and validation of existing models

    Science.gov (United States)

    van der Wijk, Lars; Proost, Johannes H.; Sinha, Bhanu; Touw, Daan J.

    2017-01-01

    Gentamicin shows large variations in half-life and volume of distribution (Vd) within and between individuals. Thus, monitoring and accurately predicting serum levels are required to optimize effectiveness and minimize toxicity. Currently, two population pharmacokinetic models are applied for predicting gentamicin doses in adults. For endocarditis patients the optimal model is unknown. We aimed at: 1) creating an optimal model for endocarditis patients; and 2) assessing whether the endocarditis and existing models can accurately predict serum levels. We performed a retrospective observational two-cohort study: one cohort to parameterize the endocarditis model by iterative two-stage Bayesian analysis, and a second cohort to validate and compare all three models. The Akaike Information Criterion and the weighted sum of squares of the residuals divided by the degrees of freedom were used to select the endocarditis model. Median Prediction Error (MDPE) and Median Absolute Prediction Error (MDAPE) were used to test all models with the validation dataset. We built the endocarditis model based on data from the modeling cohort (65 patients) with a fixed 0.277 L/h/70kg metabolic clearance, 0.698 (±0.358) renal clearance as fraction of creatinine clearance, and Vd 0.312 (±0.076) L/kg corrected lean body mass. External validation with data from 14 validation cohort patients showed a similar predictive power of the endocarditis model (MDPE -1.77%, MDAPE 4.68%) as compared to the intensive-care (MDPE -1.33%, MDAPE 4.37%) and standard (MDPE -0.90%, MDAPE 4.82%) models. All models acceptably predicted pharmacokinetic parameters for gentamicin in endocarditis patients. However, these patients appear to have an increased Vd, similar to intensive care patients. Vd mainly determines the height of peak serum levels, which in turn correlate with bactericidal activity. In order to maintain simplicity, we advise to use the existing intensive-care model in clinical practice to avoid

  12. Pharmacokinetic modeling of gentamicin in treatment of infective endocarditis: Model development and validation of existing models.

    Directory of Open Access Journals (Sweden)

    Anna Gomes

    Full Text Available Gentamicin shows large variations in half-life and volume of distribution (Vd within and between individuals. Thus, monitoring and accurately predicting serum levels are required to optimize effectiveness and minimize toxicity. Currently, two population pharmacokinetic models are applied for predicting gentamicin doses in adults. For endocarditis patients the optimal model is unknown. We aimed at: 1 creating an optimal model for endocarditis patients; and 2 assessing whether the endocarditis and existing models can accurately predict serum levels. We performed a retrospective observational two-cohort study: one cohort to parameterize the endocarditis model by iterative two-stage Bayesian analysis, and a second cohort to validate and compare all three models. The Akaike Information Criterion and the weighted sum of squares of the residuals divided by the degrees of freedom were used to select the endocarditis model. Median Prediction Error (MDPE and Median Absolute Prediction Error (MDAPE were used to test all models with the validation dataset. We built the endocarditis model based on data from the modeling cohort (65 patients with a fixed 0.277 L/h/70kg metabolic clearance, 0.698 (±0.358 renal clearance as fraction of creatinine clearance, and Vd 0.312 (±0.076 L/kg corrected lean body mass. External validation with data from 14 validation cohort patients showed a similar predictive power of the endocarditis model (MDPE -1.77%, MDAPE 4.68% as compared to the intensive-care (MDPE -1.33%, MDAPE 4.37% and standard (MDPE -0.90%, MDAPE 4.82% models. All models acceptably predicted pharmacokinetic parameters for gentamicin in endocarditis patients. However, these patients appear to have an increased Vd, similar to intensive care patients. Vd mainly determines the height of peak serum levels, which in turn correlate with bactericidal activity. In order to maintain simplicity, we advise to use the existing intensive-care model in clinical practice to

  13. Leflunomide in dialysis patients with rheumatoid arthritis--a pharmacokinetic study.

    Science.gov (United States)

    Bergner, Raoul; Peters, Lena; Schmitt, Verena; Löffler, Christian

    2013-02-01

    Pharmacokinetic data of disease modifying antirheumatic drugs during hemodialysis are limited to sulfasalazine, methotrexate, and cyclosporine. Only respective anecdotal data have been reported on leflunomide. We repeatedly measured teriflunomide (A77-1726), the active metabolite of leflunomide, during standard hemodialysis sessions and calculated teriflunomide clearances in five patients with rheumatoid arthritis (RA) and end-stage renal disease. The calculated teriflunomide clearances during a standardized dialysis session of 3-4.5 h at a blood flow rate of 160-300 ml/min were between 0 and 4.3 ml/min, the mean clearances of the total dialysis ranged between 1.1 and 3.4 ml/min. Total amount of teriflunomide removed was 5.8-8.8 μg per dialysis session. Dialytic removal of the active metabolite of leflunomide, teriflunomide (A77-1726), is negligible. Leflunomide can be used for RA patients on chronic dialysis without any dosage modification.

  14. Simultaneous quantification of lenalidomide, ibrutinib and its active metabolite PCI-45227 in rat plasma by LC-MS/MS: application to a pharmacokinetic study.

    Science.gov (United States)

    Veeraraghavan, Sridhar; Viswanadha, Srikant; Thappali, Satheeshmanikandan; Govindarajulu, Babu; Vakkalanka, Swaroopkumar; Rangasamy, Manivannan

    2015-03-25

    Efficacy assessments using a combination of ibrutinib and lenalidomide necessitate the development of an analytical method for determination of both drugs in plasma with precision. A high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the simultaneous determination of lenalidomide, ibrutinib, and its active metabolite PCI45227 in rat plasma. Extraction of lenalidomide, ibrutinib, PCI45227 and tolbutamide (internal standard; IS) from 50 μl rat plasma was carried out by liquid-liquid extraction with ethyl acetate:dichloromethane (90:10) ratio. Chromatographic separation of analytes was performed on YMC pack ODS AM (150 mm × 4.6 mm, 5 μm) column under gradient conditions with acetonitrile:0.1% formic acid buffer as the mobile phases at a flow rate of 1 ml/min. Precursor ion and product ion transition for analytes and IS were monitored on a triple quadrupole mass spectrometer, operated in the selective reaction monitoring with positive ionization mode. Method was validated over a concentration range of 0.72-183.20 ng/ml for ibrutinib, 0.76-194.33 ng/ml for PCI-45227 and 1.87-479.16 ng/ml for lenalidomide. Mean extraction recovery for ibrutinib, PCI-45227, lenalidomide and IS of 75.2%, 84.5%, 97.3% and 92.3% were consistent across low, medium, and high QC levels. Precision and accuracy at low, medium and high quality control levels were less than 15% across analytes. Bench top, wet, freeze-thaw and long term stability was evaluated for all the analytes. The analytical method was applied to support a pharmacokinetic study of simultaneous estimation of lenalidomide, ibrutinib, and its active metabolite PCI-45227 in Wistar rat. Assay reproducibility was demonstrated by re-analysis of 18 incurred samples. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. Estimating Margin of Exposure to Thyroid Peroxidase Inhibitors Using High-Throughput in vitro Data, High-Throughput Exposure Modeling, and Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling

    Science.gov (United States)

    Leonard, Jeremy A.; Tan, Yu-Mei; Gilbert, Mary; Isaacs, Kristin; El-Masri, Hisham

    2016-01-01

    Some pharmaceuticals and environmental chemicals bind the thyroid peroxidase (TPO) enzyme and disrupt thyroid hormone production. The potential for TPO inhibition is a function of both the binding affinity and concentration of the chemical within the thyroid gland. The former can be determined through in vitro assays, and the latter is influenced by pharmacokinetic properties, along with environmental exposure levels. In this study, a physiologically based pharmacokinetic (PBPK) model was integrated with a pharmacodynamic (PD) model to establish internal doses capable of inhibiting TPO in relation to external exposure levels predicted through exposure modeling. The PBPK/PD model was evaluated using published serum or thyroid gland chemical concentrations or circulating thyroxine (T4) and triiodothyronine (T3) hormone levels measured in rats and humans. After evaluation, the model was used to estimate human equivalent intake doses resulting in reduction of T4 and T3 levels by 10% (ED10) for 6 chemicals of varying TPO-inhibiting potencies. These chemicals were methimazole, 6-propylthiouracil, resorcinol, benzophenone-2, 2-mercaptobenzothiazole, and triclosan. Margin of exposure values were estimated for these chemicals using the ED10 and predicted population exposure levels for females of child-bearing age. The modeling approach presented here revealed that examining hazard or exposure alone when prioritizing chemicals for risk assessment may be insufficient, and that consideration of pharmacokinetic properties is warranted. This approach also provides a mechanism for integrating in vitro data, pharmacokinetic properties, and exposure levels predicted through high-throughput means when interpreting adverse outcome pathways based on biological responses. PMID:26865668

  16. Biotransformation of a novel antimitotic agent, I-387, by mouse, rat, dog, monkey, and human liver microsomes and in vivo pharmacokinetics in mice.

    Science.gov (United States)

    Ahn, Sunjoo; Kearbey, Jeffrey D; Li, Chien-Ming; Duke, Charles B; Miller, Duane D; Dalton, James T

    2011-04-01

    3-(1H-Indol-2-yl)phenyl)(3,4,5-trimethoxyphenyl)methanone (I-387) is a novel indole compound with antitubulin action and potent antitumor activity in various preclinical models. I-387 avoids drug resistance mediated by P-glycoprotein and showed less neurotoxicity than vinca alkaloids during in vivo studies. We examined the pharmacokinetics and metabolism of I-387 in mice as a component of our preclinical development of this compound and continued interest in structure-activity relationships for antitubulin agents. After a 1 mg/kg intravenous dose, noncompartmental pharmacokinetic analysis in plasma showed that clearance (CL), volume of distribution at steady state (Vd(ss)), and terminal half-life (t(1/2)) of I-387 were 27 ml per min/kg, 5.3 l/kg, and 7 h, respectively. In the in vitro metabolic stability study, half-lives of I-387 were between 10 and 54 min by mouse, rat, dog, monkey, and human liver microsomes in the presence of NADPH, demonstrating interspecies variability. I-387 was most stable in rat liver microsomes and degraded quickly in monkey liver microsomes. Liquid chromatography-tandem mass spectrometry was used to identify phase I metabolites. Hydroxylation, reduction of a ketone group, and O-demethylation were the major metabolites formed by the liver microsomes of the five species. The carbonyl group of I-387 was reduced and identified as the most labile site in human liver microsomes. The results of these drug metabolism and pharmacokinetic studies provide the foundation for future structural modification of this pharmacophore to improve stability of drugs with potent anticancer effects in cancer patients.

  17. A comprehensive physiologically based pharmacokinetic knowledgebase and web-based interface for rapid model ranking and querying

    Science.gov (United States)

    Published physiologically based pharmacokinetic (PBPK) models from peer-reviewed articles are often well-parameterized, thoroughly-vetted, and can be utilized as excellent resources for the construction of models pertaining to related chemicals. Specifically, chemical-specific pa...

  18. Reconstructing Organophosphorus Pesticide Doses Using the Reversed Dosimetry Approach in a Simple Physiologically-Based Pharmacokinetic Model

    Directory of Open Access Journals (Sweden)

    Chensheng Lu

    2012-01-01

    Full Text Available We illustrated the development of a simple pharmacokinetic (SPK model aiming to estimate the absorbed chlorpyrifos doses using urinary biomarker data, 3,5,6-trichlorpyridinol as the model input. The effectiveness of the SPK model in the pesticide risk assessment was evaluated by comparing dose estimates using different urinary composite data. The dose estimates resulting from the first morning voids appeared to be lower than but not significantly different to those using before bedtime, lunch or dinner voids. We found similar trend for dose estimates using three different urinary composite data. However, the dose estimates using the SPK model for individual children were significantly higher than those from the conventional physiologically based pharmacokinetic (PBPK modeling using aggregate environmental measurements of chlorpyrifos as the model inputs. The use of urinary data in the SPK model intuitively provided a plausible alternative to the conventional PBPK model in reconstructing the absorbed chlorpyrifos dose.

  19. Exposure-safety and efficacy response relationships and population pharmacokinetics of eslicarbazepine acetate.

    Science.gov (United States)

    Gidal, B E; Jacobson, M P; Ben-Menachem, E; Carreño, M; Blum, D; Soares-da-Silva, P; Falcão, A; Rocha, F; Moreira, J; Grinnell, T; Ludwig, E; Fiedler-Kelly, J; Passarell, J; Sunkaraneni, S

    2018-05-06

    Eslicarbazepine acetate (ESL) is a once-daily (QD) oral antiepileptic drug (AED) for focal-onset seizures (FOS). Pharmacokinetic (PK) and pharmacodynamic (PD) models were developed to assess dose selection, identify significant AED drug interactions, and quantitate relationships between exposure and safety and efficacy outcomes from Phase 3 trials of adjunctive ESL. Eslicarbazepine (the primary active metabolite of ESL) population PK was evaluated using data from 1351 subjects enrolled in 14 studies (11 Phase 1 and three Phase 3 studies) after multiple oral doses ranging from 400 to 1200 mg. Population PK and PD models related individual eslicarbazepine exposures to safety outcomes and efficacy responses. Eslicarbazepine PK was described by a one-compartment model with linear absorption and elimination. The probability of a treatment-emergent adverse event (TEAE; dizziness, headache, or somnolence) was higher with an initial dose of ESL 800 mg than with an initial dose of ESL 400 mg QD. Body weight, sex, region, and baseline use of carbamazepine (CBZ) or lamotrigine were also found to influence the probability of TEAEs. Eslicarbazepine exposure influenced serum sodium concentration, standardized seizure frequency, and probability of response; better efficacy outcomes were predicted in patients not from Western Europe (WE; vs WE patients) and those not taking CBZ (vs taking CBZ) at baseline. Pharmacokinetic and PK/PD modeling were implemented during the development of ESL for adjunctive treatment of FOS in adults. This quantitative approach supported decision-making during the development of ESL, and contributed to dosing recommendations and labeling information related to drug interactions. © 2018 The Authors. Acta Neurologica Scandinavica Published by John Wiley & Sons Ltd.

  20. Effect of concomitant artesunate administration and cytochrome P4502C8 polymorphisms on the pharmacokinetics of amodiaquine in Ghanaian children with uncomplicated malaria

    DEFF Research Database (Denmark)

    Adjei, George O; Kristensen, Kim; Goka, Bamenla Q

    2008-01-01

    Artesunate (AS) is used in combination with amodiaquine (AQ) as first-line treatment for uncomplicated malaria in many countries. We investigated the effect of concomitant AS administration on the pharmacokinetics of AQ and compared concentrations of desethylamodiaquine (DEAQ), the main metabolite...... implications for weight-based dosing of higher-body-weight children with AQ. The pharmacokinetics of artemisinin combination therapies should be studied in malaria patients, because the rapid parasite clearance caused by the artemisinin may affect the kinetics of the partner drug and the combination....

  1. Pharmacokinetics and tolerability of DA-8031, a novel selective serotonin reuptake inhibitor for premature ejaculation in healthy male subjects

    Directory of Open Access Journals (Sweden)

    Shin D

    2017-03-01

    Full Text Available Dongseong Shin,1 SeungHwan Lee,2 Sojeong Yi,2 Seo Hyun Yoon,2 Joo-Youn Cho,2 Mi Young Bahng,3 In-Jin Jang,2 Kyung-Sang Yu2 1Clinical Trials Center, Gachon University Gil Medical Center, Incheon, 2Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, 3Department of Product Development, Dong-A ST, Seoul, Korea Objective: DA-8031 is a selective serotonin reuptake inhibitor under development for the treatment of premature ejaculation. This is the first-in-human study aimed at evaluating the pharmacokinetics and tolerability of DA-8031 and its metabolites (M1, M2, M4, and M5 in the plasma and urine after administration of a single oral dose in healthy male subjects.Methods: A dose block-randomized, double-blind, placebo-controlled, single ascending dose study was conducted. Subjects received either placebo or a single dose of DA-8031 at 5, 10, 20, 40, 60, 80, or 120 mg. DA-8031 and its four metabolites were analyzed in the plasma and urine for pharmacokinetic evaluation. The effect of genetic polymorphisms of cytochrome-P450 (CYP enzymes on the pharmacokinetics of DA-8031 was evaluated.Results: After a single dose, plasma DA-8031 reached the maximum concentration at a median of 2–3 h and was eliminated with terminal elimination half-life of 17.9–28.7 h. The mean renal clearance was 3.7–5.6 L/h. Dose-proportional pharmacokinetics was observed over the dose range of 20–80 mg. Among the metabolites, M4 had the greatest plasma concentration, followed by M5 and M1. Subjects with CYP2D6 intermediate metabolizer had significantly greater dose-normalized Cmax and AUC0–t of DA-8031 as well as smaller metabolic ratios than those subjects with CYP2D6 extensive metabolizer. The most common adverse events were nausea, dizziness, and headache, and no serious adverse events were reported.Conclusion: In conclusion, the systemic exposure of DA-8031 was increased proportionally to the dose within 20

  2. The pharmacokinetics of the interstitial space in humans

    OpenAIRE

    Levitt, David G

    2003-01-01

    Background The pharmacokinetics of extracellular solutes is determined by the blood-tissue exchange kinetics and the volume of distribution in the interstitial space in the different organs. This information can be used to develop a general physiologically based pharmacokinetic (PBPK) model applicable to most extracellular solutes. Methods The human pharmacokinetic literature was surveyed to tabulate the steady state and equilibrium volume of distribution of the solutes mannitol, EDTA, morphi...

  3. A Multi-Route Model of Nicotine-Cotinine Pharmacokinetics, Pharmacodynamics and Brain Nicotinic Acetylcholine Receptor Binding in Humans

    Energy Technology Data Exchange (ETDEWEB)

    Teeguarden, Justin G.; Housand, Conrad; Smith, Jordan N.; Hinderliter, Paul M.; Gunawan, Rudy; Timchalk, Charles

    2013-02-01

    The pharmacokinetics of nicotine, the pharmacologically active alkaloid in tobacco responsible for addiction, are well characterized in humans. We developed a physiologically based pharmacokinetic/pharmacodynamic model of nicotine pharmacokinetics, brain dosimetry and brain nicotinic acetylcholine receptor (nAChRs) occupancy. A Bayesian framework was applied to optimize model parameters against multiple human data sets. The resulting model was consistent with both calibration and test data sets, but in general underestimated variability. A pharmacodynamic model relating nicotine levels to increases in heart rate as a proxy for the pharmacological effects of nicotine accurately described the nicotine related changes in heart rate and the development and decay of tolerance to nicotine. The PBPK model was utilized to quantitatively capture the combined impact of variation in physiological and metabolic parameters, nicotine availability and smoking compensation on the change in number of cigarettes smoked and toxicant exposure in a population of 10,000 people presented with a reduced toxicant (50%), reduced nicotine (50%) cigarette Across the population, toxicant exposure is reduced in some but not all smokers. Reductions are not in proportion to reductions in toxicant yields, largely due to partial compensation in response to reduced nicotine yields. This framework can be used as a key element of a dosimetry-driven risk assessment strategy for cigarette smoke constituents.

  4. Inhibition of endocannabinoid metabolism by the metabolites of ibuprofen and flurbiprofen.

    Science.gov (United States)

    Karlsson, Jessica; Fowler, Christopher J

    2014-01-01

    In addition to their effects upon prostaglandin synthesis, the non-steroidal anti-inflammatory drugs ibuprofen and flurbiprofen inhibit the metabolism of the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA) by cyclooxygenase-2 (COX-2) and fatty acid amide hydrolase (FAAH), respectively. Here, we investigated whether these effects upon endocannabinoid metabolism are shared by the main metabolites of ibuprofen and flurbiprofen. COX activities were measured via changes in oxygen consumption due to oxygenation of arachidonic acid (for COX-1) and arachidonic acid and 2-AG (for COX-2). FAAH activity was quantified by measuring hydrolysis of tritium labelled AEA in rat brain homogenates. The ability of ibuprofen and flurbiprofen to inhibit COX-2-catalysed oxygenation of 2-AG at lower concentrations than the oxygenation of arachidonic acid was seen with 4'-hydroxyflurbiprofen and possibly also 3'-hydroxyibuprofen, albeit at lower potencies than the parent compounds. All ibuprofen and flurbiprofen metabolites retained the ability to inhibit FAAH in a pH-dependent manner, although the potency was lower than seen with the parent compounds. It is concluded that the primary metabolites of ibuprofen and flurbiprofen retain some of the properties of the parent compound with respect to inhibition of endocannabinoid metabolism. However, these effects are unlikely to contribute to the actions of the parent compounds in vivo.

  5. Inhibition of endocannabinoid metabolism by the metabolites of ibuprofen and flurbiprofen.

    Directory of Open Access Journals (Sweden)

    Jessica Karlsson

    Full Text Available In addition to their effects upon prostaglandin synthesis, the non-steroidal anti-inflammatory drugs ibuprofen and flurbiprofen inhibit the metabolism of the endocannabinoids 2-arachidonoylglycerol (2-AG and anandamide (AEA by cyclooxygenase-2 (COX-2 and fatty acid amide hydrolase (FAAH, respectively. Here, we investigated whether these effects upon endocannabinoid metabolism are shared by the main metabolites of ibuprofen and flurbiprofen.COX activities were measured via changes in oxygen consumption due to oxygenation of arachidonic acid (for COX-1 and arachidonic acid and 2-AG (for COX-2. FAAH activity was quantified by measuring hydrolysis of tritium labelled AEA in rat brain homogenates. The ability of ibuprofen and flurbiprofen to inhibit COX-2-catalysed oxygenation of 2-AG at lower concentrations than the oxygenation of arachidonic acid was seen with 4'-hydroxyflurbiprofen and possibly also 3'-hydroxyibuprofen, albeit at lower potencies than the parent compounds. All ibuprofen and flurbiprofen metabolites retained the ability to inhibit FAAH in a pH-dependent manner, although the potency was lower than seen with the parent compounds.It is concluded that the primary metabolites of ibuprofen and flurbiprofen retain some of the properties of the parent compound with respect to inhibition of endocannabinoid metabolism. However, these effects are unlikely to contribute to the actions of the parent compounds in vivo.

  6. The Use and Method of Action of Intravenous Lidocaine and Its Metabolite in Headache Disorders.

    Science.gov (United States)

    Berk, Thomas; Silberstein, Stephen D

    2018-03-14

    Lidocaine, an amide anesthetic, has been used in the treatment of a wide variety of pain disorders for over 75 years. In addition to pain control, lidocaine is an anti-arrhythmic agent and has anti-inflammatory properties. Lidocaine's unique properties, including nonlinear pharmacokinetics, have limited its modern-day use. The purpose of this review is to offer a better understanding of the properties of this unique treatment, which we hope will allow more practitioners to offer this to their patients. An analysis of the history, pharmacokinetics, and relevant uses of lidocaine in headache medicine based on a synthesis of the medical literature and clinical experience. Lidocaine is an amide anesthetic that inhibits voltage gated sodium channels, and lidocaine metabolism occurs exclusively in the liver. One lidocaine metabolite has its own unique properties and may be an active form of the drug. Open label and retrospective studies have investigated the use of lidocaine in many headache disorders, primarily via injection or infusion. Further research into the active metabolite of lidocaine may allow for its use as a novel nonopiate treatment of chronic pain. © 2018 American Headache Society.

  7. Pharmacokinetic-Pharmacodynamic Modeling to Study the Antipyretic Effect of Qingkailing Injection on Pyrexia Model Rats

    Directory of Open Access Journals (Sweden)

    Zhixin Zhang

    2016-03-01

    Full Text Available Qingkailing injection (QKLI is a modern Chinese medicine preparation derived from a well-known classical formulation, An-Gong-Niu-Huang Wan. Although the clinical efficacy of QKLI has been well defined, its severe adverse drug reactions (ADRs were extensively increased. Through thorough attempts to reduce ADR rates, it was realized that the effect-based rational use plays the key role in clinical practices. Hence, the pharmacokinetic-pharmacodynamic (PK-PD model was introduced in the present study, aiming to link the pharmacokinetic profiles with the therapeutic outcomes of QKLI, and subsequently to provide valuable guidelines for the rational use of QKLI in clinical settings. The PK properties of the six dominant ingredients in QKLI were compared between the normal treated group (NTG and the pyrexia model group (MTG. Rectal temperatures were measured in parallel with blood sampling for NTG, MTG, model control group (MCG, and normal control group (NCG. Baicalin and geniposide exhibited appropriate PK parameters, and were selected as the PK markers to map the antipyretic effect of QKLI. Then, a PK-PD model was constructed upon the bacalin and geniposide plasma concentrations vs. the rectal temperature variation values, by a two-compartment PK model with a Sigmoid Emax PD model to explain the time delay between the drug plasma concentration of PK markers and the antipyretic effect after a single dose administration of QKLI. The findings obtained would provide fundamental information to propose a more reasonable dosage regimen and improve the level of individualized drug therapy in clinical settings.

  8. Synthesis and positron emission tomography studies of C-11-labeled isotopomers and metabolites of GTS-21, a partial α7 nicotinic cholinergic agonist drug

    International Nuclear Information System (INIS)

    Kim, Sung Won; Ding Yushin; Alexoff, David; Patel, Vinal; Logan, Jean; Lin, K.-S.; Shea, Colleen; Muench, Lisa; Xu Youwen; Carter, Pauline; King, Payton; Constanzo, Jasmine R.; Ciaccio, James A.; Fowler, Joanna S.

    2007-01-01

    Introduction: (3E)-3-[(2,4-dimethoxyphenyl)methylene]-3,4,5,6-tetrahydro-2,3'-bipyridine (GTS-21), a partial α7 nicotinic acetylcholine receptor agonist drug, has recently been shown to improve cognition in schizophrenia and Alzheimer's disease. One of its two major demethylated metabolites, 4-OH-GTS-21, has been suggested to contribute to its therapeutic effects. Methods: We labeled GTS-21 in two different positions with carbon-11 ([2-methoxy- 11 C]GTS-21 and [4- 11 C]GTS-21) along with two corresponding demethylated metabolites ([2-methoxy- 11 C]4-OH-GTS-21 and [4-methoxy- 11 C]2-OH-GTS-21) for pharmacokinetic studies in baboons and mice with positron emission tomography (PET). Results: Both [2- 11 C]GTS-21 and [4-methoxy- 11 C]GTS-21 showed similar initial high rapid uptake in baboon brain, peaking from 1 to 3.5 min (0.027-0.038%ID/cc) followed by rapid clearance (t 1/2 11 C]GTS-21 continued to clear while [4-methoxy- 11 C]GTS-21 plateaued, suggesting the entry of a labeled metabolite into the brain. Comparison of the pharmacokinetics of the two labeled metabolites confirmed expected higher brain uptake and retention of [4-methoxy- 11 C]2-OH-GTS-21 (the labeled metabolite of [4-methoxy- 11 C]GTS-21) relative to [2-methoxy- 11 C]4-OH-GTS-21 (the labeled metabolite of [2-methoxy- 11 C]GTS-21), which had negligible brain uptake. Ex vivo studies in mice showed that GTS-21 is the major chemical form in the mouse brain. Whole-body dynamic PET imaging in baboon and mouse showed that the major route of excretion of C-11 is through the gallbladder. Conclusions: The major findings are as follows: (a) extremely rapid uptake and clearance of [2-methoxy- 11 C]GTS-21 from the brain, which may need to be considered in developing optimal dosing of GTS-21 for patients, and (b) significant brain uptake of 2-OH-GTS-21, suggesting that it might contribute to the therapeutic effects of GTS-21. This study illustrates the value of comparing different label positions and labeled

  9. Simultaneous determination of the novel tyrosine kinase inhibitor meditinib and its active metabolite demethylation meditinib in monkey plasma by liquid chromatography-tandem mass spectrometry and its application to pharmacokinetic studies.

    Science.gov (United States)

    Liang, Feng; Kong, Qi; Guo, Yongqi; Wang, Yu; Sun, Dejie; Liu, Shi; Cai, Jinling; Guan, Yongbiao; Ding, Rigao

    2015-08-01

    Meditinib (ME) is a novel tyrosine kinase inhibitor used as an antichronic myeloid leukemia drug. A simple, sensitive and specific LC/MS/MS method was developed and validated for the analysis of ME and its metabolite demethylation meditinib (PI) in monkey plasma using naltrexone as the internal standard. Sample preparation involved protein precipitation with methanol. The analysis was carried out on an Agilent C8 column (3.5 µm, 2.1 × 50 mm). Elution was achieved with a mobile phase gradient varying the proportion of a water solution containing 0.1% formic acid (solvent A) and a 0.1% formic acid in methanol solution (solvent B) at a flow rate of 300 μL/min. The method had a linear calibration curve over the concentration range of 2-1000 ng/mL for ME and 2-1000 ng/mL for PI. The lower limits of quantification of ME and PI were 2 and 2 ng/mL, respectively. The intra- and inter-day precision values were 85%. The assay has been successfully used for pharmacokinetic evaluation of ME and PI using the monkey as an animal model, and those data are reported for the first time. Copyright © 2015 John Wiley & Sons, Ltd.

  10. A pharmacokinetic-pharmacodynamic model of morphine exposure and subsequent morphine consumption in postoperative pain

    DEFF Research Database (Denmark)

    Juul, Rasmus Vestergaard; Nyberg, Joakim; Lund, Trine Meldgaard

    2016-01-01

    Purpose To characterize the pharmacokinetic-pharmacodynamic (PK-PD) relationship between exposure of morphine and subsequent morphine consumption and to develop simulation tools for model validation. Methods Dose, formulation and time of morphine administration was available from a published study...

  11. Metabolic and Pharmacokinetic Differentiation of STX209 and Racemic Baclofen in Humans

    Directory of Open Access Journals (Sweden)

    Raymundo Sanchez-Ponce

    2012-09-01

    Full Text Available STX209 is an exploratory drug comprising the single, active R-enantiomer of baclofen which is in later stage clinical trials for the treatment of fragile x syndrome (FXS and autism spectrum disorders (ASD. New clinical data in this article on the metabolism and pharmacokinetics of the R- and S-enantiomers of baclofen presents scientific evidence for stereoselective metabolism of only S-baclofen to an abundant oxidative deamination metabolite that is sterically resolved as the S-enantiomeric configuration. This metabolite undergoes some further metabolism by glucuronide conjugation. Consequences of this metabolic difference are a lower Cmax and lower early plasma exposure of S-baclofen compared to R-baclofen and marginally lower urinary excretion of S-baclofen after racemic baclofen administration. These differences introduce compound-related exposure variances in humans in which subjects dosed with racemic baclofen are exposed to a prominent metabolite of baclofen whilst subjects dosed with STX209 are not. For potential clinical use, our findings suggest that STX209 has the advantage of being a biologically defined and active enantiomer.

  12. Integrated identification, qualification and quantification strategy for pharmacokinetic profile study of Guizhi Fuling capsule in healthy volunteers.

    Science.gov (United States)

    Zhong, Yun-Xi; Jin, Xiao-Liang; Gu, Shi-Yin; Peng, Ying; Zhang, Ke-Rong; Ou-Yang, Bing-Chen; Wang, Yu; Xiao, Wei; Wang, Zhen-Zhong; Aa, Ji-Ye; Wang, Guang-Ji; Sun, Jian-Guo

    2016-08-16

    Guizhi Fuling capsule (GZFL), a traditional Chinese medicine formulation, is widely used in China to relieve pain from dysmenorrhea and is now in a Phase II clinical trial in the USA. Due to the low exposure of the five main medicative ingredients (amygdalin, cinnamic acid, gallic acid, paeoniflorin and paeonol) of GZFL in human, a strategy was built to qualitatively and quantitatively identify the possible metabolites of GZFL and to describe the pharmacokinetic profiles of GZFL in human. In this strategy, LC-Q-TOF/MS was used to identify and structurally elucidate the possible metabolites of GZFL in vivo; and a time-based metabolite-confirming step (TBMCs) was used to confirm uncertain metabolites. The simultaneously quantitation results by LC-MS/MS showed low exposure of the five medicative ingredients. According to the strategy we built, a total of 36 metabolites were found and structurally elucidated. The simultaneously semi-quantitative analysis by LC-MS/MS showed that obvious time-concentration curves could be established for 12 of the metabolites, and most of them showed a relatively higher exposure. This study provides a better understanding of the metabolic processes of GZFL in human.

  13. The sheep as a model of preclinical safety and pharmacokinetic evaluations of candidate microbicides.

    Science.gov (United States)

    Holt, Jonathon D S; Cameron, David; Dias, Nicola; Holding, Jeremy; Muntendam, Alex; Oostebring, Freddy; Dreier, Peter; Rohan, Lisa; Nuttall, Jeremy

    2015-07-01

    When developing novel microbicide products for the prevention of HIV infection, the preclinical safety program must evaluate not only the active pharmaceutical ingredient but also the product itself. To that end, we applied several relatively standard toxicology study methodologies to female sheep, incorporating an assessment of the pharmacokinetics, safety, tolerability, and local toxicity of a dapivirine-containing human vaginal ring formulation (Dapivirine Vaginal Ring-004). We performed a 3-month general toxicology study, a preliminary pharmacokinetic study using drug-loaded vaginal gel, and a detailed assessment of the kinetics of dapivirine delivery to plasma, vaginal, and rectal fluid and rectal, vaginal, and cervical tissue over 28 days of exposure and 3 and 7 days after removal of the ring. The findings of the general toxicology study supported the existing data from both preclinical and clinical studies in that there were no signs of toxicity related to dapivirine. In addition, the presence of the physical dapivirine ring did not alter local or systemic toxicity or the pharmacokinetics of dapivirine. Pharmacokinetic studies indicated that the dapivirine ring produced significant vaginal tissue levels of dapivirine. However, no dapivirine was detected in cervical tissue samples using the methods described here. Plasma and vaginal fluid levels were lower than those in previous clinical studies, while there were detectable dapivirine levels in the rectal tissue and fluid. All tissue and fluid levels tailed off rapidly to undetectable levels following removal of the ring. The sheep represents a very useful model for the assessment of the safety and pharmacokinetics of microbicide drug delivery devices, such as the vaginal ring. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  14. Pharmacokinetic-Pharmacodynamic Modeling of Enrofloxacin Against Escherichia coli in Broilers.

    Science.gov (United States)

    Sang, KaNa; Hao, HaiHong; Huang, LingLi; Wang, Xu; Yuan, ZongHui

    2015-01-01

    The purpose of the present study was to establish a pharmacokinetic/pharmacodynamic (PK/PD) modeling approach for the dosage schedule design and decreasing the emergence of drug-resistant bacteria. The minimal inhibitory concentration (MIC) of 929 Escherichia coli isolates from broilers to enrofloxacin and ciprofloxacin was determined following CLSI guidance. The MIC50 was calculated as the populational PD parameter for enrofloxacin against E. coli in broilers. The 101 E. coli strains with MIC closest to the MIC50 (0.05 μg/mL) were submitted for serotype identification. The 13 E. coli strains with O and K serotype were further utilized for determining pathogencity in mice. Of all the strains tested, the E. coli designated strain Anhui 112 was selected for establishing the disease model and PK/PD study. The PKs of enrofloxacin after oral administration at the dose of 10 mg/kg body weights (BW) in healthy and infected broilers was evaluated with high-performance liquid chromatography (HPLC) method. For intestinal contents after oral administration, the peak concentration (C max), the time when the maximum concentration reached (T max), and the area under the concentration-time curve (AUC) were 21.69-31.69 μg/mL, 1.13-1.23 h, and 228.97-444.86 μg h/mL, respectively. The MIC and minimal bactericidal concentration (MBC) of enrofloxacin against E. coli (Anhui 112) in Mueller-Hinton (MH) broth and intestinal contents were determined to be similar, 0.25 and 0.5 μg/mL respectively. In this study, the sum of concentrations of enrofloxacin and its metabolite (ciprofloxacin) was used for the PK/PD integration and modeling. The ex vivo growth inhibition data were fitted to the sigmoid E max (Hill) equation to provide values for intestinal contents of 24 h area under concentration-time curve/MIC ratios (AUC0-24 h/MIC) producing, bacteriostasis (624.94 h), bactericidal activity (1065.93 h) and bacterial eradication (1343.81 h). PK/PD modeling was

  15. Disposition pathways and pharmacokinetics of herbal medicines in humans.

    Science.gov (United States)

    He, S-M; Li, C G; Liu, J-P; Chan, E; Duan, W; Zhou, S-F

    2010-01-01

    Pharmacokinetic studies have become an integral part of modern drug development, but these studies are not regulatory needs for herbal remedies. This paper updates our current knowledge on the disposition pathways and pharmacokinetic properties of commonly used herbal medicines in humans. To retrieve relevant data, the authors have searched through computer-based literatures by full text search in Medline (via Pubmed), ScienceDirect, Current Contents Connect (ISI), Cochrance Library, CINAHL (EBSCO), CrossRef Search and Embase (all from inception to May 2010). Many herbal compounds undergo Phase I and/or Phase II metabolism in vivo, with cytochrome P450s (CYPs) and uridine diphosphate glucuronosyltransferases (UGTs) playing a major role. Some herbal ingredients are substrates of P-glycoprotein (P-gp) which is highly expressed in the intestine, liver, brain and kidney. As such, the activities of these drug metabolizing enzymes and drug transporters are determining factors for the in vivo bioavailability, disposition and distribution of herbal remedies. There are increasing pharmacokinetic studies of herbal remedies, but these studies are mainly focused on a small number of herbal remedies including St John's wort, milk thistle, sculcap, curcumin, echinacea, ginseng, ginkgo, and ginger. The pharmacokinetic data of a small number of purified herbal ingredients, including anthocyanins, berberine, catechins, curcumin, lutein and quercetin, are available. For the majority of herbal remedies used in folk medicines, data on their disposition and biological fate in humans are lacking or in paucity. For a herbal medicine, the pharmacological effect is achieved when the bioactive agents or the metabolites reach and sustain proper levels at their sites of action. Both the dose levels and fates of active components in the body govern their target-site concentrations after administration of an herbal remedy. In this regard, a safe and optimal use of herbal medicines requires a

  16. Diclofenac hypersensitivity: antibody responses to the parent drug and relevant metabolites.

    Directory of Open Access Journals (Sweden)

    Andrea Harrer

    2010-10-01

    Full Text Available Hypersensitivity reactions against nonsteroidal antiinflammatory drugs (NSAIDs like diclofenac (DF can manifest as Type I-like allergic reactions including systemic anaphylaxis. However, except for isolated case studies experimental evidence for an IgE-mediated pathomechanism of DF hypersensitivity is lacking. In this study we aimed to investigate the possible involvement of drug- and/or metabolite-specific antibodies in selective DF hypersensitivity.DF, an organochemically synthesized linkage variant, and five major Phase I metabolites were covalently coupled to carrier proteins. Drug conjugates were analyzed for coupling degree and capacity to crosslink receptor-bound IgE antibodies from drug-sensitized mice. With these conjugates, the presence of hapten-specific IgE antibodies was investigated in patients' samples by ELISA, mediator release assay, and basophil activation test. Production of sulfidoleukotrienes by drug conjugates was determined in PBMCs from DF-hypersensitive patients. All conjugates were shown to carry more than two haptens per carrier molecule. Immunization of mice with drug conjugates induced drug-specific IgE antibodies capable of triggering mediator release. Therefore, the conjugates are suitable tools for detection of drug-specific antibodies and for determination of their anaphylactic activity. Fifty-nine patients were enrolled and categorized as hypersensitive either selectively to DF or to multiple NSAIDs. In none of the patients' samples evidence for drug/metabolite-specific IgE in serum or bound to allergic effector cells was found. In contrast, a small group of patients (8/59, 14% displayed drug/metabolite-specific IgG.We found no evidence for an IgE-mediated effector mechanism based on haptenation of protein carriers in DF-hypersensitive patients. Furthermore, a potential involvement of the most relevant metabolites in DF hypersensitivity reactions could be excluded.

  17. Pharmacokinetics of Rolapitant in Patients With Mild to Moderate Hepatic Impairment.

    Science.gov (United States)

    Wang, Jing; Wang, Xiaodong; Zhang, Zhi-Yi; Arora, Sujata; Lu, Sharon; Kansra, Vikram

    2018-05-01

    Rolapitant is a selective and long-acting neurokinin-1 receptor antagonist approved in an oral formulation in combination with other antiemetic agents for the prevention of delayed chemotherapy-induced nausea and vomiting in adults. This was a phase 1 open-label, parallel-group pharmacokinetic and safety study of a single oral dose of 180 mg of rolapitant and its major active metabolite, M19, in subjects with mild and moderate hepatic impairment compared with healthy matched controls. Pharmacokinetics were assessed by a mixed-model analysis of variance of log-transformed values for maximum observed plasma concentration (C max ), observed time at C max (t max ), area under the plasma concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration (AUC 0-t ), and AUC from time 0 to 120 hours (AUC 0-120 ), with hepatic group as a fixed effect. Mean rolapitant C max , AUC 0-t , and AUC 0-120 were similar in the mild hepatic impairment and healthy control groups. In subjects with moderate hepatic impairment, AUC 0-t was similar and C max was 25% lower than in healthy controls. Mean M19 C max and AUC 0-t were similar in the mild hepatic impairment group and healthy controls, but impairment versus healthy controls. Fraction of unbound rolapitant was comparable in all groups for rolapitant and M19. Rolapitant was well tolerated in all groups, without serious adverse events. Pharmacokinetic differences between healthy subjects and those with mild or moderate hepatic impairment are unlikely to pose a safety risk and do not warrant predefined dosage adjustment in the presence of hepatic impairment. © 2018, The American College of Clinical Pharmacology.

  18. Parenting and antisocial behavior: a model of the relationship between adolescent self-disclosure, parental closeness, parental control, and adolescent antisocial behavior.

    Science.gov (United States)

    Vieno, Alessio; Nation, Maury; Pastore, Massimiliano; Santinello, Massimo

    2009-11-01

    This study used data collected from a sample of 840 Italian adolescents (418 boys; M age = 12.58) and their parents (657 mothers; M age = 43.78) to explore the relations between parenting, adolescent self-disclosure, and antisocial behavior. In the hypothesized model, parenting practices (e.g., parental monitoring and control) have direct effects on parental knowledge and antisocial behavior. Parenting style (e.g., parent-child closeness), on the other hand, is directly related to adolescent self-disclosure, which in turn is positively related to parental knowledge and negatively related to adolescents' antisocial behavior. A structural equation model, which incorporated data from parents and adolescents, largely supported the hypothesized model. Gender-specific models also found some gender differences among adolescents and parents, as the hypothesized model adequately fit the subsample of mothers but not fathers. Mothers' closeness to girls predicted their knowledge of their daughters' behavior; mothers' control predicted boys' antisocial behavior.

  19. Integration of Life-Stage Physiologically Based Pharmacokinetic Models with Adverse Outcome Pathways and Environmental Exposure Models to Screen for Environmental Hazards

    Science.gov (United States)

    A Life-stage Physiologically-Based Pharmacokinetic (PBPK) model was developed to include descriptions of several life-stage events such as pregnancy, fetal development, the neonate and child growth. The overall modeling strategy was used for in vitro to in vivo (IVIVE) extrapolat...

  20. Absorption and pharmacokinetics of grapefruit flavanones in beagles.

    Science.gov (United States)

    Mata-Bilbao, Maria de Lourdes; Andrés-Lacueva, Cristina; Roura, Elena; Jáuregui, Olga; Escribano, Elvira; Torre, Celina; Lamuela-Raventós, Rosa Maria

    2007-07-01

    The present study evaluated the pharmacokinetics of three different grapefruit flavanone forms in dog plasma and demonstrated their absorption after an oral intake of a grapefruit extract; pharmacokinetic parameters of these forms were also determined. Ten healthy beagles were administered 70 mg citrus flavonoids as a grapefruit extract contained in capsules, while two additional dogs were used as controls and given an excipient. The grapefruit flavanone naringin, along with its metabolites naringenin and naringenin glucuronide, was detected in dog plasma. Blood samples were collected between 0 and 24 h after administration of the extract. Naringin reached its maximun plasma concentration at around 80 min, whereas naringenin and naringenin glucuronide reached their maximun plasma concentrations at around 20 and 30 min, respectively. Maximum plasma concentrations of naringin, naringenin and naringenin glucuronide (medians and ranges) were 0.24 (0.05-2.08), 0.021 (0.001-0.3) and 0.09 (0.034-0.12) micromol/l, respectively. The areas under the curves were 23.16 l (14.04-70.62) min x micromol/for nariningin, 1.78 (0.09-4.95) min x micromol/l for naringenin and 22.5 (2.74-99.23) min x micromol/l for naringenin glucuronide. The median and range values for mean residence time were 3.3 (1.5-9.3), 2.8 (0.8-11.2) and 8.0 (2.3-13.1) h for naringin, naringenin and naringenin glucuronide, respectively. The results of the present study demonstrate the absorption of grapefruit flavanones via the presence of their metabolites in plasma, thus making an important contribution to the field since the biological activities ascribed to these compounds rely on their specific forms of absorption.

  1. Pharmacokinetic/Pharmacodynamic Relationship of Gabapentin in a CFA-induced Inflammatory Hyperalgesia Rat Model

    DEFF Research Database (Denmark)

    Larsen, Malte Selch; Keizer, Ron; Munro, Gordon

    2016-01-01

    PURPOSE: Gabapentin displays non-linear drug disposition, which complicates dosing for optimal therapeutic effect. Thus, the current study was performed to elucidate the pharmacokinetic/pharmacodynamic (PKPD) relationship of gabapentin's effect on mechanical hypersensitivity in a rat model of CFA......-induced inflammatory hyperalgesia. METHODS: A semi-mechanistic population-based PKPD model was developed using nonlinear mixed-effects modelling, based on gabapentin plasma and brain extracellular fluid (ECF) time-concentration data and measurements of CFA-evoked mechanical hyperalgesia following administration...

  2. Pharmacokinetics, pharmacodynamics and the pharmacokinetic/ pharmacodynamic relationship of zolpidem in healthy subjects.

    Science.gov (United States)

    de Haas, S L; Schoemaker, R C; van Gerven, J M A; Hoever, P; Cohen, A F; Dingemanse, J

    2010-11-01

    Zolpidem is one of the most frequently prescribed hypnotics, as it is a very short-acting compound with relatively few side effects. Zolpidem's short duration of action is partly related to its short elimination half-life, but the associations between plasma levels and pharmacodynamic (PD) effects are not precisely known. In this study, the concentration-effect relationships for zolpidem were modelled. Zolpidem (10 mg) was administered in a double-blind, randomised, placebo-controlled trial to determine PD and pharmacokinetics (PK) in 14 healthy volunteers. Zolpidem was absorbed and eliminated quickly, with a median T(max) of 0.78 h (range: 0.33-2.50) and t(1/2) of 2.2 h. Zolpidem reduced saccadic peak velocity (SPV), adaptive tracking performance, electroencephalogram (EEG) alpha power and visual analogue scale (VAS) alertness score and increased body sway, EEG beta power and VAS 'feeling high'. Short- and long-term memory was not affected. Central nervous system effects normalised more rapidly than the decrease of plasma concentrations. For most effects, zolpidem's short duration of action could be adequately described by both a sigmoid E(max) model and a transit tolerance model. For SPV and EEG alpha power, the tolerance model seemed less suitable. These PK/PD models have different implications for the mechanism underlying zolpidem's short duration of action. A sigmoid E(max) model (which is based on ligand binding theory) would imply a threshold value for the drug's effective concentrations. A transit tolerance model (in which a hypothetical factor builds up with time that antagonises the effects of the parent compound) is compatible with a rapid reversible desensitisation of GABAergic subunits.

  3. Use of Physiologically Based Pharmacokinetic (PBPK) Models ...

    Science.gov (United States)

    EPA announced the availability of the final report, Use of Physiologically Based Pharmacokinetic (PBPK) Models to Quantify the Impact of Human Age and Interindividual Differences in Physiology and Biochemistry Pertinent to Risk Final Report for Cooperative Agreement. This report describes and demonstrates techniques necessary to extrapolate and incorporate in vitro derived metabolic rate constants in PBPK models. It also includes two case study examples designed to demonstrate the applicability of such data for health risk assessment and addresses the quantification, extrapolation and interpretation of advanced biochemical information on human interindividual variability of chemical metabolism for risk assessment application. It comprises five chapters; topics and results covered in the first four chapters have been published in the peer reviewed scientific literature. Topics covered include: Data Quality ObjectivesExperimental FrameworkRequired DataTwo example case studies that develop and incorporate in vitro metabolic rate constants in PBPK models designed to quantify human interindividual variability to better direct the choice of uncertainty factors for health risk assessment. This report is intended to serve as a reference document for risk assors to use when quantifying, extrapolating, and interpretating advanced biochemical information about human interindividual variability of chemical metabolism.

  4. Population pharmacokinetic analysis of clopidogrel in healthy Jordanian subjects with emphasis optimal sampling strategy.

    Science.gov (United States)

    Yousef, A M; Melhem, M; Xue, B; Arafat, T; Reynolds, D K; Van Wart, S A

    2013-05-01

    Clopidogrel is metabolized primarily into an inactive carboxyl metabolite (clopidogrel-IM) or to a lesser extent an active thiol metabolite. A population pharmacokinetic (PK) model was developed using NONMEM(®) to describe the time course of clopidogrel-IM in plasma and to design a sparse-sampling strategy to predict clopidogrel-IM exposures for use in characterizing anti-platelet activity. Serial blood samples from 76 healthy Jordanian subjects administered a single 75 mg oral dose of clopidogrel were collected and assayed for clopidogrel-IM using reverse phase high performance liquid chromatography. A two-compartment (2-CMT) PK model with first-order absorption and elimination plus an absorption lag-time was evaluated, as well as a variation of this model designed to mimic enterohepatic recycling (EHC). Optimal PK sampling strategies (OSS) were determined using WinPOPT based upon collection of 3-12 post-dose samples. A two-compartment model with EHC provided the best fit and reduced bias in C(max) (median prediction error (PE%) of 9.58% versus 12.2%) relative to the basic two-compartment model, AUC(0-24) was similar for both models (median PE% = 1.39%). The OSS for fitting the two-compartment model with EHC required the collection of seven samples (0.25, 1, 2, 4, 5, 6 and 12 h). Reasonably unbiased and precise exposures were obtained when re-fitting this model to a reduced dataset considering only these sampling times. A two-compartment model considering EHC best characterized the time course of clopidogrel-IM in plasma. Use of the suggested OSS will allow for the collection of fewer PK samples when assessing clopidogrel-IM exposures. Copyright © 2013 John Wiley & Sons, Ltd.

  5. Evaluation of three physiologically based pharmacokinetic (PBPK) modeling tools for emergency risk assessment after acute dichloromethane exposure

    NARCIS (Netherlands)

    Boerleider, R. Z.; Olie, J. D N; van Eijkeren, J. C H; Bos, P. M J; Hof, B. G H; de Vries, I.; Bessems, J. G M; Meulenbelt, J.; Hunault, C. C.

    2015-01-01

    Introduction: Physiologically based pharmacokinetic (PBPK) models may be useful in emergency risk assessment, after acute exposure to chemicals, such as dichloromethane (DCM). We evaluated the applicability of three PBPK models for human risk assessment following a single exposure to DCM: one model

  6. Bioanalytical methods for determination of tamoxifen and its phase I metabolites: A review

    International Nuclear Information System (INIS)

    Teunissen, S.F.; Rosing, H.; Schinkel, A.H.; Schellens, J.H.M.; Beijnen, J.H.

    2010-01-01

    The selective estrogen receptor modulator tamoxifen is used in the treatment of early and advanced breast cancer and in selected cases for breast cancer prevention in high-risk subjects. The cytochrome P450 enzyme system and flavin-containing monooxygenase are responsible for the extensive metabolism of tamoxifen into several phase I metabolites that vary in toxicity and potencies towards estrogen receptor (ER) alpha and ER beta. An extensive overview of publications on the determination of tamoxifen and its phase I metabolites in biological samples is presented. In these publications techniques were used such as capillary electrophoresis, liquid, gas and thin layer chromatography coupled with various detection techniques (mass spectrometry, ultraviolet or fluorescence detection, liquid scintillation counting and nuclear magnetic resonance spectroscopy). A trend is seen towards the use of liquid chromatography coupled to mass spectrometry (LC-MS). State-of-the-art LC-MS equipment allowed for identification of unknown metabolites and quantification of known metabolites reaching lower limit of quantification levels in the sub pg mL -1 range. Although tamoxifen is also metabolized into phase II metabolites, the number of publications reporting on phase II metabolism of tamoxifen is scarce. Therefore the focus of this review is on phase I metabolites of tamoxifen. We conclude that in the past decades tamoxifen metabolism has been studied extensively and numerous metabolites have been identified. Assays have been developed for both the identification and quantification of tamoxifen and its metabolites in an array of biological samples. This review can be used as a resource for method transfer and development of analytical methods used to support pharmacokinetic and pharmacodynamic studies of tamoxifen and its phase I metabolites.

  7. 11C-ORM-13070, a novel PET ligand for brain α2C-adrenoceptors: radiometabolism, plasma pharmacokinetics, whole-body distribution and radiation dosimetry in healthy men

    International Nuclear Information System (INIS)

    Luoto, Pauliina; Oikonen, Vesa; Arponen, Eveliina; Helin, Semi; Virta, Jere; Virtanen, Kirsi; Roivainen, Anne; Suilamo, Sami; Herttuainen, Jukka; Hietamaeki, Johanna; Holopainen, Aila; Rouru, Juha; Sallinen, Jukka; Kailajaervi, Marita; Peltonen, Juha M.; Scheinin, Mika; Volanen, Iina; Rinne, Juha O.

    2014-01-01

    11 C-labelled 1-[(S)-1-(2,3-dihydrobenzo[1,2]dioxin-2-yl)methyl] -4-(3-methoxy-methylpyridin-2- yl)-piperazine ( 11 C-ORM-13070) is a novel PET tracer for imaging of α 2C -adrenoceptors in the human brain. Brain α 2C -adrenoceptors may be therapeutic targets in several neuropsychiatric disorders, including depression, schizophrenia and Alzheimer's disease. To validate the use of 11 C-ORM-13070 in humans, we investigated its radiometabolism, pharmacokinetics, whole-body distribution and radiation dose. Radiometabolism was studied in a test-retest setting in six healthy men. After intravenous injection of 11 C-ORM-13070, blood samples were drawn over 60 min. Plasma samples were analysed by radio-HPLC for intact tracer and its radioactive metabolites. Metabolite-corrected plasma time-activity curves were used for calculation of pharmacokinetics. In a separate group of 12 healthy men, the whole-body distribution of 11 C-ORM-13070 and radiation exposure were investigated by dynamic PET/CT imaging without blood sampling. Two radioactive metabolites of 11 C-ORM-13070 were detected in human arterial plasma. The proportion of unchanged 11 C-ORM-13070 decreased from 81 ± 4 % of total radioactivity at 4 min after tracer injection to 23 ± 4 % at 60 min. At least one of the radioactive metabolites penetrated into red blood cells, while the parent tracer remained in plasma. The apparent elimination rate constant and corresponding half-life of unchanged 11 C-ORM-13070 in arterial plasma were 0.0117 ± 0.0056 min -1 and 73.6 ± 35.8 min, respectively. The organs with the highest absorbed doses were the liver (12 μSv/MBq), gallbladder wall (12 μSv/MBq) and pancreas (9.1 μSv/MBq). The mean effective dose was 3.9 μSv/MBq, with a range of 3.6 - 4.2 μSv/MBq. 11 C-ORM-13070 was rapidly metabolized in human subjects after intravenous injection. The effective radiation dose of 11 C-ORM-13070 was in the same range as that of other 11 C-labelled brain receptor tracers. An injection

  8. Pharmacokinetics of mitragynine in man

    Directory of Open Access Journals (Sweden)

    Trakulsrichai S

    2015-04-01

    the study without adverse reactions. The median duration of abuse was 1.75 years. We analyzed one subject separately due to the abnormal behavior of blood concentration. From data of nine subjects, the pharmacokinetic parameters established were time to reach the maximum plasma concentration (0.83±0.35 hour, terminal half-life (23.24±16.07 hours, and the apparent volume of distribution (38.04±24.32 L/kg. The urine excretion of unchanged form was 0.14%. The pharmacokinetics were observed to be oral two-compartment model. Conclusion: This was the first pharmacokinetic study in humans, which demonstrated linearity and was consistent with the oral two-compartment model with a terminal half-life of about 1 day. The pharmacokinetic linearity and parameters reported are necessary pharmacological information of Kratom, and there is a possibility for it to be developed medically as a pain killer or better opioid substitute in the future. Keywords: kratom, human, pharmacokinetics

  9. Electrosynthesis methods and approaches for the preparative production of metabolites from parent drugs

    NARCIS (Netherlands)

    Gül, Turan; Bischoff, Rainer; Permentier, Hjalmar

    2015-01-01

    Identification of potentially toxic metabolites is important for drug discovery and development. Synthesis of drug metabolites is typically performed by organic synthesis or enzymatic methods, but is not always straightforward. Electrochemical (EC) methods are increasingly used to study drug

  10. Investigation of the Effect of Rice Wine on the Metabolites of the Main Components of Herbal Medicine in Rat Urine by Ultrahigh-Performance Liquid Chromatography-Quadrupole/Time-of-Flight Mass Spectrometry: A Case Study on Cornus officinalis

    Directory of Open Access Journals (Sweden)

    Gang Cao

    2013-01-01

    Full Text Available Ultrahigh-performance liquid chromatography-quadrupole/time-of-flight mass spectrometry (UPLC-QTOF/MS was developed for rapid and sensitive analysis of the effect of rice wine on the metabolites of the main components of herbal medicine in rat urine. Using Cornus officinalis as a model of herbal medicine, the metabolite profiles of crude and processed (steaming the crude drug presteeped in rice wine Cornus officinalis extracts in rat urine were investigated. The metabolites of Cornus officinalis were identified by using dynamic adjustment of the fragmentor voltage to produce structure-relevant fragment ions. In this work, we identified the parent compounds and metabolites of crude and processed Cornus officinalis in rats. In total, three parent compounds and seventeen new metabolites of Cornus officinalis were found in rats. The contents of the parent compounds and metabolites in vivo varied significantly after intragastric (i.g. administration of aqueous extracts of crude and processed Cornus officinalis. Data from this study suggests that UPLC-QTOF/MS could be used as a potential tool for uncovering the effects of excipients found in the metabolites of the main components of herbal medicine, in vivo, to predict and discover the processing mechanisms of herbal medicine.

  11. Becoming a parent: a model of parents' post-partum experience

    Directory of Open Access Journals (Sweden)

    Francine de Montigny

    2006-04-01

    Full Text Available Perceiving oneself as parent is a key challenge during the transition to parenthood. The importance of health professionals in determining perceived efficacy in parents upon the birth of their child is few explored. The objective of this study is to analayze the relations between the first time parents' perceived efficacy and their perceptions of nurses' help-giving and critical events during post-partum period. SAMPLE AND METHOD: One hundred sixty couples participated in a correlational study by completing questionaires after the birth of their first child. RESULTS: A model of parents' postpartum experience was established where nurses' collaboration and help-giving practices contribute directly and indirectly to the parents' perception of control and perceptions of events. They contribute indirectly to parent's perceived self-efficacy. IMPLICATIONS: The help given by health professionals, especially nurses, to parents following the birth of a child makes a major positive difference in the parents' experiences.

  12. Population pharmacokinetics of caffeine and its metabolites theobromine, paraxanthine and theophylline after inhalation in combination with diacetylmorphine

    NARCIS (Netherlands)

    Zandvliet, Anthe S.; Huitema, Alwin D. R.; de Jonge, Milly E.; den Hoed, Rob; Sparidans, Rolf W.; Hendriks, Vincent M.; van den Brink, Wim; van Ree, Jan M.; Beijnen, Jos H.

    2005-01-01

    The stimulant effect of caffeine, as an additive in diacetylmorphine preparations for study purposes, may interfere with the pharmacodynamic effects of diacetylmorphine. In order to obtain insight into the pharmacology of caffeine after inhalation in heroin users, the pharmacokinetics of caffeine

  13. Ofloxacin pharmacokinetics in renal failure.

    OpenAIRE

    Fillastre, J P; Leroy, A; Humbert, G

    1987-01-01

    The pharmacokinetics of ofloxacin were investigated in 12 normal subjects and 21 uremic patients after the administration of a single oral 200-mg dose. An open three-compartment body model was used to calculate ofloxacin pharmacokinetic parameters. In healthy subjects, the peak plasma level averaged 2.24 +/- 0.90 micrograms/ml and was obtained at 0.83 +/- 0.31 h. The absorption rate constant was 4.22 +/- 1.64 h-1. The terminal half-life was 7.86 +/- 1.81 h. The apparent volume of distribution...

  14. Population pharmacokinetics of artesunate and amodiaquine in African children

    Directory of Open Access Journals (Sweden)

    Ouedraogo Alphonse

    2009-08-01

    Full Text Available Abstract Background Pharmacokinetic (PK data on amodiaquine (AQ and artesunate (AS are limited in children, an important risk group for malaria. The aim of this study was to evaluate the PK properties of a newly developed and registered fixed dose combination (FDC of artesunate and amodiaquine. Methods A prospective population pharmacokinetic study of AS and AQ was conducted in children aged six months to five years. Participants were randomized to receive the new artesunate and amodiaquine FDC or the same drugs given in separate tablets. Children were divided into two groups of 70 (35 in each treatment arm to evaluate the pharmacokinetic properties of AS and AQ, respectively. Population pharmacokinetic models for dihydroartemisinin (DHA and desethylamodiaquine (DeAq, the principal pharmacologically active metabolites of AS and AQ, respectively, and total artemisinin anti-malarial activity, defined as the sum of the molar equivalent plasma concentrations of DHA and artesunate, were constructed using the non-linear mixed effects approach. Relative bioavailability between products was compared by estimating the ratios (and 95% CI between the areas under the plasma concentration-time curves (AUC. Results The two regimens had similar PK properties in young children with acute malaria. The ratio of loose formulation to fixed co-formulation AUCs, was estimated as 1.043 (95% CI: 0.956 to 1.138 for DeAq. For DHA and total anti-malarial activity AUCs were estimated to be the same. Artesunate was rapidly absorbed, hydrolysed to DHA, and eliminated. Plasma concentrations were significantly higher following the first dose, when patients were acutely ill, than after subsequent doses when patients were usually afebrile and clinically improved. Amodiaquine was converted rapidly to DeAq, which was then eliminated with an estimated median (range elimination half-life of 9 (7 to 12 days. Efficacy was similar in the two treatments groups, with cure rates of 0

  15. Quantification of metoprolol beta 2-adrenoceptor antagonism in asthmatic patients by pharmacokinetic-pharmacodynamic modelling

    NARCIS (Netherlands)

    Braat, M. C.; Jonkers, R. E.; van Boxtel, C. J.

    1992-01-01

    An integrated pharmacokinetic-pharmacodynamic model was used to quantify the beta 2-blocking activity of metoprolol in seven asthmatic patients. The patients received a subcutaneous dose of terbutaline on two consecutive days. On day 1 they were pretreated with placebo and on day 2 with metoprolol

  16. Pharmacokinetic/Pharmacodynamic Relationship of Gabapentin in a CFA-induced Inflammatory Hyperalgesia Rat Model.

    Science.gov (United States)

    Larsen, Malte Selch; Keizer, Ron; Munro, Gordon; Mørk, Arne; Holm, René; Savic, Rada; Kreilgaard, Mads

    2016-05-01

    Gabapentin displays non-linear drug disposition, which complicates dosing for optimal therapeutic effect. Thus, the current study was performed to elucidate the pharmacokinetic/pharmacodynamic (PKPD) relationship of gabapentin's effect on mechanical hypersensitivity in a rat model of CFA-induced inflammatory hyperalgesia. A semi-mechanistic population-based PKPD model was developed using nonlinear mixed-effects modelling, based on gabapentin plasma and brain extracellular fluid (ECF) time-concentration data and measurements of CFA-evoked mechanical hyperalgesia following administration of a range of gabapentin doses (oral and intravenous). The plasma/brain ECF concentration-time profiles of gabapentin were adequately described with a two-compartment plasma model with saturable intestinal absorption rate (K m  = 44.1 mg/kg, V max  = 41.9 mg/h∙kg) and dose-dependent oral bioavailability linked to brain ECF concentration through a transit compartment. Brain ECF concentration was directly linked to a sigmoid E max function describing reversal of hyperalgesia (EC 50, plasma  = 16.7 μg/mL, EC 50, brain  = 3.3 μg/mL). The proposed semi-mechanistic population-based PKPD model provides further knowledge into the understanding of gabapentin's non-linear pharmacokinetics and the link between plasma/brain disposition and anti-hyperalgesic effects. The model suggests that intestinal absorption is the primary source of non-linearity and that the investigated rat model provides reasonable predictions of clinically effective plasma concentrations for gabapentin.

  17. Physiologically-based pharmacokinetic model for Fentanyl in support of the development of Provisional Advisory Levels

    Energy Technology Data Exchange (ETDEWEB)

    Shankaran, Harish, E-mail: harish.shankaran@pnnl.gov [Computational Biology and Bioinformatics Group, Pacific Northwest National Laboratory, Richland, WA 99352 (United States); Adeshina, Femi [National Homeland Security Research Center, United States Environmental Protection Agency, Washington, DC 20460 (United States); Teeguarden, Justin G. [Systems Toxicology Group, Pacific Northwest National Laboratory, Richland, WA 99352 (United States)

    2013-12-15

    Provisional Advisory Levels (PALs) are tiered exposure limits for toxic chemicals in air and drinking water that are developed to assist in emergency responses. Physiologically-based pharmacokinetic (PBPK) modeling can support this process by enabling extrapolations across doses, and exposure routes, thereby addressing gaps in the available toxicity data. Here, we describe the development of a PBPK model for Fentanyl – a synthetic opioid used clinically for pain management – to support the establishment of PALs. Starting from an existing model for intravenous Fentanyl, we first optimized distribution and clearance parameters using several additional IV datasets. We then calibrated the model using pharmacokinetic data for various formulations, and determined the absorbed fraction, F, and time taken for the absorbed amount to reach 90% of its final value, t90. For aerosolized pulmonary Fentanyl, F = 1 and t90 < 1 min indicating complete and rapid absorption. The F value ranged from 0.35 to 0.74 for oral and various transmucosal routes. Oral Fentanyl was absorbed the slowest (t90 ∼ 300 min); the absorption of intranasal Fentanyl was relatively rapid (t90 ∼ 20–40 min); and the various oral transmucosal routes had intermediate absorption rates (t90 ∼ 160–300 min). Based on these results, for inhalation exposures, we assumed that all of the Fentanyl inhaled from the air during each breath directly, and instantaneously enters the arterial circulation. We present model predictions of Fentanyl blood concentrations in oral and inhalation scenarios relevant for PAL development, and provide an analytical expression that can be used to extrapolate between oral and inhalation routes for the derivation of PALs. - Highlights: • We develop a Fentanyl PBPK model for relating external dose to internal levels. • We calibrate the model to oral and inhalation exposures using > 50 human datasets. • Model predictions are in good agreement with the available

  18. Biotransformation of the citrus flavone tangeretin in rats. Identification of metabolites with intact flavane nucleus

    DEFF Research Database (Denmark)

    Nielsen, S.E.; Breinholt, V.; Cornett, C.

    2000-01-01

    were separated and identified by HPLC and the structures elucidated by LC/MS and H-1 NMR. Ten new, major metabolites with intact flavonoid structure were identified. The metabolites identified were either demethylated or hydroxylated derivatives of the parent compound and metabolic changes were found...

  19. Towards a model of contemporary parenting: the parenting behaviours and dimensions questionnaire.

    Directory of Open Access Journals (Sweden)

    Carly A Y Reid

    Full Text Available The assessment of parenting has been problematic due to theoretical disagreement, concerns over generalisability, and problems with the psychometric properties of current parenting measures. The aim of this study was to develop a comprehensive, psychometrically sound self-report parenting measure for use with parents of preadolescent children, and to use this empirical scale development process to identify the core dimensions of contemporary parenting behaviour. Following item generation and parent review, 846 parents completed an online survey comprising 116 parenting items. Exploratory and confirmatory factor analyses supported a six factor parenting model, comprising Emotional Warmth, Punitive Discipline, Anxious Intrusiveness, Autonomy Support, Permissive Discipline and Democratic Discipline. This measure will allow for the comprehensive and consistent assessment of parenting in future research and practice.

  20. Towards a model of contemporary parenting: the parenting behaviours and dimensions questionnaire.

    Science.gov (United States)

    Reid, Carly A Y; Roberts, Lynne D; Roberts, Clare M; Piek, Jan P

    2015-01-01

    The assessment of parenting has been problematic due to theoretical disagreement, concerns over generalisability, and problems with the psychometric properties of current parenting measures. The aim of this study was to develop a comprehensive, psychometrically sound self-report parenting measure for use with parents of preadolescent children, and to use this empirical scale development process to identify the core dimensions of contemporary parenting behaviour. Following item generation and parent review, 846 parents completed an online survey comprising 116 parenting items. Exploratory and confirmatory factor analyses supported a six factor parenting model, comprising Emotional Warmth, Punitive Discipline, Anxious Intrusiveness, Autonomy Support, Permissive Discipline and Democratic Discipline. This measure will allow for the comprehensive and consistent assessment of parenting in future research and practice.

  1. Modelling the influence of metabolite diffusion on non-starter lactic acid bacteria growth in ripening Cheddar cheese

    DEFF Research Database (Denmark)

    Czárán, Tamás; Rattray, Fergal P.; Møller, Cleide O.de A.

    2018-01-01

    The influence of metabolite diffusion within the cheese matrix on growth of non-starter lactic acid bacteria (NSLAB) during Cheddar cheese ripening was mathematically modelled. The model was calibrated at a realistic range of diffusion of metabolites and the decay and growth parameters...

  2. 24-hour human urine and serum profiles of bisphenol A following ingestion in soup: Individual pharmacokinetic data and emographics

    Directory of Open Access Journals (Sweden)

    Justin G. Teeguarden

    2015-09-01

    Full Text Available Here we present data to evaluate potential absorption of Bisphenol A through non-metabolizing tissues of the upper digestive tract. Concurrent serum and urine concentrations of d6-BPA, and its glucuronide and sulfate conjugates, were measured over a 24 h period in 10 adult male volunteers following ingestion of 30 μg d6-BPA/kg body weight in soup. The pharmacokinetic behavior of BPA and its metabolites in this cohort (rapid absorption, complete elimination, evidence against sublingual absorption was reported. This Data in Brief article contains the corresponding individual pharmacokinetic data, reports the demographics of the cohort and provides additional details related to the analytical methods employed and is related to [4].

  3. 24-hour human urine and serum profiles of bisphenol A following ingestion in soup: Individual pharmacokinetic data and emographics

    Science.gov (United States)

    Teeguarden, Justin G.; Twaddle, Nathan C.; Churchwell, Mona I.; Yang, Xiaoxia; Fisher, Jeffrey W.; Seryak, Liesel M.; Doerge, Daniel R.

    2015-01-01

    Here we present data to evaluate potential absorption of Bisphenol A through non-metabolizing tissues of the upper digestive tract. Concurrent serum and urine concentrations of d6-BPA, and its glucuronide and sulfate conjugates, were measured over a 24 h period in 10 adult male volunteers following ingestion of 30 μg d6-BPA/kg body weight in soup. The pharmacokinetic behavior of BPA and its metabolites in this cohort (rapid absorption, complete elimination, evidence against sublingual absorption) was reported. This Data in Brief article contains the corresponding individual pharmacokinetic data, reports the demographics of the cohort and provides additional details related to the analytical methods employed and is related to [4]. PMID:26217767

  4. A Review on Pharmacokinetic Modeling and the Effects of Environmental Stressors on Pharmacokinetics for Operational Medicine: Operational Pharmacokinetics

    Science.gov (United States)

    2009-09-01

    Manning et al. 1986), which may cause physiological changes. For example, emotional distress may lead to elevated heart rate, blood pressure and...related changes in renal functions were reported during a Stroop word color conflict test (Fauvel, Hadj-Aissa et al. 1991). Emotional stressors could...M. Skee, et al. (2001). "Pharmacokinetics of norelgestromin and ethinyl estradiol delivered by a contraceptive patch (Ortho Evra (TM)/Evra (TM

  5. Synthesis and positron emission tomography studies of C-11-labeled isotopomers and metabolites of GTS-21, a partial {alpha}7 nicotinic cholinergic agonist drug

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sung Won [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States) and Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794-3400 (United States)]. E-mail: swkim@bnl.gov; Ding Yushin [Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794-3400 (United States); Department of Radiology, Yale University School of Medicine, New Haven, CT 06520-8048 (United States); Alexoff, David [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Patel, Vinal [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Logan, Jean [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Lin, K.-S. [Department of Radiology, University of Pittsburgh, Pittsburgh, PA 15213 (United States); Shea, Colleen [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Muench, Lisa [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Xu Youwen [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Carter, Pauline [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); King, Payton [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Constanzo, Jasmine R. [Department of Chemistry, Fordham University, Bronx, NY 10458 (United States); Ciaccio, James A. [Department of Chemistry, Fordham University, Bronx, NY 10458 (United States); Fowler, Joanna S. [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794-3400 (United States); Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029 (United States)

    2007-07-15

    Introduction: (3E)-3-[(2,4-dimethoxyphenyl)methylene]-3,4,5,6-tetrahydro-2,3'-bipyridine (GTS-21), a partial {alpha}7 nicotinic acetylcholine receptor agonist drug, has recently been shown to improve cognition in schizophrenia and Alzheimer's disease. One of its two major demethylated metabolites, 4-OH-GTS-21, has been suggested to contribute to its therapeutic effects. Methods: We labeled GTS-21 in two different positions with carbon-11 ([2-methoxy-{sup 11}C]GTS-21 and [4-{sup 11}C]GTS-21) along with two corresponding demethylated metabolites ([2-methoxy-{sup 11}C]4-OH-GTS-21 and [4-methoxy-{sup 11}C]2-OH-GTS-21) for pharmacokinetic studies in baboons and mice with positron emission tomography (PET). Results: Both [2-{sup 11}C]GTS-21 and [4-methoxy-{sup 11}C]GTS-21 showed similar initial high rapid uptake in baboon brain, peaking from 1 to 3.5 min (0.027-0.038%ID/cc) followed by rapid clearance (t {sub 1/2}<15 min), resulting in low brain retention by 30 min. However, after 30 min, [2-methoxy-{sup 11}C]GTS-21 continued to clear while [4-methoxy-{sup 11}C]GTS-21 plateaued, suggesting the entry of a labeled metabolite into the brain. Comparison of the pharmacokinetics of the two labeled metabolites confirmed expected higher brain uptake and retention of [4-methoxy-{sup 11}C]2-OH-GTS-21 (the labeled metabolite of [4-methoxy-{sup 11}C]GTS-21) relative to [2-methoxy-{sup 11}C]4-OH-GTS-21 (the labeled metabolite of [2-methoxy-{sup 11}C]GTS-21), which had negligible brain uptake. Ex vivo studies in mice showed that GTS-21 is the major chemical form in the mouse brain. Whole-body dynamic PET imaging in baboon and mouse showed that the major route of excretion of C-11 is through the gallbladder. Conclusions: The major findings are as follows: (a) extremely rapid uptake and clearance of [2-methoxy-{sup 11}C]GTS-21 from the brain, which may need to be considered in developing optimal dosing of GTS-21 for patients, and (b) significant brain uptake of 2-OH-GTS-21

  6. A quantitative systems pharmacology approach, incorporating a novel liver model, for predicting pharmacokinetic drug-drug interactions.

    Science.gov (United States)

    Cherkaoui-Rbati, Mohammed H; Paine, Stuart W; Littlewood, Peter; Rauch, Cyril

    2017-01-01

    All pharmaceutical companies are required to assess pharmacokinetic drug-drug interactions (DDIs) of new chemical entities (NCEs) and mathematical prediction helps to select the best NCE candidate with regard to adverse effects resulting from a DDI before any costly clinical studies. Most current models assume that the liver is a homogeneous organ where the majority of the metabolism occurs. However, the circulatory system of the liver has a complex hierarchical geometry which distributes xenobiotics throughout the organ. Nevertheless, the lobule (liver unit), located at the end of each branch, is composed of many sinusoids where the blood flow can vary and therefore creates heterogeneity (e.g. drug concentration, enzyme level). A liver model was constructed by describing the geometry of a lobule, where the blood velocity increases toward the central vein, and by modeling the exchange mechanisms between the blood and hepatocytes. Moreover, the three major DDI mechanisms of metabolic enzymes; competitive inhibition, mechanism based inhibition and induction, were accounted for with an undefined number of drugs and/or enzymes. The liver model was incorporated into a physiological-based pharmacokinetic (PBPK) model and simulations produced, that in turn were compared to ten clinical results. The liver model generated a hierarchy of 5 sinusoidal levels and estimated a blood volume of 283 mL and a cell density of 193 × 106 cells/g in the liver. The overall PBPK model predicted the pharmacokinetics of midazolam and the magnitude of the clinical DDI with perpetrator drug(s) including spatial and temporal enzyme levels changes. The model presented herein may reduce costs and the use of laboratory animals and give the opportunity to explore different clinical scenarios, which reduce the risk of adverse events, prior to costly human clinical studies.

  7. A quantitative systems pharmacology approach, incorporating a novel liver model, for predicting pharmacokinetic drug-drug interactions.

    Directory of Open Access Journals (Sweden)

    Mohammed H Cherkaoui-Rbati

    Full Text Available All pharmaceutical companies are required to assess pharmacokinetic drug-drug interactions (DDIs of new chemical entities (NCEs and mathematical prediction helps to select the best NCE candidate with regard to adverse effects resulting from a DDI before any costly clinical studies. Most current models assume that the liver is a homogeneous organ where the majority of the metabolism occurs. However, the circulatory system of the liver has a complex hierarchical geometry which distributes xenobiotics throughout the organ. Nevertheless, the lobule (liver unit, located at the end of each branch, is composed of many sinusoids where the blood flow can vary and therefore creates heterogeneity (e.g. drug concentration, enzyme level. A liver model was constructed by describing the geometry of a lobule, where the blood velocity increases toward the central vein, and by modeling the exchange mechanisms between the blood and hepatocytes. Moreover, the three major DDI mechanisms of metabolic enzymes; competitive inhibition, mechanism based inhibition and induction, were accounted for with an undefined number of drugs and/or enzymes. The liver model was incorporated into a physiological-based pharmacokinetic (PBPK model and simulations produced, that in turn were compared to ten clinical results. The liver model generated a hierarchy of 5 sinusoidal levels and estimated a blood volume of 283 mL and a cell density of 193 × 106 cells/g in the liver. The overall PBPK model predicted the pharmacokinetics of midazolam and the magnitude of the clinical DDI with perpetrator drug(s including spatial and temporal enzyme levels changes. The model presented herein may reduce costs and the use of laboratory animals and give the opportunity to explore different clinical scenarios, which reduce the risk of adverse events, prior to costly human clinical studies.

  8. Effect of scutellarin on the metabolism and pharmacokinetics of clopidogrel in rats.

    Science.gov (United States)

    Chen, Xinmeng; Jin, Jing; Chen, Yaobin; Peng, Lingling; Zhong, Guoping; Li, Jiali; Bi, Huichang; Cai, Yefeng; Huang, Min

    2015-01-01

    Erigeron breviscapus (Vant.) Hand-Mazz, a traditional Chinese medicine, is often co-prescribed with clopidogrel for the treatment of ischemic vascular diseases. Scutellarin is the representative bioactive flavonoid isolated from this herb. The aim of this study was to explore the effect of scutellarin on the metabolism and pharmacokinetics of clopidogrel. The in vitro studies using rat liver microsomes showed that scutellarin significantly inhibited the metabolism of clopidogrel. The IC50 value was 2.1 µM. Ten male rats were employed to investigate the effect of scutellarin on the pharmacokinetics of clopidogrel in vivo. After pretreatment with scutellarin, there were significant increases in the AUC0-∞ (from 0.9 ± 0.4 to 1.7 ± 0.6 ng/ml h; p <0.05) and Cmax (from 0.4 ± 0.1 to 0.9 ± 0.1 ng/ml; p <0.05) of clopidogrel. The pharmacokinetic data for clopidogrel active metabolite showed significant decreases in AUC0-∞ (18.2 ± 5.6 to 11.4 ± 3.7 ng/ml h; p <0.05) and Cmax (from 8.2 ± 1.2 to 4.3 ± 0.3 ng/ml; p <0.05) after pretreatment with scutellarin. Collectively, the metabolism and pharmacokinetics of clopidogrel were significantly affected by scutellarin. This study indicated that potential herb-drug interaction between scutellarin and clopidogrel should be taken into consideration in clinical use. Copyright © 2014 John Wiley & Sons, Ltd.

  9. Simultaneous determination of clevidipine and its primary metabolite in dog plasma by liquid chromatography-tandem mass spectrometry: Application to pharmacokinetic study.

    Science.gov (United States)

    Zhou, Ying; Li, Huqun; He, Xiaomeng; Jia, Mengmeng; Ni, Yang; Xu, Mingzhen; Chen, Hui; Li, Weiyong

    2014-11-01

    A simple and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous determination of clevidipine and its primary metabolite H152/81 in dog plasma after protein precipitation with acetonitrile using felodipine as the internal standard (IS). Chromatographic separation was performed on a XB C18 column (2.1mm×50mm, 3.5μm) under isocratic conditions with the mobile phase consisting of acetonitrile and 20mM ammonium acetate buffer (pH 7.0) (40:60, v/v) at the flow rate of 0.3ml/min. The run time was 5.5min. Mass spectrometric analysis was performed on a triple quadrupole mass spectrometer operated in the multiple reaction monitoring (MRM) mode with the transitions of m/z 473.0→338.2 for clevidipine, m/z 356.1→324.0 for H152/81 and m/z 383.9→338.2 for the IS. The method was fully validated in terms of selectivity, linearity, lower limit of quantification (LLOQ), accuracy, precision, stability, matrix effect and recovery over a concentration range of 0.15-200ng/ml for clevidipine and 10-2000ng/ml for H152/81, respectively. The analytical method was applied to support a pharmacokinetic study of simultaneous determination of clevidipine and H152/81 in ten healthy beagle dogs. Copyright © 2014 Elsevier B.V. All rights reserved.

  10. Population Pharmacokinetic-Pharmacodynamic Modeling of Haloperidol in Patients With Schizophrenia Using Positive and Negative Syndrome Rating Scale

    NARCIS (Netherlands)

    Reddy, Venkatesh Pilla; Kozielska, Magdalena; Johnson, Martin; Mafirakureva, Nyashadzaishe; Vermeulen, An; Liu, Jing; de Greef, Rik; Rujescu, Dan; Groothuis, Geny M. M.; Danhof, Meindert; Proost, Johannes H.

    2013-01-01

    The aim of this study was to develop a pharmacokinetic-pharmacodynamic (PKPD) model that quantifies the efficacy of haloperidol, accounting for the placebo effect, the variability in exposure-response, and the dropouts. Subsequently, the developed model was utilized to characterize an effective

  11. In vitro and in vivo experimental data for pyrethroid pharmacokinetic models: the case of bifenthrin

    Science.gov (United States)

    Pyrethroids are a class of neurotoxic synthetic pesticides. Exposure to pyrethroids has increased due to declining use of other classes of pesticides. Our studies are focused on generating in vitro and in vivo data for the development of pharmacokinetic models for pyrethroids. Us...

  12. Clinical pharmacokinetics, safety, and preliminary efficacy evaluation of icotinib in patients with advanced non-small cell lung cancer.

    Science.gov (United States)

    Liu, Dongyang; Zhang, Li; Wu, Yiwen; Jiang, Ji; Tan, Fenlai; Wang, Yingxiang; Liu, Yong; Hu, Pei

    2015-09-01

    To receive pharmacokinetics, safety, and anti-tumor activity of icotinib, a novel epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), in patients with advanced non-small-cell lung cancer (NSCLC). Patients (n=40) with advanced NSCLC were enrolled to receive escalating doses of icotinib, which was administrated on Day 1 followed by 28-day continuous dosing starting from Day 4. Four dosing regimens, 100mg b.i.d., 150 mg b.i.d., 125 mg t.i.d., and 200mg b.i.d. were studied. Pharmacokinetics (PK), safety, and efficacy of icotinib were evaluated. Icotinib was well tolerated in Chinese patients with refractory NSCLC. No toxicity with >3 grades were reported in more than 2 patients under any dose levels. One complete response (3%) and 9 partial responses (23%) were received. Total disease control rate could reach at 73% and median progress-free survival (range) was 154 (17-462) days. PK exposure of icotinib increased with increase of dose in NSCLC patients. Food was suggested to increase PK exposure by ∼30%. Mean t1/2β was within 5.31-8.07 h. No major metabolite (>10% plasma exposure of icotinib) was found in NSCLC patients. Icotinib with up to 400 mg/day exhibited good tolerance and preliminary antitumor activity in Chinese NSCLC patients. Pharmacokinetics of icotinib and 5 major metabolites were fully investigated in NSCLC patients. Optimized biologic dose (OBD) was finally recommended to be 125 mg t.i.d. for the later clinical study. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  13. An indoor air quality-pharmacokinetic simulation of passive inhalation of marijuana smoke and the resultant buildup of 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid in urine.

    Science.gov (United States)

    Giardino, N J

    1997-03-01

    In military courts of law, the good soldier defense is often used by the defendant to explain the presence of 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid in urine (hereafter referred to as THCA) above the Department of Defense (DOD) established limit of 15 ng/mL. The defense will contend the defendant unwittingly breathed side-stream marijuana smoke, thus resulting in the presence of THCA in the defendant's urine. The purpose of this work was to link an indoor air quality model (IAQ) with a pharmacokinetic (PK) model to predict a passive marijuana smoker's resultant concentration of the major urinary metabolite THCA.

  14. The flavonoid pathway in tomato seedlings: transcript abundance and the modeling of metabolite dynamics.

    Directory of Open Access Journals (Sweden)

    Marian Groenenboom

    Full Text Available Flavonoids are secondary metabolites present in all terrestrial plants. The flavonoid pathway has been extensively studied, and many of the involved genes and metabolites have been described in the literature. Despite this extensive knowledge, the functioning of the pathway in vivo is still poorly understood. Here, we study the flavonoid pathway using both experiments and mathematical models. We measured flavonoid metabolite dynamics in two tissues, hypocotyls and cotyledons, during tomato seedling development. Interestingly, the same backbone of interactions leads to very different accumulation patterns in the different tissues. Initially, we developed a mathematical model with constant enzyme concentrations that described the metabolic networks separately in both tissues. This model was unable to fit the measured flavonoid dynamics in the hypocotyls, even if we allowed unrealistic parameter values. This suggested us to investigate the effect of transcript abundance on flavonoid accumulation. We found that the expression of candidate flavonoid genes varies considerably with time. Variation in transcript abundance results in enzymatic variation, which could have a large effect on metabolite accumulation. Candidate transcript abundance was included in the mathematical model as representative for enzyme concentration. We fitted the resulting model to the flavonoid dynamics in the cotyledons, and tested it by applying it to the data from hypocotyls. When transcript abundance is included, we are indeed able to explain flavonoid dynamics in both tissues. Importantly, this is possible under the biologically relevant restriction that the enzymatic properties estimated by the model are conserved between the tissues.

  15. Accelerated pharmacokinetic map determination for dynamic contrast enhanced MRI using frequency-domain based Tofts model.

    Science.gov (United States)

    Vajuvalli, Nithin N; Nayak, Krupa N; Geethanath, Sairam

    2014-01-01

    Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) is widely used in the diagnosis of cancer and is also a promising tool for monitoring tumor response to treatment. The Tofts model has become a standard for the analysis of DCE-MRI. The process of curve fitting employed in the Tofts equation to obtain the pharmacokinetic (PK) parameters is time-consuming for high resolution scans. Current work demonstrates a frequency-domain approach applied to the standard Tofts equation to speed-up the process of curve-fitting in order to obtain the pharmacokinetic parameters. The results obtained show that using the frequency domain approach, the process of curve fitting is computationally more efficient compared to the time-domain approach.

  16. Simultaneous determination of imperatorin and its 2 metabolites in dog plasma by using liquid chromatography-tandem mass spectrometry.

    Science.gov (United States)

    Wang, Lu; Lu, Wen; Shen, Qi; Wang, Shengjia; Zhou, Hui; Yu, Lushan; Wang, Sicen; Jiang, Huidi; He, Langchong; Zeng, Su

    2012-11-01

    In this study, 2 metabolites of imperatorin, imperatorin hydroxylate (IMH) and imperatorin epoxide (IME), were identified for the first time in dog plasma. A sensitive, specific, and accurate high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was then developed for the simultaneous quantification of imperatorin and its 2 metabolites in dog plasma. Separation was achieved on an Agilent ZORBAX Extend-C(18) column (2.1 mm × 50 mm, 3.5 μm) at 30 °C. The mobile phase consisted of 0.02% ammonium acetate solution-methanol with a gradient program at a flow rate of 0.3 mL/min. Detection was performed using an electrospray ionization source operating in positive ion multiple reaction monitoring mode and by monitoring the ion transitions from 271 to 203 m/z for imperatorin, 309.4-224.1 m/z for IMH, 287-203 m/z for IME, and 441.3-325.2 m/z for simvastatin (the internal standard). Good linearity was shown over the concentration range of 1-500 ng/mL for imperatorin, and 0.2-500 ng/mL for IMH and IME. The validated method was successfully applied to a pharmacokinetic study of imperatorin in beagle dogs. The pharmacokinetic profiles of imperatorin and its 2 metabolites showed sex differences after the i.v. administration of imperatorin at a dose of 5 mg/kg. Copyright © 2012 Elsevier B.V. All rights reserved.

  17. Oseltamivir Pharmacokinetics and Clinical Experience in Neonates and Infants during an Outbreak of H1N1 Influenza A Virus Infection in a Neonatal Intensive Care Unit

    Science.gov (United States)

    Nika, Angela; Tsagris, Vasileios; Kapetanakis, Ioannis; Maltezou, Helena C.; Kafetzis, Dimitris A.; Tsolia, Maria N.

    2012-01-01

    Detailed oseltamivir pharmacokinetics have yet to be reported in neonates and infants; this group is at high risk of serious influenza-associated complications. Extrapolation of doses from older patients is complicated by rapid organ and drug-metabolizing enzyme maturation. A pharmacokinetic study has been conducted during an influenza A(H1N1) outbreak in a neonatal intensive care unit. Each included patient provided 4 samples for oseltamivir and 4 samples for its active metabolite oseltamivir carboxylate. A population pharmacokinetic model was developed with NONMEM. Allometric weight scaling and maturation functions were added a priori to scale for size and age based on literature values. Nine neonates and infants were recruited. A physiologically parameterized pharmacokinetic model predicted typical day 1 area under the curve (AUC0-12) values of 1,966 and 2,484 μg · h/liter for neonates and infants of ≤37 weeks of postmenstrual age (PMA) and >37 weeks of PMA treated with 1 mg/kg of body weight and 2 mg/kg, respectively. The corresponding steady-state AUC0-12 values were 3,670 and 4,559 μg · h/liter. Premature neonates treated with 1 mg/kg and term babies treated with 2 mg/kg should have average oseltamivir carboxylate concentrations in a range similar to that for adults treated with 75 mg, corresponding to >200-fold above the half-maximal inhibitory concentration (IC50) value for influenza A(H1N1) from the start of therapy. PMID:22564835

  18. Metabolite profiling with HPLC-ICP-MS as a tool for in vivo characterization of imaging probes.

    Science.gov (United States)

    Boros, Eszter; Pinkhasov, Omar R; Caravan, Peter

    2018-01-01

    Current analytical methods for characterizing pharmacokinetic and metabolic properties of positron emission tomography (PET) and single photon emission computed tomography (SPECT) probes are limited. Alternative methods to study tracer metabolism are needed. The study objective was to assess the potential of high performance liquid chromatography - inductively coupled plasma - mass spectrometry (HPLC-ICP-MS) for quantification of molecular probe metabolism and pharmacokinetics using stable isotopes. Two known peptide-DOTA conjugates were chelated with nat Ga and nat In. Limit of detection of HPLC-ICP-MS for 69 Ga and 115 In was determined. Rats were administered 50-150 nmol of Ga- and/or In-labeled probes, blood was serially sampled, and plasma analyzed by HPLC-ICP-MS using both reverse phase and size exclusion chromatography. The limits of detection were 0.16 pmol for 115 In and 0.53 pmol for 69 Ga. Metabolites as low as 0.001 %ID/g could be detected and transchelation products identified. Simultaneous administration of Ga- and In-labeled probes allowed the determination of pharmacokinetics and metabolism of both probes in a single animal. HPLC-ICP-MS is a robust, sensitive and radiation-free technique to characterize the pharmacokinetics and metabolism of imaging probes.

  19. Physiologically Based Pharmacokinetic Modeling: Methodology, Applications, and Limitations with a Focus on Its Role in Pediatric Drug Development

    Directory of Open Access Journals (Sweden)

    Feras Khalil

    2011-01-01

    Full Text Available The concept of physiologically based pharmacokinetic (PBPK modeling was introduced years ago, but it has not been practiced significantly. However, interest in and implementation of this modeling technique have grown, as evidenced by the increased number of publications in this field. This paper demonstrates briefly the methodology, applications, and limitations of PBPK modeling with special attention given to discuss the use of PBPK models in pediatric drug development and some examples described in detail. Although PBPK models do have some limitations, the potential benefit from PBPK modeling technique is huge. PBPK models can be applied to investigate drug pharmacokinetics under different physiological and pathological conditions or in different age groups, to support decision-making during drug discovery, to provide, perhaps most important, data that can save time and resources, especially in early drug development phases and in pediatric clinical trials, and potentially to help clinical trials become more “confirmatory” rather than “exploratory”.

  20. Uncertainty and Variability in Physiologically-Based Pharmacokinetic (PBPK) Models: Key Issues and Case Studies (Final Report)

    Science.gov (United States)

    EPA announced the availability of the final report, Uncertainty and Variability in Physiologically-Based Pharmacokinetic (PBPK) Models: Key Issues and Case Studies. This report summarizes some of the recent progress in characterizing uncertainty and variability in physi...

  1. Correlative analysis of metabolite profiling of Danggui Buxue Tang in rat biological fluids by rapid resolution LC-TOF/MS.

    Science.gov (United States)

    Li, Chang-Yin; Qi, Lian-Wen; Li, Ping

    2011-04-28

    In this work, the metabolite profiles of Danggui Buxue Tang (DBT) in rat bile and plasma were qualitatively described, and the possible metabolic pathways of DBT were subsequently proposed. Emphasis was put on correlative analysis of metabolite profiling in different biological fluids. After oral administration of DBT, bile and plasma samples were collected and pretreated by solid phase extraction. Rapid resolution liquid chromatography coupled to time-of-flight mass spectrometry (RRLC-TOFMS) was used for characterization of DBT-related compounds (parent compounds and metabolites) in biological matrices. A total of 142 metabolites were detected and tentatively identified from the drug-containing bile and plasma samples. Metabolite profiling shows that rat bile contained relatively more glutathione-derived conjugates, more saponins compounds and more diverse forms of metabolites than urine. The metabolite profile in plasma revealed that glucuronide conjugates of isoflavonoids, dimmers, acetylcysteine conjugates and parent form of phthalides, as well as saponin aglycones were the major circulating forms of DBT. Collectively, the metabolite profile analysis of DBT in different biological matrices provided a comprehensive understanding of the in vivo metabolic fates of constituents in DBT. Copyright © 2011 Elsevier B.V. All rights reserved.

  2. Chimeric mice transplanted with human hepatocytes as a model for prediction of human drug metabolism and pharmacokinetics.

    Science.gov (United States)

    Sanoh, Seigo; Ohta, Shigeru

    2014-03-01

    Preclinical studies in animal models are used routinely during drug development, but species differences of pharmacokinetics (PK) between animals and humans have to be taken into account in interpreting the results. Human hepatocytes are also widely used to examine metabolic activities mediated by cytochrome P450 (P450) and other enzymes, but such in vitro metabolic studies also have limitations. Recently, chimeric mice with humanized liver (h-chimeric mice), generated by transplantation of human donor hepatocytes, have been developed as a model for the prediction of metabolism and PK in humans, using both in vitro and in vivo approaches. The expression of human-specific metabolic enzymes and metabolic activities was confirmed in humanized liver of h-chimeric mice with high replacement ratios, and several reports indicate that the profiles of P450 and non-P450 metabolism in these mice adequately reflect those in humans. Further, the combined use of h-chimeric mice and r-chimeric mice, in which endogenous hepatocytes are replaced with rat hepatocytes, is a promising approach for evaluation of species differences in drug metabolism. Recent work has shown that data obtained in h-chimeric mice enable the semi-quantitative prediction of not only metabolites, but also PK parameters, such as hepatic clearance, of drug candidates in humans, although some limitations remain because of differences in the metabolic activities, hepatic blood flow and liver structure between humans and mice. In addition, fresh h-hepatocytes can be isolated reproducibly from h-chimeric mice for metabolic studies. Copyright © 2013 John Wiley & Sons, Ltd.

  3. Parents as Role Models: Parental Behavior Affects Adolescents' Plans for Work Involvement

    Science.gov (United States)

    Wiese, Bettina S.; Freund, Alexandra M.

    2011-01-01

    This study (N = 520 high-school students) investigates the influence of parental work involvement on adolescents' own plans regarding their future work involvement. As expected, adolescents' perceptions of parental work behavior affected their plans for own work involvement. Same-sex parents served as main role models for the adolescents' own…

  4. Pharmacokinetics and effects on serum cholinesterase activities of organophosphorus pesticides acephate and chlorpyrifos in chimeric mice transplanted with human hepatocytes.

    Science.gov (United States)

    Suemizu, Hiroshi; Sota, Shigeto; Kuronuma, Miyuki; Shimizu, Makiko; Yamazaki, Hiroshi

    2014-11-01

    Organophosphorus pesticides acephate and chlorpyrifos in foods have potential to impact human health. The aim of the current study was to investigate the pharmacokinetics of acephate and chlorpyrifos orally administered at lowest-observed-adverse-effect-level doses in chimeric mice transplanted with human hepatocytes. Absorbed acephate and its metabolite methamidophos were detected in serum from wild type mice and chimeric mice orally administered 150mg/kg. Approximately 70% inhibition of cholinesterase was evident in plasma of chimeric mice with humanized liver (which have higher serum cholinesterase activities than wild type mice) 1day after oral administrations of acephate. Adjusted animal biomonitoring equivalents from chimeric mice studies were scaled to human biomonitoring equivalents using known species allometric scaling factors and in vitro metabolic clearance data with a simple physiologically based pharmacokinetic (PBPK) model. Estimated plasma concentrations of acephate and chlorpyrifos in humans were consistent with reported concentrations. Acephate cleared similarly in humans and chimeric mice but accidental/incidental overdose levels of chlorpyrifos cleared (dependent on liver metabolism) more slowly from plasma in humans than it did in mice. The data presented here illustrate how chimeric mice transplanted with human hepatocytes in combination with a simple PBPK model can assist evaluations of toxicological potential of organophosphorus pesticides. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. Effect of In Vivo Nicotine Exposure on Chlorpyrifos Pharmacokinetics and Pharmacodynamics in Rats

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Sookwang; Poet, Torka S.; Smith, Jordan N.; Busby-Hjerpe, Andrea L.; Timchalk, Charles

    2010-03-30

    Routine use of tobacco products may modify physiological and metabolic functions, including drug metabolizing enzymes, which may impact the pharmacokinetics of environmental contaminants. Chlorpyrifos is an organophosphorus (OP) insecticide that is bioactivated to chlorpyrifos-oxon, and manifests its neurotoxicity by inhibiting acetylcholinesterase (AChE). The objective of this study was to evaluate the impact of repeated nicotine exposure on the pharmacokinetics of chlorpyrifos (CPF) and its major metabolite, 3,5,6-trichloro-2-pyridinol (TCPy) in blood and urine and also to determine the impact on cholinesterase (ChE) activity in plasma and brain. Animals were exposed to 7-daily doses of either 1 mg nicotine/kg or saline (sc), and to either a single oral dose of 35 mg CPF/kg or a repeated dose of 5 mg CPF/kg/day for 7 days. Groups of rats were then sacrificed at multiple time-points after receiving the last dose of CPF. Repeated nicotine and CPF exposures resulted in enhanced metabolism of CPF to TCPy, as evidenced by increases in the measured TCPy concentration and AUC in blood. However, there was no significant difference in the amount of TCPy (free or total) excreted in the urine. The extent of brain acetylcholinesterase (AChE) inhibition was reduced due to nicotine co-exposure consistent with an increase in CYP450-mediated dearylation (detoxification) versus desulfuration. It was of interest to note that the impact of nicotine co-exposure was experimentally observed only after repeated CPF doses. Physiologically based pharmacokinetic model simulations of CPF-oxon concentrations in blood and brain were predicted to be lower in nicotine treated groups, which were simulated by increasing the dearylation Vmax based upon previously conducted in vitro metabolism studies. These results were consistent with the experimental data. The current study demonstrated that repeated nicotine exposure could alter CPF metabolism in vivo, further modulating brain AChE inhibition.

  6. Estimation of pharmacokinetic parameters from non-compartmental variables using Microsoft Excel.

    Science.gov (United States)

    Dansirikul, Chantaratsamon; Choi, Malcolm; Duffull, Stephen B

    2005-06-01

    This study was conducted to develop a method, termed 'back analysis (BA)', for converting non-compartmental variables to compartment model dependent pharmacokinetic parameters for both one- and two-compartment models. A Microsoft Excel spreadsheet was implemented with the use of Solver and visual basic functions. The performance of the BA method in estimating pharmacokinetic parameter values was evaluated by comparing the parameter values obtained to a standard modelling software program, NONMEM, using simulated data. The results show that the BA method was reasonably precise and provided low bias in estimating fixed and random effect parameters for both one- and two-compartment models. The pharmacokinetic parameters estimated from the BA method were similar to those of NONMEM estimation.

  7. Performance of target-controlled infusion of propofol using two different pharmacokinetic models in open heart surgery - a randomised controlled study.

    Science.gov (United States)

    Mathew, P J; Sailam, S; Sivasailam, R; Thingnum, S K S; Puri, G D

    2016-01-01

    We compared the performance of a propofol target-controlled infusion (TCI) using Marsh versus PGIMER models in patients undergoing open heart surgery, in terms of measured plasma levels of propofol and objective pharmacodynamic effect. Twenty-three, ASA II/III adult patients aged 18-65 years and scheduled for elective open heart surgery received Marsh or PGIMER (Postgraduate Institute of Medical Education and Research) pharmacokinetic models of TCI for the induction and maintenance of anaesthesia with propofol in a randomized, active-controlled, non-inferiority trial. The plasma levels of propofol were measured at specified time points before, during and after bypass. The performances of both the models were similar, as determined by the error (%) in maintaining the target plasma concentrations: MDPE of -5.0 (-12.0, 5.0) in the PGIMER group vs -6.4 (-7.7 to 0.5) in the Marsh group and MDAPE of 9.1 (5, 15) in the PGIMER group vs 8 (6.7, 10.1) in the Marsh group. These values indicate that both models over-predicted the plasma propofol concentration. The new pharmacokinetic model based on data from Indian patients is comparable in performance to the commercially available Marsh pharmacokinetic model. © The Author(s) 2015.

  8. A safety and pharmacokinetic dosing study of glucagon-like peptide 2 in infants with intestinal failure

    DEFF Research Database (Denmark)

    Sigalet, David L; Brindle, Mary E; Boctor, Dana

    2017-01-01

    BACKGROUND & AIMS: Glucagon-like peptide 2 (GLP-2) analogues are approved for adults with intestinal failure (IF), but no studies have included infants. This study examined the pharmacokinetics (PK), safety, and nutritional effects of GLP-2 in infants with IF. METHODS: With parental consent (Health...

  9. Pharmacokinetics of Snake Venom

    Directory of Open Access Journals (Sweden)

    Suchaya Sanhajariya

    2018-02-01

    Full Text Available Understanding snake venom pharmacokinetics is essential for developing risk assessment strategies and determining the optimal dose and timing of antivenom required to bind all venom in snakebite patients. This review aims to explore the current knowledge of snake venom pharmacokinetics in animals and humans. Literature searches were conducted using EMBASE (1974–present and Medline (1946–present. For animals, 12 out of 520 initially identified studies met the inclusion criteria. In general, the disposition of snake venom was described by a two-compartment model consisting of a rapid distribution phase and a slow elimination phase, with half-lives of 5 to 48 min and 0.8 to 28 h, respectively, following rapid intravenous injection of the venoms or toxins. When the venoms or toxins were administered intramuscularly or subcutaneously, an initial absorption phase and slow elimination phase were observed. The bioavailability of venoms or toxins ranged from 4 to 81.5% following intramuscular administration and 60% following subcutaneous administration. The volume of distribution and the clearance varied between snake species. For humans, 24 out of 666 initially identified publications contained sufficient information and timed venom concentrations in the absence of antivenom therapy for data extraction. The data were extracted and modelled in NONMEM. A one-compartment model provided the best fit, with an elimination half-life of 9.71 ± 1.29 h. It is intended that the quantitative information provided in this review will provide a useful basis for future studies that address the pharmacokinetics of snakebite in humans.

  10. Prediction of clinical response based on pharmacokinetic/pharmacodynamic models of 5-hydroxytryptamine reuptake inhibitors in mice

    DEFF Research Database (Denmark)

    Kreilgaard, Mads; Smith, D. G.; Brennum, L. T.

    2008-01-01

    Bridging the gap between preclinical research and clinical trials is vital for drug development. Predicting clinically relevant steady-state drug concentrations (Css) in serum from preclinical animal models may facilitate this transition. Here we used a pharmacokinetic/pharmacodynamic (PK...

  11. Applying a Global Sensitivity Analysis Workflow to Improve the Computational Efficiencies in Physiologically-Based Pharmacokinetic Modeling

    Directory of Open Access Journals (Sweden)

    Nan-Hung Hsieh

    2018-06-01

    Full Text Available Traditionally, the solution to reduce parameter dimensionality in a physiologically-based pharmacokinetic (PBPK model is through expert judgment. However, this approach may lead to bias in parameter estimates and model predictions if important parameters are fixed at uncertain or inappropriate values. The purpose of this study was to explore the application of global sensitivity analysis (GSA to ascertain which parameters in the PBPK model are non-influential, and therefore can be assigned fixed values in Bayesian parameter estimation with minimal bias. We compared the elementary effect-based Morris method and three variance-based Sobol indices in their ability to distinguish “influential” parameters to be estimated and “non-influential” parameters to be fixed. We illustrated this approach using a published human PBPK model for acetaminophen (APAP and its two primary metabolites APAP-glucuronide and APAP-sulfate. We first applied GSA to the original published model, comparing Bayesian model calibration results using all the 21 originally calibrated model parameters (OMP, determined by “expert judgment”-based approach vs. the subset of original influential parameters (OIP, determined by GSA from the OMP. We then applied GSA to all the PBPK parameters, including those fixed in the published model, comparing the model calibration results using this full set of 58 model parameters (FMP vs. the full set influential parameters (FIP, determined by GSA from FMP. We also examined the impact of different cut-off points to distinguish the influential and non-influential parameters. We found that Sobol indices calculated by eFAST provided the best combination of reliability (consistency with other variance-based methods and efficiency (lowest computational cost to achieve convergence in identifying influential parameters. We identified several originally calibrated parameters that were not influential, and could be fixed to improve computational

  12. Predicting Cortisol Exposure from Paediatric Hydrocortisone Formulation Using a Semi-Mechanistic Pharmacokinetic Model Established in Healthy Adults.

    Science.gov (United States)

    Melin, Johanna; Parra-Guillen, Zinnia P; Hartung, Niklas; Huisinga, Wilhelm; Ross, Richard J; Whitaker, Martin J; Kloft, Charlotte

    2018-04-01

    Optimisation of hydrocortisone replacement therapy in children is challenging as there is currently no licensed formulation and dose in Europe for children under 6 years of age. In addition, hydrocortisone has non-linear pharmacokinetics caused by saturable plasma protein binding. A paediatric hydrocortisone formulation, Infacort ® oral hydrocortisone granules with taste masking, has therefore been developed. The objective of this study was to establish a population pharmacokinetic model based on studies in healthy adult volunteers to predict hydrocortisone exposure in paediatric patients with adrenal insufficiency. Cortisol and binding protein concentrations were evaluated in the absence and presence of dexamethasone in healthy volunteers (n = 30). Dexamethasone was used to suppress endogenous cortisol concentrations prior to and after single doses of 0.5, 2, 5 and 10 mg of Infacort ® or 20 mg of Infacort ® /hydrocortisone tablet/hydrocortisone intravenously. A plasma protein binding model was established using unbound and total cortisol concentrations, and sequentially integrated into the pharmacokinetic model. Both specific (non-linear) and non-specific (linear) protein binding were included in the cortisol binding model. A two-compartment disposition model with saturable absorption and constant endogenous cortisol baseline (Baseline cort ,15.5 nmol/L) described the data accurately. The predicted cortisol exposure for a given dose varied considerably within a small body weight range in individuals weighing cortisol exposure indicated the importance of defining an accurate hydrocortisone dose to mimic physiological concentrations for neonates and infants weighing <20 kg. EudraCT number: 2013-000260-28, 2013-000259-42.

  13. Effect of N-methyl deuteration on metabolism and pharmacokinetics of enzalutamide

    Directory of Open Access Journals (Sweden)

    Jiang J

    2016-07-01

    /KD value of ~2. The maximum observed plasma concentration, Cmax, and area under the plasma concentration -time curve from time zero to the last measurable sampling time point (AUC0–t were 35% and 102% higher than those of ENT when orally administered to rats (10 mg/kg. The exposure of the N-demethyl metabolite M2 was eightfold lower, whereas that of the amide hydrolysis metabolite M1 and other minor metabolites was unchanged. The observed hydrolysis rate of M2 was at least ten times higher than that of ENT and d3-ENT in rat plasma.Conclusion: ENT was mainly metabolized through the “parent→M2→M1” pathway based on in vitro and in vivo elimination behavior. The observed in vitro deuterium isotope effect translated into increased exposure of the deuterated analog in rats. Once the carbon–hydrogen was replaced with carbon–deuterium (C–D bonds, the major metabolic pathway was retarded because of the relatively stable C–D bonds. The systemic exposure to d3-ENT can increase in humans, so the dose requirements can be reduced appropriately. Keywords: enzalutamide, N-methyl deuteration, deuterium kinetic isotope effect, pharmacokinetics

  14. Metabolite cross-feeding enhances virulence in a model polymicrobial infection.

    Directory of Open Access Journals (Sweden)

    Matthew M Ramsey

    2011-03-01

    Full Text Available Microbes within polymicrobial infections often display synergistic interactions resulting in enhanced pathogenesis; however, the molecular mechanisms governing these interactions are not well understood. Development of model systems that allow detailed mechanistic studies of polymicrobial synergy is a critical step towards a comprehensive understanding of these infections in vivo. In this study, we used a model polymicrobial infection including the opportunistic pathogen Aggregatibacter actinomycetemcomitans and the commensal Streptococcus gordonii to examine the importance of metabolite cross-feeding for establishing co-culture infections. Our results reveal that co-culture with S. gordonii enhances the pathogenesis of A. actinomycetemcomitans in a murine abscess model of infection. Interestingly, the ability of A. actinomycetemcomitans to utilize L-lactate as an energy source is essential for these co-culture benefits. Surprisingly, inactivation of L-lactate catabolism had no impact on mono-culture growth in vitro and in vivo suggesting that A. actinomycetemcomitans L-lactate catabolism is only critical for establishing co-culture infections. These results demonstrate that metabolite cross-feeding is critical for A. actinomycetemcomitans to persist in a polymicrobial infection with S. gordonii supporting the idea that the metabolic properties of commensal bacteria alter the course of pathogenesis in polymicrobial communities.

  15. Utilizing relative potency factors (RPF) and threshold of toxicological concern (TTC) concepts to assess hazard and human risk assessment profiles of environmental metabolites: a case study.

    Science.gov (United States)

    Terry, C; Rasoulpour, R J; Knowles, S; Billington, R

    2015-03-01

    There is currently no standard paradigm for hazard and human risk assessment of environmental metabolites for agrochemicals. Using an actual case study, solutions to challenges faced are described and used to propose a generic concept to address risk posed by metabolites to human safety. A novel approach - built on the foundation of predicted human exposures to metabolites in various compartments (such as food and water), the threshold of toxicological concern (TTC) and the concept of comparative toxicity - was developed for environmental metabolites of a new chemical, sulfoxaflor (X11422208). The ultimate aim was to address the human safety of the metabolites with the minimum number of in vivo studies, while at the same time, ensuring that human safety would be considered addressed on a global regulatory scale. The third component, comparative toxicity, was primarily designed to determine whether the metabolites had the same or similar toxicity profiles to their parent molecule, and also to one another. The ultimate goal was to establish whether the metabolites had the potential to cause key effects - such as cancer and developmental toxicity, based on mode-of-action (MoA) studies - and to develop a relative potency factor (RPF) compared to the parent molecule. Collectively, the work presented here describes the toxicology programme developed for sulfoxaflor and its metabolites, and how it might be used to address similar future challenges aimed at determining the relevance of the metabolites from a human hazard and risk perspective. Sulfoxaflor produced eight environmental metabolites at varying concentrations in various compartments - soil, water, crops and livestock. The MoA for the primary effects of the parent molecule were elucidated in detail and a series of in silico, in vitro, and/or in vivo experiments were conducted on the environmental metabolites to assess relative potency of their toxicity profiles when compared to the parent. The primary metabolite

  16. Dermal pharmacokinetics of microemulsion formulations determined by in vivo microdialysis

    DEFF Research Database (Denmark)

    Kreilgaard, Mads

    2001-01-01

    To investigate the potential of improving dermal drug delivery of hydrophilic and lipophilic substances by formulation in microemulsion vehicles and to establish a reliable pharmacokinetic model to analyze cutaneous microdialysis data.......To investigate the potential of improving dermal drug delivery of hydrophilic and lipophilic substances by formulation in microemulsion vehicles and to establish a reliable pharmacokinetic model to analyze cutaneous microdialysis data....

  17. Population Pharmacokinetics and Optimal Sampling Strategy for Model-Based Precision Dosing of Melphalan in Patients Undergoing Hematopoietic Stem Cell Transplantation.

    Science.gov (United States)

    Mizuno, Kana; Dong, Min; Fukuda, Tsuyoshi; Chandra, Sharat; Mehta, Parinda A; McConnell, Scott; Anaissie, Elias J; Vinks, Alexander A

    2018-05-01

    High-dose melphalan is an important component of conditioning regimens for patients undergoing hematopoietic stem cell transplantation. The current dosing strategy based on body surface area results in a high incidence of oral mucositis and gastrointestinal and liver toxicity. Pharmacokinetically guided dosing will individualize exposure and help minimize overexposure-related toxicity. The purpose of this study was to develop a population pharmacokinetic model and optimal sampling strategy. A population pharmacokinetic model was developed with NONMEM using 98 observations collected from 15 adult patients given the standard dose of 140 or 200 mg/m 2 by intravenous infusion. The determinant-optimal sampling strategy was explored with PopED software. Individual area under the curve estimates were generated by Bayesian estimation using full and the proposed sparse sampling data. The predictive performance of the optimal sampling strategy was evaluated based on bias and precision estimates. The feasibility of the optimal sampling strategy was tested using pharmacokinetic data from five pediatric patients. A two-compartment model best described the data. The final model included body weight and creatinine clearance as predictors of clearance. The determinant-optimal sampling strategies (and windows) were identified at 0.08 (0.08-0.19), 0.61 (0.33-0.90), 2.0 (1.3-2.7), and 4.0 (3.6-4.0) h post-infusion. An excellent correlation was observed between area under the curve estimates obtained with the full and the proposed four-sample strategy (R 2  = 0.98; p strategy promises to achieve the target area under the curve as part of precision dosing.

  18. Parental monitoring, parental warmth, and minority youths' academic outcomes: exploring the integrative model of parenting.

    Science.gov (United States)

    Lowe, Katie; Dotterer, Aryn M

    2013-09-01

    Guided by the integrative model of parenting, the present study investigated the relationship between parental monitoring and racial/ethnic minority adolescents' school engagement and academic motivation as a function of parental warmth, and explored whether these associations varied for boys and girls. Participants (60 % female) were 208 sixth through eighth grade students (63 % African American, 19 % Latino, 18 % Multiracial) from an urban middle school in the Midwestern United States. Youth completed an in-school survey with items on parenting (parental monitoring, mothers'/fathers' warmth), cognitive engagement (school self-esteem), behavioral engagement (school trouble), and academic motivation (intrinsic motivation). As hypothesized, mothers' warmth enhanced the association between parental monitoring and youths' engagement and motivation. No gender differences in these associations emerged. Fathers' warmth strengthened the negative association between parental monitoring and school trouble, and this association was stronger for boys. Implications regarding the importance of sustaining a high level of monitoring within the context of warm parent-adolescent relationships to best support academic outcomes among minority youth are discussed.

  19. Antagonism of presynaptic dopamine receptors by phenothiazine drug metabolites

    International Nuclear Information System (INIS)

    Nowak, J.Z.; Arbilla, S.; Langer, S.Z.; Dahl, S.G.

    1990-01-01

    Electrically evoked release of dopamine from the caudate nucleus is reduced by the dopamine receptor agonists, apomorphine and bromocriptine, and facilitated by neuroleptic drugs, which act as dopamine autoreceptor antagonists. The potencies of chlorpromazine, fluphenazine, levomepromazine and their hydroxy-metabolites in modulating electrically evoked release of dopamine were examined by superfusion of rabbit caudate nucleus slices pre-incubated with 3 H-dopamine. O-Desmethyl levomepromazine, 3-hydroxy- and 7-hydroxy metabolites of chlorpromazine and levomepromazine facilitated electrically evoked release of 3 H-dopamine, having potencies similar to that of the parent compounds. 7-Hydroxy fluphenazine was less active than fluphenazine in this system. These results indicate that phenolic metabolites of chlorpromazine and levomepromazine, but not of fluphenazine, may contribute to effects of the drugs mediated by presynaptic dopamine receptors

  20. Myotoxicity of Gemfibrozil in Cynomolgus Monkey Model and Its Relationship to Pharmacokinetic Properties

    Science.gov (United States)

    Liu, Aiming; Xie, Shuilin; Sun, He; Gonzalez, Frank J.; Wei, Xiaoxiong; Dai, Renke

    2008-01-01

    Fibrate drugs are PPARα agonists prescribed for the treatment of dyslipidemia. Severe myotoxicity has been reported associated with their use albeit at a low frequency, especially for gemfibrozil. Few studies have investigated the mechanism of fibrate-induced myotoxicity in vivo. Considering the apparent species-related differences in PPARα agonist-induced hepatotoxicity, we studied the myotoxicity of gemfibrozil in a Cynomolgus monkey model and explored the relationship between myotoxicity and pharmacokinetics. Six Cynomolgus monkeys were dosed with gemfibrozil twice daily at 600 mg/kg/day for the first two periods (P1 and P2, 8 days and 9 days respectively) and 300 mg/kg/day for the third period (P3, 14 days). Creatine kinase and myoglobin were measured, together with hepatotoxicity and nephrotoxicity markers. Behavioral responses were recorded for indication of toxicity. Pharmacokinetics was carried out following the 16th dosage of P1 and 17th dosage of P2 when myotoxicity was identified. Multivariable data analysis was employed to explore the relationship between pharmacokinetic parameters and myotoxicity markers. Consequently, myotoxicity occurred in monkey #2 (M2) and M6 in P1, M3 and M4 in P2, M3 and M6 in P3. Data analysis showed T80-150 (sustained time above the given concentration) contributed for myotoxicity discriminance and correlated with myotoxicity risk. This study revealed Cynomolgus monkey may be a good animal model for myotoxicity evaluation with sensitivity, reproducibility and similarities to humans. More interestingly they exhibited a much higher incidence of myotoxicity than that of human. Sustained high drug concentration plays an important role for the occurrence of myotoxicity. This may suggest an influence of drug transport and metabolism on myotoxicity. PMID:19150455

  1. Myotoxicity of gemfibrozil in Cynomolgus monkey model and its relationship to pharmacokinetic properties

    International Nuclear Information System (INIS)

    Liu Aiming; Xie Shuilin; Sun He; Gonzalez, Frank J.; Wei Xiaoxiong; Dai Renke

    2009-01-01

    Fibrate drugs are PPARα agonists prescribed for the treatment of dyslipidemia. Severe myotoxicity has been reportedly associated with their use albeit at a low frequency, especially for gemfibrozil. Few studies have investigated the mechanism of fibrate-induced myotoxicity in vivo. Considering the apparent species-related differences in PPARα agonist-induced hepatotoxicity, we studied the myotoxicity of gemfibrozil in a Cynomolgus monkey model and explored the relationship between myotoxicity and pharmacokinetics. Six Cynomolgus monkeys were dosed with gemfibrozil twice daily at 600 mg/kg/day for the first two periods (P1 and P2, 8 days and 9 days respectively) and 300 mg/kg/day for the third period (P3, 14 days). Creatine kinase and myoglobin were measured, together with hepatotoxicity and nephrotoxicity markers. Behavioral responses were recorded for indication of toxicity. Pharmacokinetics was carried out following the 16th dosage of P1 and 17th dosage of P2 when myotoxicity was identified. Multivariable data analysis was employed to explore the relationship between pharmacokinetic parameters and myotoxicity markers. Consequently, myotoxicity occurred in monkey no. 2 (M2) and M6 in P1, M3 and M4 in P2, M3 and M6 in P3. Data analysis showed T80-150 (sustained time above the given concentration) contributed for myotoxicity discriminance and correlated with myotoxicity risk. This study revealed Cynomolgus monkey may be a good animal model for myotoxicity evaluation with sensitivity, reproducibility and similarities to humans. More interestingly, they exhibited a much higher incidence of myotoxicity than that of humans. Sustained high drug concentration plays an important role for the occurrence of myotoxicity. This may suggest an influence of drug transport and metabolism on myotoxicity

  2. Myotoxicity of gemfibrozil in Cynomolgus monkey model and its relationship to pharmacokinetic properties

    Energy Technology Data Exchange (ETDEWEB)

    Aiming, Liu; Shuilin, Xie [Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510663 (China); He, Sun [School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072 (China); Gonzalez, Frank J [National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (United States); Xiaoxiong, Wei [Medpace, Inc., Cincinnati, OH 45212 (United States); Dai Renke [Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510663 (China)], E-mail: dai_renke@gibh.ac.cn

    2009-03-15

    Fibrate drugs are PPAR{alpha} agonists prescribed for the treatment of dyslipidemia. Severe myotoxicity has been reportedly associated with their use albeit at a low frequency, especially for gemfibrozil. Few studies have investigated the mechanism of fibrate-induced myotoxicity in vivo. Considering the apparent species-related differences in PPAR{alpha} agonist-induced hepatotoxicity, we studied the myotoxicity of gemfibrozil in a Cynomolgus monkey model and explored the relationship between myotoxicity and pharmacokinetics. Six Cynomolgus monkeys were dosed with gemfibrozil twice daily at 600 mg/kg/day for the first two periods (P1 and P2, 8 days and 9 days respectively) and 300 mg/kg/day for the third period (P3, 14 days). Creatine kinase and myoglobin were measured, together with hepatotoxicity and nephrotoxicity markers. Behavioral responses were recorded for indication of toxicity. Pharmacokinetics was carried out following the 16th dosage of P1 and 17th dosage of P2 when myotoxicity was identified. Multivariable data analysis was employed to explore the relationship between pharmacokinetic parameters and myotoxicity markers. Consequently, myotoxicity occurred in monkey no. 2 (M2) and M6 in P1, M3 and M4 in P2, M3 and M6 in P3. Data analysis showed T80-150 (sustained time above the given concentration) contributed for myotoxicity discriminance and correlated with myotoxicity risk. This study revealed Cynomolgus monkey may be a good animal model for myotoxicity evaluation with sensitivity, reproducibility and similarities to humans. More interestingly, they exhibited a much higher incidence of myotoxicity than that of humans. Sustained high drug concentration plays an important role for the occurrence of myotoxicity. This may suggest an influence of drug transport and metabolism on myotoxicity.

  3. Pharmacokinetics: curiosity or cure

    International Nuclear Information System (INIS)

    Notari, R.E.

    1979-01-01

    What is the fate of a drug from the time of its introduction into the body to the end of its duration. Pharmacokinetic studies are often designed to provide an answer to this question. But this question may be asked of any drug and research that is limited to answering it will remain empirical. Pharmacokinetic studies can provide answers to many other drug-related questions. In doing so pharmacokinetic research has the potential of improving drug therapy as well as the design and evaluation of drugs. While significant contributions can be cited, the future of pharmacokinetics depends upon its increased impact on clinical practice and drug design. How can a molecule be tailored for site specificity. Can chemical modification selectively alter absorption, distribution, metabolism, binding or excretion. In what new ways can pharmacokinetic information increase the predictability of drug therapy. Such questions, to which pharmacokinetics should provide answers, are numerous and easily identified. But the definitive studies are difficult both to create and conduct. Whether or not pharmacokinetics can achieve its full potential will depend upon the extent to which it can provide answers to these currently unanswered questions

  4. Medicinal cannabis does not influence the clinical pharmacokinetics of irinotecan and docetaxel.

    Science.gov (United States)

    Engels, Frederike K; de Jong, Floris A; Sparreboom, Alex; Mathot, Ron A A; Loos, Walter J; Kitzen, Jos J E M; de Bruijn, Peter; Verweij, Jaap; Mathijssen, Ron H J

    2007-03-01

    To date, data regarding the potential of cannabinoids to modulate cytochrome P450 isozyme 3A (CYP3A) activity are contradictory. Recently, a standardized medicinal cannabis product was introduced in The Netherlands. We anticipated an increased use of medicinal cannabis concurrent with anticancer drugs, and undertook a drug-interaction study to evaluate the effect of concomitant medicinal cannabis on the pharmacokinetics of irinotecan and docetaxel, both subject to CYP3A-mediated biotransformation. Twenty-four cancer patients were treated with i.v. irinotecan (600 mg, n = 12) or docetaxel (180 mg, n = 12), followed 3 weeks later by the same drugs concomitant with medicinal cannabis (200 ml herbal tea, 1 g/l) for 15 consecutive days, starting 12 days before the second treatment. Blood samples were obtained up to 55 hours after dosing and analyzed for irinotecan and its metabolites (SN-38, SN-38G), respectively, or docetaxel. Pharmacokinetic analyses were performed during both treatments. Results are reported as the mean ratio (95% confidence interval [CI]) of the observed pharmacokinetic parameters with and without concomitant medicinal cannabis. Medicinal cannabis administration did not significantly influence exposure to and clearance of irinotecan (1.04; CI, 0.96-1.11 and 0.97; CI, 0.90-1.05, respectively) or docetaxel (1.11; CI, 0.94-1.28 and 0.95; CI, 0.82-1.08, respectively). Coadministration of medicinal cannabis, as herbal tea, in cancer patients treated with irinotecan or docetaxel does not significantly influence the plasma pharmacokinetics of these drugs. The evaluated variety of medicinal cannabis can be administered concomitantly with both anticancer agents without dose adjustments.

  5. The Pharmacokinetics of Enrofloxacin in Adult African Clawed Frogs (Xenopus laevis)

    Science.gov (United States)

    Howard, Antwain M; Papich, Mark G; Felt, Stephen A; Long, Charles T; McKeon, Gabriel P; Bond, Emmitt S; Torreilles, Stéphanie L; Luong, Richard H; Green, Sherril L

    2010-01-01

    Pharmacokinetics of enrofloxacin, a fluoroquinolone antibiotic, was determined in adult female Xenopus laevis after single-dose administration (10 mg/kg) by intramuscular or subcutaneous injection. Frogs were evaluated at various time points until 8 h after injection. Plasma was analyzed for antibiotic concentration levels by HPLC. We computed pharmacokinetic parameters by using noncompartmental analysis of the pooled concentrations (naive pooled samples). After intramuscular administration of enrofloxacin, the half-life was 5.32 h, concentration maximum was 10.85 µg/mL, distribution volume was 841.96 mL/kg, and area under the time–concentration curve was 57.59 µg×h/mL; after subcutaneous administration these parameters were 4.08 h, 9.76 µg/mL, 915.85 mL/kg, and 47.42 µg×h/mL, respectively. According to plasma pharmacokinetics, Xenopus seem to metabolize enrofloxacin in a manner similar to mammals: low levels of the enrofloxacin metabolite, ciprofloxacin, were detected in the frogs’ habitat water and plasma. At necropsy, there were no gross or histologic signs of toxicity after single-dose administration; toxicity was not evaluated for repeated dosing. The plasma concentrations reached levels considered effective against common aquatic pathogens and suggest that a single, once-daily dose would be a reasonable regimen to consider when treating sick frogs. The treatment of sick frogs should be based on specific microbiologic identification of the pathogen and on antibiotic susceptibility testing. PMID:21205443

  6. The Use of Physiology-Based Pharmacokinetic and Pharmacodynamic Modeling in the Discovery of the Dual Orexin Receptor Antagonist ACT-541468.

    Science.gov (United States)

    Treiber, Alexander; de Kanter, Ruben; Roch, Catherine; Gatfield, John; Boss, Christoph; von Raumer, Markus; Schindelholz, Benno; Muehlan, Clemens; van Gerven, Joop; Jenck, Francois

    2017-09-01

    The identification of new sleep drugs poses particular challenges in drug discovery owing to disease-specific requirements such as rapid onset of action, sleep maintenance throughout major parts of the night, and absence of residual next-day effects. Robust tools to estimate drug levels in human brain are therefore key for a successful discovery program. Animal models constitute an appropriate choice for drugs without species differences in receptor pharmacology or pharmacokinetics. Translation to man becomes more challenging when interspecies differences are prominent. This report describes the discovery of the dual orexin receptor 1 and 2 (OX 1 and OX 2 ) antagonist ACT-541468 out of a class of structurally related compounds, by use of physiology-based pharmacokinetic and pharmacodynamic (PBPK-PD) modeling applied early in drug discovery. Although all drug candidates exhibited similar target receptor potencies and efficacy in a rat sleep model, they exhibited large interspecies differences in key factors determining their pharmacokinetic profile. Human PK models were built on the basis of in vitro metabolism and physicochemical data and were then used to predict the time course of OX 2 receptor occupancy in brain. An active ACT-541468 dose of 25 mg was estimated on the basis of OX 2 receptor occupancy thresholds of about 65% derived from clinical data for two other orexin antagonists, almorexant and suvorexant. Modeling predictions for ACT-541468 in man were largely confirmed in a single-ascending dose trial in healthy subjects. PBPK-PD modeling applied early in drug discovery, therefore, has great potential to assist in the identification of drug molecules when specific pharmacokinetic and pharmacodynamic requirements need to be met. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  7. Effects of andrographolide on the pharmacokinetics of aminophylline and doxofylline in rats.

    Science.gov (United States)

    Li, X P; Zhang, C L; Gao, P; Gao, J; Liu, D

    2013-05-01

    Andrographolide, which is one of the main pharmaceutical ingredients in traditional Chinese medicine Andrographis paniculata, can clear heat, detoxify human body, cool blood and reduce swelling, etc. Respiratory tract infectious diseases have been treated with the combination of andrographolide and theophyllines clinically. As andrographolide inhibits the CYP1A2 activity in vitro, it potentially interacts with theophyllines that are mainly metabolized by CYP1A2. Therefore, we herein studied the effects of andrographolide on the pharmacokinetics of aminophylline and doxofylline in rats. The blood drug concentrations of aminophylline, doxofylline and its metabolite theophylline were determined by HPLC. The theophylline AUC(0-t) was significantly elevated confronting the combination of andrographolide and aminophylline compared to that of the control group (Pandrographolide. The results suggest that andrographolide and aminophylline should not be simultaneously administered because the former may raise the risks of side effects by inhibiting the clearance of the latter. In contrast, it is more secure to combine doxofylline with andrographolide owing to the almost intact pharmacokinetics. © Georg Thieme Verlag KG Stuttgart · New York.

  8. The Parental Environment Cluster Model of Child Neglect: An Integrative Conceptual Model.

    Science.gov (United States)

    Burke, Judith; Chandy, Joseph; Dannerbeck, Anne; Watt, J. Wilson

    1998-01-01

    Presents Parental Environment Cluster model of child neglect which identifies three clusters of factors involved in parents' neglectful behavior: (1) parenting skills and functions; (2) development and use of positive social support; and (3) resource availability and management skills. Model offers a focal theory for research, structure for…

  9. Analysis of fenretinide and its metabolites in human plasma by liquid chromatography-tandem mass spectrometry and its application to clinical pharmacokinetics.

    Science.gov (United States)

    Cho, Hwang Eui; Min, H Kang

    2017-01-05

    A simple and accurate high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the determination of N-(4-hydroxyphenyl)retinamide (fenretinide, 4-HPR) and its metabolites, 4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR) and N-(4-methoxyphenyl)retinamide (4-MPR), in human plasma. Plasma samples were prepared using protein precipitation with ethanol. Chromatographic separation of the three analytes and N-(4-ethoxyphenyl)retinamide (4-EPR), an internal standard, was achieved on a Zorbax SB-C18 column (3.5μm, 50×2.1mm) using gradient elution with the mobile phase of 0.1% formic acid in water and acetonitrile (pH* 2.4) at a flow rate of 0.5mL/min. Electrospray ionization (ESI) mass spectrometry was operated in the positive ion mode with multiple reaction monitoring (MRM). The calibration curves obtained were linear over the concentration range of 0.2-50ng/mL with a lower limit of quantification of 0.2ng/mL. The relative standard deviation of intra-day and inter-day precision was below 7.64%, and the accuracy ranged from 94.92 to 105.43%. The extraction recoveries were found to be higher than 90.39% and no matrix effect was observed. The analytes were stable for the durations of the stability studies. The validated method was successfully applied to the analyses of the pharmacokinetic study for patients treated with 4-HPR in a clinical trial. Copyright © 2016 Elsevier B.V. All rights reserved.

  10. Individualized Hydrocodone Therapy Based on Phenotype, Pharmacogenetics, and Pharmacokinetic Dosing.

    Science.gov (United States)

    Linares, Oscar A; Fudin, Jeffrey; Daly, Annemarie L; Boston, Raymond C

    2015-12-01

    (1) To quantify hydrocodone (HC) and hydromorphone (HM) metabolite pharmacokinetics with pharmacogenetics in CYP2D6 ultra-rapid metabolizer (UM), extensive metabolizer (EM), and poor metabolizer (PM) metabolizer phenotypes. (2) To develop an HC phenotype-specific dosing strategy for HC that accounts for HM production using clinical pharmacokinetics integrated with pharmacogenetics for patient safety. In silico clinical trial simulation. Healthy white men and women without comorbidities or history of opioid, or any other drug or nutraceutical use, age 26.3±5.7 years (mean±SD; range, 19 to 36 y) and weight 71.9±16.8 kg (range, 50 to 108 kg). CYP2D6 phenotype-specific HC clinical pharmacokinetic parameter estimates and phenotype-specific percentages of HM formed from HC. PMs had lower indices of HC disposition compared with UMs and EMs. Clearance was reduced by nearly 60% and the t1/2 was increased by about 68% compared with EMs. The canonical order for HC clearance was UM>EM>PM. HC elimination mainly by the liver, represented by ke, was reduced about 70% in PM. However, HC's apparent Vd was not significantly different among UMs, EMs, and PM. The canonical order of predicted plasma HM concentrations was UM>EM>PM. For each of the CYP2D6 phenotypes, the mean predicted HM levels were within HM's therapeutic range, which indicates HC has significant phenotype-dependent pro-drug effects. Our results demonstrate that pharmacogenetics afford clinicians an opportunity to individualize HC dosing, while adding enhanced opportunity to account for its conversion to HM in the body.

  11. Development Parenting Model to Increase the Independence of Children

    Science.gov (United States)

    Sunarty, Kustiah; Dirawan, Gufran Darma

    2015-01-01

    This study examines parenting and the child's independence model. The research problem is whether there is a relationship between parenting and the child's independence. The purpose of research is to determine: firstly, the type of parenting in an effort to increase the independence of the child; and the relationship between parenting models and…

  12. Pharmacokinetics of Botanical Drugs and Plant Extracts.

    Science.gov (United States)

    Dominguez More, Gina Paola; Cardenas, Paola Andrea; Costa, Geison M; Simoes, Claudia M O; Aragon, Diana Marcela

    2017-01-01

    Botanical drugs contain plant extracts, which are complex mixtures of compounds. As with conventional drugs, it is necessary to validate their efficacy and safety through preclinical and clinical studies. However, pharmacokinetic studies for active constituents or characteristic markers in botanical drugs are rare. The objective of this review was to investigate the global state of the art in pharmacokinetic studies of active ingredients present in plant extracts and botanical drugs. A review of pharmacokinetics studies of chemical constituents of plant extracts and botanical drugs was performed, with a total of 135 studies published between January 2004 and February 2015 available in recognized scientific databases. Botanical preparations were mainly found in the form of aqueous extracts of roots and rhizomes. The most widely studied species was Salvia miltiorrhiza Bunge, and the compound most frequently used as a pharmacokinetic marker was berberine. Most studies were performed using the Sprague Dawley rat model, and the preparations were mainly administered orally in a single dose. Quantification of plasma concentrations of pharmacokinetic markers was performed mainly by liquid-liquid extraction, followed by high performance liquid chromatography coupled to mass spectrometry detector. In conclusion, in recent years there has been an increasing interest among researchers worldwide in the study of pharmacokinetics of bioactive compounds in botanical drugs and plant extracts, especially those from the Traditional Chinese Medicine. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  13. Identification of ionic chloroacetanilide-herbicide metabolites in surface water and groundwater by HPLC/MS using negative ion spray

    Science.gov (United States)

    Ferrer, I.; Thurman, E.M.; Barcelo, D.

    1997-01-01

    Solid-phase extraction (SPE) was combined with high-performance liquid chromatography/high-flow pneumatically assisted electrospray mass spectrometry (HPLC/ESP/MS) for the trace analysis of oxanilic and sulfonic acids of acetochlor, alachlor, and metolachlor. The isolation procedure separated the chloroacetanilide metabolites from the parent herbicides during the elution from C18 cartridges using ethyl acetate for parent compounds, followed by methanol for the anionic metabolites. The metabolites were separated chromatographically using reversed-phase HPLC and analyzed by negative-ion MS using electrospray ionization in selected ion mode. Quantitation limits were 0.01 ??g/L for both the oxanilic and sulfonic acids based on a 100-mL water sample. This combination of methods represents an important advance in environmental analysis of chloroacetanilide-herbicide metabolites in surface water and groundwater for two reasons. First, anionic chloroacetanilide metabolites are a major class of degradation products that are readily leached to groundwater in agricultural areas. Second, anionic metabolites, which are not able to be analyzed by conventional methods such as liquid extraction and gas chromatography/mass spectrometry, are effectively analyzed by SPE and high-flow pneumatically assisted electrospray mass spectrometry. This paper reports the first HPLC/MS identification of these metabolites in surface water and groundwater.

  14. Limitations of Single Slice Dynamic Contrast Enhanced MR in Pharmacokinetic Modeling of Bone Sarcomas

    Energy Technology Data Exchange (ETDEWEB)

    Toms, Andoni P. (Dept. of Radiology, The Norfolk and Norwich Univ. Hospital, Norwich, Norfolk (United Kingdom)); White, Lawrence M.; Bleakney, Robert R. (Dept. of Medical Imaging, Mount Sinai Hospital, Toronto, ON (Canada)); Kandel, Rita (Dept. of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON (Canada)); Noseworthy, Michael (Health Sciences Centre, Faculty of Health Sciences, McMaster Univ., Hamilton, ON (Canada)); Lee, Shepstone (Institute of Health, Univ. of East Anglia, Norwich, Norfolk (United Kingdom)); Blackstein, Martin E. (Dept. of Oncology, Mount Sinai Hospital, Toronto, ON (Canada)); Wunder, Jay (Musculoskeletal Oncology Unit, Mount Sinai Hospital, Toronto, ON (Canada))

    2009-06-15

    Background: Single slice dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) appears to provide perfusion data about sarcomas in vivo that correlate with tumor necrosis on equivalent pathological sections. However, sarcomas are heterogeneous and therefore single slice DCE-MRI may not correlate with total tumor necrosis. Purpose: To determine whether changes in pharmacokinetic modeling of DCE-MRI, during chemotherapy for primary bone sarcomas correlated with histological measures of total tumor necrosis. Material and Methods: Twelve patients with appendicular primary bone sarcomas were included in the study. Each patient had DCE-MRI before, and after completion, of pre-operative chemotherapy. The mean arterial slope (A), endothelial permeability coefficient (Ktrans), and extravascular extracellular volume (Ve) were derived from each data set using a modified two compartment pharmacokinetic model. Total tumor necrosis rates were compared with changes in A, Ktrans, and Ve. Results: Six patients had total tumor necrosis of =90% and six had a measure of <90%. The median percentage changes in A, Ktrans, and Ve for the =90% necrosis group were -52.5% (-83 to 6), -66% (-82 to 26), and 23.5% (-26 to 40), respectively. For the <90% necrosis group, A = - 35% (-75 to 132), Ktrans= - 53 (-66 to 149) and Ve= - 14.5% (-42 to 40). One patient with >90% necrosis had increases in all three measures. Comparison of the two groups generated P-values of 0.699 for A, 0.18 for Ktrans, and 0.31 for Ve. Conclusion: There was no statistically significant correlation between changes in pharmacokinetic perfusion parameters and total tumor necrosis. When using single slice DCE-MRI heterogeneous histology of primary bone sarcomas and repair mediated angiogenesis might both be confounding factors

  15. Integrated identification, qualification and quantification strategy for pharmacokinetic profile study of Guizhi Fuling capsule in healthy volunteers

    OpenAIRE

    Yun-Xi Zhong; Xiao-Liang Jin; Shi-Yin Gu; Ying Peng; Ke-Rong Zhang; Bing-Chen Ou-Yang; Yu Wang; Wei Xiao; Zhen-Zhong Wang; Ji-Ye Aa; Guang-Ji Wang; Jian-Guo Sun

    2016-01-01

    Guizhi Fuling capsule (GZFL), a traditional Chinese medicine formulation, is widely used in China to relieve pain from dysmenorrhea and is now in a Phase II clinical trial in the USA. Due to the low exposure of the five main medicative ingredients (amygdalin, cinnamic acid, gallic acid, paeoniflorin and paeonol) of GZFL in human, a strategy was built to qualitatively and quantitatively identify the possible metabolites of GZFL and to describe the pharmacokinetic profiles of GZFL in human. In ...

  16. Plasma metabolite score correlates with Hypoxia time in a newly born piglet model for asphyxia

    Directory of Open Access Journals (Sweden)

    Julia Kuligowski

    2017-08-01

    Full Text Available Hypoxic-ischemic encephalopathy (HIE secondary to perinatal asphyxia is a leading cause of mortality and acquired long-term neurologic co-morbidities in the neonate. The most successful intervention for the treatment of moderate to severe HIE is moderate whole body hypothermia initiated within 6 h from birth. The objective and prompt identification of infants who are at risk of developing moderate to severe HIE in the critical first hours still remains a challenge. This work proposes a metabolite score calculated based on the relative intensities of three metabolites (choline, 6,8-dihydroxypurine and hypoxanthine that showed maximum correlation with hypoxia time in a consolidated piglet model for neonatal hypoxia-ischemia. The metabolite score's performance as a biomarker for perinatal hypoxia and its usefulness for clinical grading and decision making have been assessed and compared to the performance of lactate which is currently considered the gold standard. For plasma samples withdrawn before and directly after a hypoxic insult, the metabolite score performed similar to lactate. However, it provided an enhanced predictive capacity at 2 h after resuscitation. The present study evidences the usefulness of the metabolite score for improving the early assessment of the severity of the hypoxic insult based on serial determinations in a minimally invasive biofluid. The applicability of the metabolite score for clinical diagnosis and patient stratification for hypothermia treatment has to be confirmed in multicenter trials involving newborns suffering from HIE. Keywords: Hypoxia, Perinatal asphyxia, Newborn, Metabolic biomarker, Neonatal piglet model, Liquid Chromatography – Time-of-Flight Mass Spectrometry (LC-TOF-MS

  17. Examining a conceptual model of parental nurturance, parenting practices and physical activity among 5-6 year olds.

    Science.gov (United States)

    Sebire, Simon J; Jago, Russell; Wood, Lesley; Thompson, Janice L; Zahra, Jezmond; Lawlor, Deborah A

    2016-01-01

    Parenting is an often-studied correlate of children's physical activity, however there is little research examining the associations between parenting styles, practices and the physical activity of younger children. This study aimed to investigate whether physical activity-based parenting practices mediate the association between parenting styles and 5-6 year-old children's objectively-assessed physical activity. 770 parents self-reported parenting style (nurturance and control) and physical activity-based parenting practices (logistic and modeling support). Their 5-6 year old child wore an accelerometer for five days to measure moderate-to-vigorous physical activity (MVPA). Linear regression was used to examine direct and indirect (mediation) associations. Data were collected in the United Kingdom in 2012/13 and analyzed in 2014. Parent nurturance was positively associated with provision of modeling (adjusted unstandardized coefficient, β = 0.11; 95% CI = 0.02, 0.21) and logistic support (β = 0.14; 0.07, 0.21). Modeling support was associated with greater child MVPA (β = 2.41; 0.23, 4.60) and a small indirect path from parent nurturance to child's MVPA was identified (β = 0.27; 0.04, 0.70). Physical activity-based parenting practices are more strongly associated with 5-6 year old children's MVPA than parenting styles. Further research examining conceptual models of parenting is needed to understand in more depth the possible antecedents to adaptive parenting practices beyond parenting styles. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  18. Prediction of Deoxypodophyllotoxin Disposition in Mouse, Rat, Monkey and Dog by Physiologically-based Pharmacokinetic Model and the Extrapolation to Human

    Directory of Open Access Journals (Sweden)

    Yang Chen

    2016-12-01

    Full Text Available Deoxypodophyllotoxin (DPT is a potential anti-tumor candidate prior to its clinical phase. The aim of the study was to develop a physiologically-based pharmacokinetic (PBPK model consisting of 13 tissue compartments to predict DPT disposition in mouse, rat, monkey and dog based on in vitro and in silico inputs. Since large interspecies difference was found in unbound fraction of DPT in plasma, we assumed that Kt:pl,u (unbound tissue-to-plasma concentration ratio was identical across species. The predictions of our model were then validated by in vivo data of corresponding preclinical species, along with visual predictive checks. Reasonable matches were found between observed and predicted plasma concentrations and pharmacokinetic parameters in all four animal species. The prediction in the related seven tissues of mouse was also desirable. We also attempted to predict human pharmacokinetic profile by both the developed PBPK model and interspecies allometric scaling across mouse, rat and monkey, while dog was excluded from the scaling. The two approaches reached similar results. We hope the study will help in the efficacy and safety assessment of DPT in future clinical studies and provide a reference to the preclinical screening of similar compounds by PBPK model.

  19. A physiologically based pharmacokinetic (PB/PK) model for multiple exposure routes for soman in multiple species

    NARCIS (Netherlands)

    Sweeney, R.E.; Langenberg, J.P.; Maxwell, D.M.

    2006-01-01

    A physiologically based pharmacokinetic (PB/PK) model has been developed in advanced computer simulation language (ACSL) to describe blood and tissue concentration-time profiles of the C(±)P(-) stereoisomers of soman after inhalation, subcutaneous and intravenous exposures at low (0.8-1.0 × LD50),

  20. General unknown screening procedure for the characterization of human drug metabolites in forensic toxicology: applications and constraints.

    Science.gov (United States)

    Sauvage, François-Ludovic; Picard, Nicolas; Saint-Marcoux, Franck; Gaulier, Jean-Michel; Lachâtre, Gérard; Marquet, Pierre

    2009-09-01

    LC coupled to single (LC-MS) and tandem (LC-MS/MS) mass spectrometry is recognized as the most powerful analytical tools for metabolic studies in drug discovery. In this article, we describe five cases illustrating the utility of screening xenobiotic metabolites in routine analysis of forensic samples using LC-MS/MS. Analyses were performed using a previously published LC-MS/MS general unknown screening (GUS) procedure developed using a hybrid linear IT-tandem mass spectrometer. In each of the cases presented, the presence of metabolites of xenobiotics was suspected after analyzing urine samples. In two cases, the parent drug was also detected and the metabolites were merely useful to confirm drug intake, but in three other cases, metabolite detection was of actual forensic interest. The presented results indicate that: (i) the GUS procedure developed is useful to detect a large variety of drug metabolites, which would have been hardly detected using targeted methods in the context of clinical or forensic toxicology; (ii) metabolite structure can generally be inferred from their "enhanced" product ion scan spectra; and (iii) structure confirmation can be achieved through in vitro metabolic experiments or through the analysis of urine samples from individuals taking the parent drug.

  1. Simultaneous determination of 3,3',4',5,7-pentamethylquercetin and its possible metabolite 3,3',4',7-tetramethylquercetin in dog plasma by liquid chromatography-tandem mass spectrometry and its application to preclinical pharmacokinetic study.

    Science.gov (United States)

    Chen, Xiaomei; Li, Dongyan; Hu, Yan; Jin, Manwen; Zhou, Liping; Peng, Kelong; Zheng, Heng

    2011-08-01

    A sensitive, simple and rapid ultra fast liquid chromatography (UFLC)-ESI-MS/MS method was established for the simultaneous determination of 3,3',4',5,7-pentamethylquercetin (PMQ) and its possible metabolite 3,3',4',7-tetramethylquercetin (TMQ) in dog plasma using 4',5,7-trimethylapigenin (TMA) as the internal standard. The plasma sample was pretreated with acetonitrile for protein precipitation and the analytes were separated on an Ultimate XB-CN column (5 μm, 2.1 mm × 150 mm) with the mobile phase consisting of acetonitrile and water (2:1, v/v). Detection was performed on a triple-quadrupole tandem mass spectrometer under a positive multiple reaction-monitoring mode (MRM). The mass transition ion-pair was followed as m/z 373.1-312.1 for PMQ, 359.1-344.0 for TMQ and 313.1-298.1 for TMA. The validated concentration ranged from 1.272 to 3060 ng/mL for PMQ and from 10.35 to 1725 ng/mL for TMQ. The lower limit of quantifications for PMQ and TMQ were 1.272 ng/mL and 10.35 ng/mL, respectively. The developed-method was successfully applied for the pharmacokinetic study of PMQ and its metabolite TMQ in dogs following a single oral dose. Copyright © 2011 Elsevier B.V. All rights reserved.

  2. Pharmacokinetics of Chinese medicines: strategies and perspectives.

    Science.gov (United States)

    Yan, Ru; Yang, Ying; Chen, Yijia

    2018-01-01

    The modernization and internationalization of Chinese medicines (CMs) are hampered by increasing concerns on the safety and the efficacy. Pharmacokinetic (PK) study is indispensable to establish concentration-activity/toxicity relationship and facilitate target identification and new drug discovery from CMs. To cope with tremendous challenges rooted from chemical complexity of CMs, the classic PK strategies have evolved rapidly from PK study focusing on marker/main drug components to PK-PD correlation study adopting metabolomics approaches to characterize associations between disposition of global drug-related components and host metabolic network shifts. However, the majority of PK studies of CMs have adopted the approaches tailored for western medicines and focused on the systemic exposures of drug-related components, most of which were found to be too low to account for the holistic benefits of CMs. With an area under concentration-time curve- or activity-weighted approach, integral PK attempts to understand the PK-PD relevance with the integrated PK profile of multiple co-existing structural analogs (prototyes/metabolites). Cellular PK-PD complements traditional PK-PD when drug targets localize inside the cells, instead of at the surface of cell membrane or extracellular space. Considering the validated clinical benefits of CMs, reverse pharmacology-based reverse PK strategy was proposed to facilitate target identification and new drug discovery. Recently, gut microbiota have demonstrated multifaceted roles in drug efficacy/toxicity. In traditional oral intake, the presystemic interactions of CMs with gut microbiota seem inevitable, which can contribute to the holistic benefits of CMs through biotransforming CMs components, acting as the peripheral target, and regulating host drug disposition. Hence, we propose a global PK-PD approach which includes the presystemic interaction of CMs with gut microbiota and combines omics with physiologically based

  3. Modeling Substrate Utilization, Metabolite Production, and Uranium Immobilization in Shewanella oneidensis Biofilms

    Directory of Open Access Journals (Sweden)

    Ryan S. Renslow

    2017-06-01

    Full Text Available In this study, we developed a two-dimensional mathematical model to predict substrate utilization and metabolite production rates in Shewanella oneidensis MR-1 biofilm in the presence and absence of uranium (U. In our model, lactate and fumarate are used as the electron donor and the electron acceptor, respectively. The model includes the production of extracellular polymeric substances (EPS. The EPS bound to the cell surface and distributed in the biofilm were considered bound EPS (bEPS and loosely associated EPS (laEPS, respectively. COMSOL® Multiphysics finite element analysis software was used to solve the model numerically (model file provided in the Supplementary Material. The input variables of the model were the lactate, fumarate, cell, and EPS concentrations, half saturation constant for fumarate, and diffusion coefficients of the substrates and metabolites. To estimate unknown parameters and calibrate the model, we used a custom designed biofilm reactor placed inside a nuclear magnetic resonance (NMR microimaging and spectroscopy system and measured substrate utilization and metabolite production rates. From these data we estimated the yield coefficients, maximum substrate utilization rate, half saturation constant for lactate, stoichiometric ratio of fumarate and acetate to lactate and stoichiometric ratio of succinate to fumarate. These parameters are critical to predicting the activity of biofilms and are not available in the literature. Lastly, the model was used to predict uranium immobilization in S. oneidensis MR-1 biofilms by considering reduction and adsorption processes in the cells and in the EPS. We found that the majority of immobilization was due to cells, and that EPS was less efficient at immobilizing U. Furthermore, most of the immobilization occurred within the top 10 μm of the biofilm. To the best of our knowledge, this research is one of the first biofilm immobilization mathematical models based on experimental

  4. A Physiologically Based Pharmacokinetic Model for the Oxime TMB-4: Simulation of Rodent and Human Data

    Science.gov (United States)

    2013-01-13

    later, Garrigue and other colleagues (Maurizis et al. 1992) pub- lished an in vitro binding study of TMB-4 with rabbit cartilaginous tissue cultures...as well as fat, kidney, liver, rapidly perfused tissues and slowly perfused tissues . All tissue compartments are diffusion limited. Model...pharmacokinetic data from the literature. The model was parameterized using rat plasma, tissue and urine time course data from intramuscular administration, as

  5. The stability of amitriptyline N-oxide and clozapine N-oxide on treated and untreated dry blood spot cards.

    Science.gov (United States)

    Temesi, David; Swales, John; Keene, Warren; Dick, Samuel

    2013-03-25

    Procedures for drug monitoring based on Dried Blood Spot (DBS) sampling are gaining acceptance for an increasing number of clinical and preclinical applications, where ease of use, small sample requirement, and improved sample stability have been shown to offer advantages over blood tube sampling. However, to-date, the vast majority of this work has described the analysis of well characterized drugs. Using amitriptyline, clozapine, and their potentially labile N-oxide metabolites as model compounds, we consider the merits of using DBS for discovery pharmacokinetic (PK) studies where the metabolic fate of test compounds are often unknown. Both N-oxide metabolites reverted to parent compound under standard drying (2hr) and extraction conditions. Card type significantly affected the outcome, with 14% and 22% degradation occurring for clozapine-N-oxide and amitriptyline-N-oxide on a brand of untreated DBS cards, compared to 59 and 88% on a brand of treated DBS cards. Enrichment of the parent compound ex vivo leads to overestimation of circulating blood concentration and inaccurate determination of the PK profile. Copyright © 2012 Elsevier B.V. All rights reserved.

  6. The Effect of Parental Modeling on Child Pain Responses: The Role of Parent and Child Sex.

    Science.gov (United States)

    Boerner, Katelynn E; Chambers, Christine T; McGrath, Patrick J; LoLordo, Vincent; Uher, Rudolf

    2017-06-01

    Social modeling is a process by which pain behaviors are learned, and research has found parents act as models for their children's behavior. Despite social learning theory predicting that same-sex models have greater effect, no experimental investigation to date has examined the role of sex of the model or observer in social learning of pediatric pain. The present study recruited 168 parent-child dyads (equal father-son, father-daughter, mother-son, and mother-daughter dyads) in which children were generally healthy and 6 to 8 years old. Unbeknownst to their child, parents were randomly assigned to exaggerate their expression of pain, minimize their expression of pain, or act naturally during the cold pressor task (CPT). Parents completed the CPT while their child observed, then children completed the CPT themselves. Children whose parents were in the exaggerate condition reported higher anxiety than children of parents in the minimize condition. Additionally, girls in the exaggerate condition rated their overall pain intensity during the CPT significantly higher than boys in the same condition. No child sex differences were observed in pain intensity for the control or minimize conditions. Parent expressions of pain affects children's anxiety, and sex-specific effects of parental exaggerated pain expression on children's own subsequent pain experience are present. This article describes how parental expressions of pain influence children's pain and anxiety, specifically examining the relevance of parent and child sex in this process. These findings have implications for children of parents with chronic pain, or situations in which parents experience pain in the presence of their child (eg, vaccinations). Copyright © 2017 American Pain Society. Published by Elsevier Inc. All rights reserved.

  7. Development and validation of a high-performance liquid chromatography-tandem mass spectrometry method for the simultaneous determination of irinotecan and its main metabolites in human plasma and its application in a clinical pharmacokinetic study.

    Directory of Open Access Journals (Sweden)

    Elena Marangon

    Full Text Available Irinotecan is currently used in several cancer regimens mainly in colorectal cancer (CRC. This drug has a narrow therapeutic range and treatment can lead to side effects, mainly neutropenia and diarrhea, frequently requiring discontinuing or lowering the drug dose. A wide inter-individual variability in irinotecan pharmacokinetic parameters and pharmacodynamics has been reported and associated to patients' genetic background. In particular, a polymorphism in the UGT1A1 gene (UGT1A1*28 has been linked to an impaired detoxification of SN-38 (irinotecan active metabolite to SN-38 glucuronide (SN-38G leading to increased toxicities. Therefore, therapeutic drug monitoring of irinotecan, SN-38 and SN-38G is recommended to personalize therapy. In order to quantify simultaneously irinotecan and its main metabolites in patients' plasma, we developed and validated a new, sensitive and specific HPLC-MS/MS method applicable to all irinotecan dosages used in clinic. This method required a small plasma volume, addition of camptothecin as internal standard and simple protein precipitation. Chromatographic separation was done on a Gemini C18 column (3 μM, 100 mm x 2.0 mm using 0.1% acetic acid/bidistilled water and 0.1% acetic acid/acetonitrile as mobile phases. The mass spectrometer worked with electrospray ionization in positive ion mode and selected reaction monitoring. The standard curves were linear (R2 ≥0.9962 over the concentration ranges (10-10000 ng/mL for irinotecan, 1-500 ng/mL for SN-38 and SN-38G and 1-5000 ng/mL for APC and had good back-calculated accuracy and precision. The intra- and inter-day precision and accuracy, determined on three quality control levels for all the analytes, were always <12.3% and between 89.4% and 113.0%, respectively. Moreover, we evaluated this bioanalytical method by re-analysis of incurred samples as an additional measure of assay reproducibility. This method was successfully applied to a pharmacokinetic study in

  8. The pharmacokinetics of oxcarbazepine and its active metabolite 10-hydroxy-carbazepine in healthy subjects and in epileptic patients treated with phenobarbitone or valproic acid.

    Science.gov (United States)

    Tartara, A; Galimberti, C A; Manni, R; Morini, R; Limido, G; Gatti, G; Bartoli, A; Strada, G; Perucca, E

    1993-01-01

    The kinetics of oxcarbazepine (OXC) and its active metabolite 10-hydroxy-carbazepine (10-OH-CZ) after a single oral OXC dose (600 mg) were compared in healthy control subjects and in epileptic patients treated with phenobarbitone or sodium valproate (n = 8 in each group). In all groups, serum 10-OH-CZ concentrations were much higher than those of the parent drug. In patients on valproate, the kinetics of OXC and 10-OH-CZ did not differ significantly from those observed in controls. In patients on phenobarbitone, AUC values of both OXC and 10-OH-CZ were lower than in controls (2.9 +/- 0.4 vs 5.1 +/- 0.7 microg ml(-1) h and 89 +/- 7 vs 119 +/- 10 microg ml(-1) h respectively, means +/- s.e. mean, P effect is unlikely to be of great clinical significance. PMID:12959317

  9. Rational Design of Glucose-Responsive Insulin Using Pharmacokinetic Modeling.

    Science.gov (United States)

    Bakh, Naveed A; Bisker, Gili; Lee, Michael A; Gong, Xun; Strano, Michael S

    2017-11-01

    A glucose responsive insulin (GRI) is a therapeutic that modulates its potency, concentration, or dosing of insulin in relation to a patient's dynamic glucose concentration, thereby approximating aspects of a normally functioning pancreas. Current GRI design lacks a theoretical basis on which to base fundamental design parameters such as glucose reactivity, dissociation constant or potency, and in vivo efficacy. In this work, an approach to mathematically model the relevant parameter space for effective GRIs is induced, and design rules for linking GRI performance to therapeutic benefit are developed. Well-developed pharmacokinetic models of human glucose and insulin metabolism coupled to a kinetic model representation of a freely circulating GRI are used to determine the desired kinetic parameters and dosing for optimal glycemic control. The model examines a subcutaneous dose of GRI with kinetic parameters in an optimal range that results in successful glycemic control within prescribed constraints over a 24 h period. Additionally, it is demonstrated that the modeling approach can find GRI parameters that enable stable glucose levels that persist through a skipped meal. The results provide a framework for exploring the parameter space of GRIs, potentially without extensive, iterative in vivo animal testing. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. Determination of the phytochemical composition of Jingning fang and the in vivo pharmacokinetics of its metabolites in rat plasma by UPLC-MS/MS.

    Science.gov (United States)

    Yang, Chunjing; Yin, XingBin; Dong, Xiaoxv; Zhang, Xin; You, Longtai; Wang, Wenping; Wang, Junhong; Chen, Qinghe; Ni, Jian

    2017-11-01

    Jingning fang (JNF) is an effective Traditional Chinese Medicine (TCM) which is used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). To clarify the bioactive constituents of JNF, a Thermo Q Exactive™ Plus Orbitrap™ mass spectrometer was used in this study. More than 127 chemical compounds were isolated and identified tentatively in the JNF extract, while 42 prototype constituents with 4 potential metabolites were identified tentatively in rat plasma. A method for simultaneous determination of polygalaxanthone III (PAIII), sibiricose A 5 (A 5 ), sibiricose A 6 (A 6 ), 3, 6'-disinapoyl sucrose (3,6'-DISS), tenuifoliside C (TEC), tenuifolin B (TNB), verbascoside (VCE), heterophyllin B (HEB) and schisandrin (SCH) in rat was developed and validated using polydatin (PLN) and psoralen (PSN) as internal standards. All calibration curves proved favorable linearity (R 2 ≥0.9923) in linear ranges. The lower limit of quantification (LLOQ) was 2.5ng/mL for PAIII, A 5 , 3, 6'-DISS, TNB, VCE, HEB and SCH, 1.0ng/mL for A 6 and TEC, respectively. Intra-day and inter-day precisions didn't exceed 14.0% for all the analytes. Extraction recoveries and matrix effects of analytes and IS were acceptable. The validated method has been successfully applied to the pharmacokinetics (PK) studies of the nine compounds in JNF. These findings are useful for predicting the bioactive components of JNF, and will aid in optimizing dose regimens of the drug. Copyright © 2017. Published by Elsevier B.V.

  11. Modeling of pharmacokinetics, efficacy, and hemodynamic effects of macitentan in patients with pulmonary arterial hypertension.

    Science.gov (United States)

    Krause, Andreas; Zisowsky, Jochen; Dingemanse, Jasper

    2018-04-01

    Macitentan is the first endothelin receptor antagonist with demonstrated efficacy on morbidity and mortality in pulmonary arterial hypertension (PAH) in the pivotal study SERAPHIN. The pharmacokinetics (PK) of macitentan and its active metabolite, ACT-132577, were characterized in a population model. Efficacy and hemodynamics (pharmacodynamics, PD) were related to PK based on PK/PD modeling. Sex, age, and body weight influenced the PK to a statistically significant extent. Model-based simulations showed that these variables are clinically not relevant. Concomitant use of PAH medication (PDE-5 inhibitors) did not influence macitentan trough concentration to a relevant extent. Efficacy and hemodynamics showed clear differences from placebo for macitentan concentrations on 3 and 10 mg with consistent superior effects for 10 mg. After 6 months, PAH patients showed model-predicted 6-min walk distance (6-MWD) improvements of 1.0 m on placebo compared to 29.8 and 34.1 m on 3 and 10 mg of macitentan, respectively. Higher macitentan concentrations were associated with reductions in pulmonary vascular resistance (PVR), mean right atrial and pulmonary arterial pressure, and total pulmonary resistance (TPR) and increases in cardiac index (CI) and mixed venous oxygen saturation. Statistical significance was determined for PVR, TPR, and CI but not for 6-MWD. In addition, PVR showed more pronounced differences between active treatment and placebo than 6-MWD. Modeling identified statistically significant inter-patient differences; simulations to assess the magnitude of the effects permitted clinical judgment. The same approach will allow for extrapolation to children. Hemodynamic markers might be better markers of treatment effects than 6-MWD. The SERAPHIN study and its open-label extension are registered with ClinicalTrials.gov with identifiers NCT00660179 (https://www.clinicaltrials.gov/ct2/show/NCT00660179) and NCT00667823 (https://clinicaltrials.gov/ct2/show

  12. A first-generation physiologically based pharmacokinetic (PBPK) model of alpha-tocopherol in human influenza vaccine adjuvant.

    Science.gov (United States)

    Tegenge, Million A; Mitkus, Robert J

    2015-04-01

    Alpha (α)-tocopherol is a component of a new generation of squalene-containing oil-in-water (SQ/W) emulsion adjuvants that have been licensed for use in certain influenza vaccines. Since regulatory pharmacokinetic studies are not routinely required for influenza vaccines, the in vivo fate of this vaccine constituent is largely unknown. In this study, we constructed a physiologically based pharmacokinetic (PBPK) model for emulsified α-tocopherol in human adults and infants. An independent sheep PBPK model was also developed to inform the local preferential lymphatic transfer and for the purpose of model evaluation. The PBPK model predicts that α-tocopherol will be removed from the injection site within 24h and rapidly transfer predominantly into draining lymph nodes. A much lower concentration of α-tocopherol was estimated to peak in plasma within 8h. Any systemically absorbed α-tocopherol was predicted to accumulate slowly in adipose tissue, but not in other tissues. Model evaluation and uncertainty analyses indicated acceptable fit, with the fraction of dose taken up into the lymphatics as most influential on plasma concentration. In summary, this study estimates the in vivo fate of α-tocopherol in adjuvanted influenza vaccine, may be relevant in explaining its immunodynamics in humans, and informs current regulatory risk-benefit analyses. Published by Elsevier Inc.

  13. Levodopa pharmacokinetic-pharmacodynamic modeling and 6-[F-18]levodopa positron emission tomography in patients with Parkinson's disease

    NARCIS (Netherlands)

    Dietz, M; Harder, S; Graff, J; Kunig, G; Vontobel, P; Leenders, KL; Baas, H

    Objective: Parameters of a pharmacokinetic-pharmacodynamic (PK-PD) model of levodopa have been claimed to reflect the magnitude of the dopaminergic deficit in patients with Parkinson's disease. The aim of this study was to correlate such parameters with positron emission tomography (PET) with

  14. Population Pharmacokinetics of Tracers: A New Tool for Medical Imaging?

    Science.gov (United States)

    Gandia, Peggy; Jaudet, Cyril; Chatelut, Etienne; Concordet, Didier

    2017-02-01

    Positron emission tomography-computed tomography is a medical imaging method measuring the activity of a radiotracer chosen to accumulate in cancer cells. A recent trend of medical imaging analysis is to account for the radiotracer's pharmacokinetic properties at a voxel (three-dimensional-pixel) level to separate the different tissues. These analyses are closely linked to population pharmacokinetic-pharmacodynamic modelling. Kineticists possess the cultural background to improve medical imaging analysis. This article stresses the common points with population pharmacokinetics and highlights the methodological locks that need to be lifted.

  15. Analysis of Chloroquine and Metabolites Directly from Whole-body Animal Tissue Sections by Liquid Extraction Surface Analysis (LESA) and Tandem Mass Spectrometry

    Energy Technology Data Exchange (ETDEWEB)

    Parson, Whitney B [ORNL; Koeniger, Stormy L [Abbott Laboratories; Johnson, Robert W [Abbott Laboratories; Erickson, Jamie [Abbott Laboratories; Tian, Yu [Abbott Laboratories; Stedman, Christopher A. [Abbott Laboratories; Schwartz, Annette [Abbott Laboratories; Tarcsa, Edit [Abbott Laboratories; Cole, Roderic [ORNL; Van Berkel, Gary J [ORNL

    2012-01-01

    The rapid and direct analysis of the amount and spatial distribution of exogenous chloroquine and chloroquine metabolites from tissue sections by liquid extraction surface sampling analysis coupled with tandem mass spectrometry (LESA-MS) was demonstrated. LESA-MS results compared well with previously published chloroquine quantification data collected by organ excision, extraction and fluorescent detection. The ability to directly sample and analyze spatially-resolved exogenous molecules from tissue sections with minimal sample preparation and analytical method development has the potential to facilitate the assessment of target tissue penetration of pharmaceutical compounds, to establish pharmacokinetic/pharmacodynamic (PK/PD) relationships, and to complement established pharmacokinetic methods used in the drug discovery process during tissue distribution assessment.

  16. Reporting, Visualization, and Modeling of Immunogenicity Data to Assess Its Impact on Pharmacokinetics, Efficacy, and Safety of Monoclonal Antibodies.

    Science.gov (United States)

    Passey, Chaitali; Suryawanshi, Satyendra; Sanghavi, Kinjal; Gupta, Manish

    2018-02-26

    The rapidly increasing number of therapeutic biologics in development has led to a growing recognition of the need for improvements in immunogenicity assessment. Published data are often inadequate to assess the impact of an antidrug antibody (ADA) on pharmacokinetics, safety, and efficacy, and enable a fully informed decision about patient management in the event of ADA development. The recent introduction of detailed regulatory guidance for industry should help address many past inadequacies in immunogenicity assessment. Nonetheless, careful analysis of gathered data and clear reporting of results are critical to a full understanding of the clinical relevance of ADAs, but have not been widely considered in published literature to date. Here, we review visualization and modeling of immunogenicity data. We present several relatively simple visualization techniques that can provide preliminary information about the kinetics and magnitude of ADA responses, and their impact on pharmacokinetics and clinical endpoints for a given therapeutic protein. We focus on individual sample- and patient-level data, which can be used to build a picture of any trends, thereby guiding analysis of the overall study population. We also discuss methods for modeling ADA data to investigate the impact of immunogenicity on pharmacokinetics, efficacy, and safety.

  17. {sup 11}C-ORM-13070, a novel PET ligand for brain α{sub 2C}-adrenoceptors: radiometabolism, plasma pharmacokinetics, whole-body distribution and radiation dosimetry in healthy men

    Energy Technology Data Exchange (ETDEWEB)

    Luoto, Pauliina; Oikonen, Vesa; Arponen, Eveliina; Helin, Semi; Virta, Jere; Virtanen, Kirsi; Roivainen, Anne [University of Turku and Turku University Hospital, Turku PET Centre, Turku (Finland); Suilamo, Sami [University of Turku and Turku University Hospital, Turku PET Centre, Turku (Finland); Turku University Hospital, Department of Oncology and Radiotherapy, Turku (Finland); Herttuainen, Jukka; Hietamaeki, Johanna; Holopainen, Aila; Rouru, Juha; Sallinen, Jukka [Orion Pharma, Espoo and Turku (Finland); Kailajaervi, Marita [GE Healthcare, Turku Imanet, Turku (Finland); Peltonen, Juha M.; Scheinin, Mika; Volanen, Iina [University of Turku, CRST, Turku (Finland); Rinne, Juha O. [University of Turku and Turku University Hospital, Turku PET Centre, Turku (Finland); University of Turku, CRST, Turku (Finland); TYKSLAB, Unit of Clinical Pharmacology, Turku (Finland); University of Turku and Turku University Hospital, Division of Clinical Neurosciences, Turku (Finland)

    2014-10-15

    {sup 11}C-labelled 1-[(S)-1-(2,3-dihydrobenzo[1,2]dioxin-2-yl)methyl] -4-(3-methoxy-methylpyridin-2- yl)-piperazine ({sup 11}C-ORM-13070) is a novel PET tracer for imaging of α{sub 2C}-adrenoceptors in the human brain. Brain α{sub 2C}-adrenoceptors may be therapeutic targets in several neuropsychiatric disorders, including depression, schizophrenia and Alzheimer's disease. To validate the use of {sup 11}C-ORM-13070 in humans, we investigated its radiometabolism, pharmacokinetics, whole-body distribution and radiation dose. Radiometabolism was studied in a test-retest setting in six healthy men. After intravenous injection of {sup 11}C-ORM-13070, blood samples were drawn over 60 min. Plasma samples were analysed by radio-HPLC for intact tracer and its radioactive metabolites. Metabolite-corrected plasma time-activity curves were used for calculation of pharmacokinetics. In a separate group of 12 healthy men, the whole-body distribution of {sup 11}C-ORM-13070 and radiation exposure were investigated by dynamic PET/CT imaging without blood sampling. Two radioactive metabolites of {sup 11}C-ORM-13070 were detected in human arterial plasma. The proportion of unchanged {sup 11}C-ORM-13070 decreased from 81 ± 4 % of total radioactivity at 4 min after tracer injection to 23 ± 4 % at 60 min. At least one of the radioactive metabolites penetrated into red blood cells, while the parent tracer remained in plasma. The apparent elimination rate constant and corresponding half-life of unchanged {sup 11}C-ORM-13070 in arterial plasma were 0.0117 ± 0.0056 min{sup -1} and 73.6 ± 35.8 min, respectively. The organs with the highest absorbed doses were the liver (12 μSv/MBq), gallbladder wall (12 μSv/MBq) and pancreas (9.1 μSv/MBq). The mean effective dose was 3.9 μSv/MBq, with a range of 3.6 - 4.2 μSv/MBq. {sup 11}C-ORM-13070 was rapidly metabolized in human subjects after intravenous injection. The effective radiation dose of {sup 11}C-ORM-13070 was in the same range

  18. Metabolism and pharmacokinetics of morphine in neonates: A review

    Directory of Open Access Journals (Sweden)

    Gian Maria Pacifici

    Full Text Available Morphine is an agonist of the µ and k receptors, whose activation results in analgesia. Morphine-like agonists act through the µ opioid receptors to cause pain relief, sedation, euphoria and respiratory depression. Morphine is glucuronidated and sulfated at positions 3 and 6; the plasma concentration ratios correlate positively with birth weight, which probably reflects increased liver weight with increasing birth weight. Moreover, morphine clearance correlates positively with gestational age and birth weight. Steady-state morphine plasma concentrations are achieved after 24-48 hours of infusion, but the glucuronide metabolite plasma concentrations do not reach steady state before 60 hours. The morphine-3-glucuronide metabolite has lower clearance, a shorter half-life and a smaller distribution volume compared with the morphine-6 metabolite, which is the most active morphine-like agonist. Ordinary doses cause constipation, urinary retention and respiratory depression. Neonatal pain relief may require a blood level of approximately 120 ng/ml, whereas lower levels (20-40 ng/ml seem adequate for children. A bibliographic search was performed using the PubMed database and the keywords “morphine metabolism neonate” and “morphine pharmacokinetics neonate”. The initial and final cutoff points were January 1990 and September 2015, respectively. The results indicate that morphine is extensively glucuronidated and sulfated at positions 3 and 6, and that the glucuronidation rate is lower in younger neonates compared with older infants. Although much is known about morphine in neonates, further research will be required to ensure that recommended therapeutic doses for analgesia in neonates are evidence based.

  19. Population pharmacokinetics of olmesartan following oral administration of its prodrug, olmesartan medoxomil: in healthy volunteers and hypertensive patients.

    Science.gov (United States)

    Yoshihara, Kazutaka; Gao, Yuying; Shiga, Hiroshi; Wada, D Russell; Hisaoka, Masafumi

    2005-01-01

    Olmesartan medoxomil (CS-866) is a new orally active angiotensin II receptor antagonist that is highly selective for the AT1 receptor subtype. To develop a population pharmacokinetic model for olmesartan (RNH-6270), the active metabolite of olmesartan medoxomil, in healthy volunteers and hypertensive patients, and to evaluate effects of covariates on the apparent oral clearance (CL/F), with particular emphasis on the effect of race. Retrospective analysis of data from 12 phase I-III trials in the US, Europe and Japan. Eighty-nine healthy volunteers and 383 hypertensive patients. Nonlinear mixed-effects modelling was used to evaluate 7911 olmesartan plasma sample concentrations. The covariates included age, bodyweight, sex, race (Westerners [including Caucasians and Hispanics] versus Japanese), patient status (hypertensive patients versus healthy volunteers), serum creatinine level as an index of renal function and serum chemistry data as indices of hepatic function. The pharmacokinetic data of olmesartan were well described by a two-compartment linear model with first-order absorption and an absorption lag-time, parameterised in terms of CL/F (6.66 L/h for a typical male Western hypertensive patient), absorption rate constant (1.46h-1), elimination rate constant (0.193h-1), rate constant from the central to peripheral compartment (0.061h-1), rate constant from the peripheral to central compartment (0.079h-1) and absorption lag-time (0.427h). Analysis of covariates showed that age, bodyweight, sex, patient status and renal function were factors influencing the clearance of olmesartan. The population pharmacokinetic analysis of olmesartan showed that: (i) severe renal impairment (serum creatinine >265 micromol/L [approximately 3 mg/dL]) could cause a clearance decrease of > or =30%; (ii) older age, lower bodyweight and being female were determinants of lower clearance but their effects on olmesartan clearance were within 20%; (iii) no statistically significant

  20. Lisdexamfetamine: A pharmacokinetic review.

    Science.gov (United States)

    Comiran, Eloisa; Kessler, Félix Henrique; Fröehlich, Pedro Eduardo; Limberger, Renata Pereira

    2016-06-30

    Lisdexamfetamine (LDX) is a d-amphetamine (d-AMPH) pro-drug used to treat Attention Deficit and Hyperactivity Disorder (ADHD) and Binge Eating Disorder (BED) symptoms. The in vivo pharmacodynamics of LDX is the same as that of its active product d-AMPH, although there are a few qualitative and quantitative differences due to pharmacokinetics. Due to the specific pharmacokinetics of the long-acting stimulants, this article revises the pharmacokinetic studies on LDX, the newest amphetamine pro-drug. The Medline/Pubmed, Science Direct and Biblioteca Virtual em Saúde (Lilacs and Ibecs) (2007-2016) databases were searched for articles and their list of references. As for basic pharmacokinetics studies, since LDX is a newly developed medication, there are few results concerning biotransformation, distribution and the use of different biological matrices for analysis. This is the first robust review on this topic, gathering data from all clinical pharmacokinetics studies available in the literature. The particular pharmacokinetics of LDX plays a major role in studying this pro-drug, since this knowledge was essential to understand some reports on clinical effects in literature, e.g. the small likelihood of reducing the effect by interactions, the effect of long duration use and the still questionable reduction of the potential for abuse. In general the already well-known pharmacokinetic properties of amphetamine make LDX relatively predictable, simplifying the use of LDX in clinical practice. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. Intracellular metabolites of mercaptopurine in children with lymphoblastic leukaemia: a possible indicator of non-compliance?

    Science.gov (United States)

    Lennard, L; Welch, J; Lilleyman, J S

    1995-10-01

    As part of a programme assessing the pharmacokinetics of oral thiopurines given for lymphoblastic leukaemia, we assayed intracellular metabolites of mercaptopurine in children from all over the United Kingdom who were given a standard dose of the drug. The metabolites we measured, thioguanine nucleotides and methylmercaptopurines, are products of two competing metabolic pathways and would be expected to show an inverse correlation. A total of 327 children from 17 centres in the UK were studied. All were on the same therapeutic schedule of mercaptopurine. All had been on an unattenuated full protocol-directed dose (at least 75 mg m-2) for a minimum of 7 days before assay. There was a very wide variation in the concentration of the two metabolites measured; the thioguanine nucleotides ranged from 0 to 1255 pmol per 8 x 10(8) red cells (median 289, lower quartile 210, upper quartile 377) and the methylmercaptopurine metabolites ranged from 0 to 46.3 nmol per 8 x 10(8) red cells (median 5.18, lower quartile 2.31, upper quartile 11.59). The anticipated negative correlation was not apparent, but the ratio between the two was not randomly distributed. No child had both metabolite concentrations in the upper quartiles, but in 32 (10%) children the concentration of both metabolites was in the lower quartile. Of the 32, only one metabolite was detected in four and none at all in six. The most likely explanation for these findings is that a minority of children with lymphoblastic leukaemia fail to take oral mercaptopurine either totally or intermittently. The extent of the problem is unknown, but we suspect it may be clinically important in at least 10% of patients.

  2. Biodegradation of clofibric acid and identification of its metabolites

    International Nuclear Information System (INIS)

    Salgado, R.; Oehmen, A.; Carvalho, G.; Noronha, J.P.; Reis, M.A.M.

    2012-01-01

    Graphical abstract: Metabolites produced during clofibric acid biodegradation. Highlights: ► Clofibric acid is biodegradable. ► Mainly heterotrophic bacteria degraded the clofibric acid. ► Metabolites of clofibric acid biodegradation were identified. ► The metabolic pathway of clofibric acid biodegradation is proposed. - Abstract: Clofibric acid (CLF) is the pharmaceutically active metabolite of lipid regulators clofibrate, etofibrate and etofyllinclofibrate, and it is considered both environmentally persistent and refractory. This work studied the biotransformation of CLF in aerobic sequencing batch reactors (SBRs) with mixed microbial cultures, monitoring the efficiency of biotransformation of CLF and the production of metabolites. The maximum removal achieved was 51% biodegradation (initial CLF concentration = 2 mg L −1 ), where adsorption and abiotic removal mechanisms were shown to be negligible, showing that CLF is indeed biodegradable. Tests showed that the observed CLF biodegradation was mainly carried out by heterotrophic bacteria. Three main metabolites were identified, including α-hydroxyisobutyric acid, lactic acid and 4-chlorophenol. The latter is known to exhibit higher toxicity than the parent compound, but it did not accumulate in the SBRs. α-Hydroxyisobutyric acid and lactic acid accumulated for a period, where nitrite accumulation may have been responsible for inhibiting their degradation. A metabolic pathway for the biodegradation of CLF is proposed in this study.

  3. Protein precipitation: an expedient procedure for the routine analysis of the plasma metabolites of [123I]IBZM

    International Nuclear Information System (INIS)

    Zea-Ponce, Yolanda; Laruelle, Marc

    1999-01-01

    Plasma metabolite analysis of the single photon emission computed tomography (SPECT) D 2 /D 3 receptor radiotracer (S)(-)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2-hydroxy-3-[ 123 I] iodo-6-methoxyb enzamide ([ 123 I]IBZM) is needed for the equilibrium analysis of the SPECT data, in brain imaging studies involving bolus plus constant infusion paradigm. The purpose of these experiments was to find an appropriate procedure to expedite this analysis during routine determinations. The procedure was applied to the plasma analysis of 22 human subjects. Each plasma sample was subjected to acetonitrile protein precipitation. After separation of the pellet, the acetonitrile fraction contained 91%±2% (n=88) of the mixture of labeled metabolites and parent compound. The recovery coefficient of unmetabolized [ 123 I]IBZM determined with an standard plasma sample was 95%±2% (n=22). The percent parent compound present in the extracted fraction, measured by high performance liquid chromatography, was 16%±9% (n=85) and the percent metabolites was 84%±9% (n=85). Free fraction determination (f 1 , fraction of radiotracer unbound to protein), was 4%±0.8% (n=22). Free fraction of parent was 15%±8% (n=85). The results indicate that acetonitrile protein precipitation is an adequate method for the analysis of the [ 123 I]IBZM plasma metabolites

  4. Pharmacokinetics of dimethoxy-6,7 (parachlorobenzyl) -4 isoquinolin 14C in normal an pregnant mouse

    International Nuclear Information System (INIS)

    Servin, A.; Wicek, D.; Fazela, S.; Renault, H.; Jacquot, C.; Lussiana, J.P.; Viel, C.

    1983-01-01

    The dimethoxy-6,7 (parachlorobenzyl) -4 isoquinolin 14 C (PV2), spasmolitic and cerebral and peripheral vasodilator, is rapidly distributed throughout the mouse's organism following intravenous administration. In the pregnant mouse, its general distribution is not modified and its passage across the placental barrier, observed by autoradiography is rapid and similar to that observed in the brain. Following oral administration, the quantitative determination of the PV2 metabolites together and of selectively extracted unchanged PV2 has allowed us to determine the pharmacokinetics in the blood, liver, brain and foetus. PV2 is intensely metabolized into 13 metabolites of which 5 are important and include 6 OH-PV2 and 7 OH-PV2. In the brain and the foetus only PV2 crosses the barriers. It is eliminated from the brain according to monoexponential kinetics, being very little metabolized, whereas in the foetus it is very largely metabolized and eliminated again according to monoexponential kinetics. The intense metabolisation in the foetus leads to the appearance of biexponential kinetics during the measurement of the PV2 metabolites together, similar to that observed in liver

  5. A Pharmacokinetic Model of a Tissue Implantable Cortisol Sensor.

    Science.gov (United States)

    Lee, Michael A; Bakh, Naveed; Bisker, Gili; Brown, Emery N; Strano, Michael S

    2016-12-01

    Cortisol is an important glucocorticoid hormone whose biochemistry influences numerous physiological and pathological processes. Moreover, it is a biomarker of interest for a number of conditions, including posttraumatic stress disorder, Cushing's syndrome, Addison's disease, and others. An implantable biosensor capable of real time monitoring of cortisol concentrations in adipose tissue may revolutionize the diagnosis and treatment of these disorders, as well as provide an invaluable research tool. Toward this end, a mathematical model, informed by the physiological literature, is developed to predict dynamic cortisol concentrations in adipose, muscle, and brain tissues, where a significant number of important processes with cortisol occur. The pharmacokinetic model is applied to both a prototypical, healthy male patient and a previously studied Cushing's disease patient. The model can also be used to inform the design of an implantable sensor by optimizing the sensor dissociation constant, apparent delay time, and magnitude of the sensor output versus system dynamics. Measurements from such a sensor would help to determine systemic cortisol levels, providing much needed insight for proper medical treatment for various cortisol-related conditions. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Quantitative 2- and 3-dimensional analysis of pharmacokinetic model-derived variables for breast lesions in dynamic, contrast-enhanced MR mammography

    International Nuclear Information System (INIS)

    Hauth, E.A.M.; Jaeger, H.J.; Maderwald, S.; Muehler, A.; Kimmig, R.; Forsting, M.

    2008-01-01

    Purpose: 2- and 3-dimensional evaluation of quantitative pharmacokinetic parameters derived from the Tofts model modeling dynamic contrast enhancement of lesions in MR mammography. Materials and methods: In 95 patients, MR mammography revealed 127 suspicious lesions. The initial rate of enhancement was coded by color intensity, the post-initial enhancement change is coded by color hue. 2D and 3D analysis of distribution of color hue and intensity, vascular permeability and extracellular volume were performed. Results: In 2D, malignant lesions showed significant higher number of bright red, medium red, dark red, bright green, medium green, dark green and bright blue pixels than benign lesions. In 3D, statistical significant differences between malignant and benign lesions was found for all this parameters. Vascular permeability was significant higher in malignant lesions than in benign lesions. Regression model using the 3D data found that the best discriminator between malignant and benign lesions was combined number of voxels and medium green pixels, with a sensitivity of 79.4% and a specificity of 83.1%. Conclusions: Quantitative analysis of pharmacokinetic variables of contrast kinetics showed significant differences between malignant and benign lesions. 3D analysis showed superior diagnostic differentiation between malignant and benign lesions than 2D analysis. The parametric analysis using a pharmacokinetic model allows objective analysis of contrast enhancement in breast lesions

  7. Albendazole nanocrystals with improved pharmacokinetic performance in mice.

    Science.gov (United States)

    Paredes, Alejandro J; Bruni, Sergio Sánchez; Allemandi, Daniel; Lanusse, Carlos; Palma, Santiago D

    2018-02-01

    Albendazole (ABZ) is a broad-spectrum antiparasitic agent with poor aqueous solubility, which leads to poor/erratic bioavailability and therapeutic failures. Here, we aimed to produce a novel formulation of ABZ nanocrystals (ABZNC) and assess its pharmacokinetic performance in mice. Results/methodology: ABZNC were prepared by high-pressure homogenization and spray-drying processes. Redispersion capacity and solid yield were measured in order to obtain an optimized product. The final particle size was 415.69±7.40 nm and the solid yield was 72.32%. The pharmacokinetic parameters obtained in a mice model for ABZNC were enhanced (p < 0.05) with respect to the control formulation. ABZNC with improved pharmacokinetic behavior were produced by a simple, inexpensive and potentially scalable methodology.

  8. Single-dose pharmacokinetics and tolerability of oral delta-9- tetrahydrocannabinol in patients with amyotrophic lateral sclerosis.

    Science.gov (United States)

    Joerger, Markus; Wilkins, Justin; Fagagnini, Stefania; Baldinger, Reto; Brenneisen, Rudolf; Schneider, Ursula; Goldman, Bea; Weber, Markus

    2012-06-01

    Cannabinoids exert neuroprotective and symptomatic effects in amyotrophic lateral sclerosis (ALS). We assessed the pharmacokinetics (PK) and tolerability of delta-9-tetrahydrocannabinol (THC) in ALS patients. Nine patients received THC single oral doses of 5mg and 10mg, separated by a wash-out period of two weeks. Blood samples for the determination of THC, 11-nor-9-carboxy-THC (THC-COOH) and hydroxy-THC (THC-OH) were taken up to 8 hours after intake. Adverse events were assessed by visual analogue scales (VAS). Plasma concentrations of the active metabolite THC-OH were submitted to sequential pharmacokinetic-pharmacodynamic population modeling on individual heart rate as a proxy for THC's cardiovasculatory effects. Drowsiness, euphoria, orthostasis, sleepiness, vertigo and weakness were significantly more frequent in patients receiving 10mg compared to 5 mg THC. A marked interindividual variability was found for the absorption of oral THC (84%) and elimination of THC-COOH (45%). PK data did not support any clinically relevant deviation from linear PK in the investigated range of concentrations. Plasma concentrations of THC-OH were positively correlated with the individual heart rate. An E(max-model) was successfully fitted to individual heart rate, with a THC-OH plasma concentration of 3.2 x 10(-4) μmol/L for EC(50) and an E(max) of 93 bpm for heart rate. The higher 10mg dose of THC was dose-limiting in patients with ALS. High interindividual PK variability requires individuell titration of THC for potential therapeutic use in patients with ALS.

  9. Phenol-Explorer 2.0: a major update of the Phenol-Explorer database integrating data on polyphenol metabolism and pharmacokinetics in humans and experimental animals

    Science.gov (United States)

    Rothwell, Joseph A.; Urpi-Sarda, Mireia; Boto-Ordoñez, Maria; Knox, Craig; Llorach, Rafael; Eisner, Roman; Cruz, Joseph; Neveu, Vanessa; Wishart, David; Manach, Claudine; Andres-Lacueva, Cristina; Scalbert, Augustin

    2012-01-01

    Phenol-Explorer, launched in 2009, is the only comprehensive web-based database on the content in foods of polyphenols, a major class of food bioactives that receive considerable attention due to their role in the prevention of diseases. Polyphenols are rarely absorbed and excreted in their ingested forms, but extensively metabolized in the body, and until now, no database has allowed the recall of identities and concentrations of polyphenol metabolites in biofluids after the consumption of polyphenol-rich sources. Knowledge of these metabolites is essential in the planning of experiments whose aim is to elucidate the effects of polyphenols on health. Release 2.0 is the first major update of the database, allowing the rapid retrieval of data on the biotransformations and pharmacokinetics of dietary polyphenols. Data on 375 polyphenol metabolites identified in urine and plasma were collected from 236 peer-reviewed publications on polyphenol metabolism in humans and experimental animals and added to the database by means of an extended relational design. Pharmacokinetic parameters have been collected and can be retrieved in both tabular and graphical form. The web interface has been enhanced and now allows the filtering of information according to various criteria. Phenol-Explorer 2.0, which will be periodically updated, should prove to be an even more useful and capable resource for polyphenol scientists because bioactivities and health effects of polyphenols are dependent on the nature and concentrations of metabolites reaching the target tissues. The Phenol-Explorer database is publicly available and can be found online at http://www.phenol-explorer.eu. Database URL: http://www.phenol-explorer.eu PMID:22879444

  10. Optimization of the reference region method for dual pharmacokinetic modeling using Gd-DTPA/MRI and (18) F-FDG/PET.

    Science.gov (United States)

    Poulin, Éric; Lebel, Réjean; Croteau, Étienne; Blanchette, Marie; Tremblay, Luc; Lecomte, Roger; Bentourkia, M'hamed; Lepage, Martin

    2015-02-01

    The combination of MRI and positron emission tomography (PET) offers new possibilities for the development of novel methodologies. In pharmacokinetic image analysis, the blood concentration of the imaging compound as a function of time, [i.e., the arterial input function (AIF)] is required for MRI and PET. In this study, we tested whether an AIF extracted from a reference region (RR) in MRI can be used as a surrogate for the manually sampled (18) F-FDG AIF for pharmacokinetic modeling. An MRI contrast agent, gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) and a radiotracer, (18) F-fluorodeoxyglucose ((18) F-FDG), were simultaneously injected in a F98 glioblastoma rat model. A correction to the RR AIF for Gd-DTPA is proposed to adequately represent the manually sampled AIF. A previously published conversion method was applied to convert this AIF into a (18) F-FDG AIF. The tumor metabolic rate of glucose (TMRGlc) calculated with the manually sampled (18) F-FDG AIF, the (18) F-FDG AIF converted from the RR AIF and the (18) F-FDG AIF converted from the corrected RR AIF were found not statistically different (P>0.05). An AIF derived from an RR in MRI can be accurately converted into a (18) F-FDG AIF and used in PET pharmacokinetic modeling. © 2014 Wiley Periodicals, Inc.

  11. Development of LC-MS determination method and back-propagation ANN pharmacokinetic model of corynoxeine in rat.

    Science.gov (United States)

    Ma, Jianshe; Cai, Jinzhang; Lin, Guanyang; Chen, Huilin; Wang, Xianqin; Wang, Xianchuan; Hu, Lufeng

    2014-05-15

    Corynoxeine(CX), isolated from the extract of Uncaria rhynchophylla, is a useful and prospective compound in the prevention and treatment for vascular diseases. A simple and selective liquid chromatography mass spectrometry (LC-MS) method was developed to determine the concentration of CX in rat plasma. The chromatographic separation was achieved on a Zorbax SB-C18 (2.1 mm × 150 mm, 5 μm) column with acetonitrile-0.1% formic acid in water as mobile phase. Selective ion monitoring (SIM) mode was used for quantification using target ions m/z 383 for CX and m/z 237 for the carbamazepine (IS). After the LC-MS method was validated, it was applied to a back-propagation artificial neural network (BP-ANN) pharmacokinetic model study of CX in rats. The results showed that after intravenous administration of CX, it was mainly distributed in blood and eliminated quickly, t1/2 was less than 1h. The predicted concentrations generated by BP-ANN model had a high correlation coefficient (R>0.99) with experimental values. The developed BP-ANN pharmacokinetic model can be used to predict the concentration of CX in rats. Copyright © 2014 Elsevier B.V. All rights reserved.

  12. Pharmacokinetics of oral terbinafine in horses and Greyhound dogs.

    Science.gov (United States)

    Williams, M M; Davis, E G; KuKanich, B

    2011-06-01

    The objective of the study was to assess the pharmacokinetics of terbinafine administered orally to horses and Greyhound dogs. A secondary objective was to assess terbinafine metabolites. Six healthy horses and six healthy Greyhound dogs were included in the pharmacokinetic data. The targeted dose of terbinafine was 20 and 30 mg/kg for horses and dogs, respectively. Blood was collected at predetermined intervals for the quantification of terbinafine concentrations with liquid chromatography and mass spectrometry. The half-life (geometric mean) was 8.1 and 8.6 h for horses and Greyhounds, respectively. The mean maximum plasma concentration was 0.31 and 4.01 μg/mL for horses and Greyhounds, respectively. The area under the curve (to infinity) was 1.793 h·μg/mL for horses and 17.253 h·μg/mL for Greyhounds. Adverse effects observed in one study horse included pawing at the ground, curling lips, head shaking, anxiety and circling, but these resolved spontaneously within 30 min of onset. No adverse effects were noted in the dogs. Ions consistent with carboxyterbinafine, n-desmethylterbinafine, hydroxyterbinafine and desmethylhydroxyterbinafine were identified in horse and Greyhound plasma after terbinafine administration. Further studies are needed assessing the safety and efficacy of terbinafine in horses and dogs. © 2010 Blackwell Publishing Ltd.

  13. Drugs in space: Pharmacokinetics and pharmacodynamics in astronauts.

    Science.gov (United States)

    Kast, Johannes; Yu, Yichao; Seubert, Christoph N; Wotring, Virginia E; Derendorf, Hartmut

    2017-11-15

    Space agencies are working intensely to push the current boundaries of human spaceflight by sending astronauts deeper into space than ever before, including missions to Mars and asteroids. Spaceflight alters human physiology due to fluid shifts, muscle and bone loss, immune system dysregulation, and changes in the gastrointestinal tract and metabolic enzymes. These alterations may change the pharmacokinetics and/or pharmacodynamics of medications used by astronauts and subsequently might impact drug efficacy and safety. Most commonly, medications are administered during space missions to treat sleep disturbances, allergies, space motion sickness, pain, and sinus congestion. These medications are administered under the assumption that they act in a similar way as on Earth, an assumption that has not been investigated systematically yet. Few inflight pharmacokinetic data have been published, and pharmacodynamic and pharmacokinetic/pharmacodynamic studies during spaceflight are also lacking. Therefore, bed-rest models are often used to simulate physiological changes observed during microgravity. In addition to pharmacokinetic/pharmacodynamic changes, decreased drug and formulation stability in space could also influence efficacy and safety of medications. These alterations along with physiological changes and their resulting pharmacokinetic and pharmacodynamic effects must to be considered to determine their ultimate impact on medication efficacy and safety during spaceflight. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Parenting and Antisocial Behavior: A Model of the Relationship between Adolescent Self-Disclosure, Parental Closeness, Parental Control, and Adolescent Antisocial Behavior

    Science.gov (United States)

    Vieno, Alessio; Nation, Maury; Pastore, Massimiliano; Santinello, Massimo

    2009-01-01

    This study used data collected from a sample of 840 Italian adolescents (418 boys; M age = 12.58) and their parents (657 mothers; M age = 43.78) to explore the relations between parenting, adolescent self-disclosure, and antisocial behavior. In the hypothesized model, parenting practices (e.g., parental monitoring and control) have direct effects…

  15. Examining a conceptual model of parental nurturance, parenting practices and physical activity among 5–6 year olds

    Science.gov (United States)

    Sebire, Simon J.; Jago, Russell; Wood, Lesley; Thompson, Janice L.; Zahra, Jezmond; Lawlor, Deborah A.

    2016-01-01

    Rationale Parenting is an often-studied correlate of children's physical activity, however there is little research examining the associations between parenting styles, practices and the physical activity of younger children. Objective This study aimed to investigate whether physical activity-based parenting practices mediate the association between parenting styles and 5–6 year-old children's objectively-assessed physical activity. Methods 770 parents self-reported parenting style (nurturance and control) and physical activity-based parenting practices (logistic and modeling support). Their 5–6 year old child wore an accelerometer for five days to measure moderate-to-vigorous physical activity (MVPA). Linear regression was used to examine direct and indirect (mediation) associations. Data were collected in the United Kingdom in 2012/13 and analyzed in 2014. Results Parent nurturance was positively associated with provision of modeling (adjusted unstandardized coefficient, β = 0.11; 95% CI = 0.02, 0.21) and logistic support (β = 0.14; 0.07, 0.21). Modeling support was associated with greater child MVPA (β = 2.41; 0.23, 4.60) and a small indirect path from parent nurturance to child's MVPA was identified (β = 0.27; 0.04, 0.70). Conclusions Physical activity-based parenting practices are more strongly associated with 5–6 year old children's MVPA than parenting styles. Further research examining conceptual models of parenting is needed to understand in more depth the possible antecedents to adaptive parenting practices beyond parenting styles. PMID:26647364

  16. Effect of in vivo nicotine exposure on chlorpyrifos pharmacokinetics and pharmacodynamics in rats

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Soo Kwang; Poet, Torka S.; Smith, Jordan N.; Busby-Hjerpe, Andrea L.; Timchalk, Charles

    2010-03-30

    Chlorpyrifos (CPF) is one of the most studied and widely used broad spectrum organophosphorus (OP) insecticides. The neurotoxicity of CPF results from inhibition of cholinesterase (ChE) by its metabolite, chlorpyrifos-oxon (CPF-oxon), which subsequently leads to cholinergic hyperstimulation. The routine consumption of alcoholic beverages and tobacco products will modify a number of metabolic and physiological processes which may impact the metabolism and pharmacokinetics of other xenobiotics including pesticides. The objective of this study was to evaluate the influence of repeated ethanol and nicotine co-exposure on in vivo CPF pharmacokinetics and pharmacodynamics. The major CPF metabolite, 3,5,6-trichloro-2-pyridinol (TCPy) in blood and urine along with changes in plasma and brain AChE activities were measured in male Sprague-Dawley (S-D) rats. Animals were repeatedly treated with either saline or ethanol (1 g/kg/day, po) and nicotine (1 mg/kg/day, sc) in addition to CPF (1 or 5 mg/kg/day, po) for 7 days. Rats were sacrificed at times from 1 to 24 hr post-last dosing of CPF. There were apparent differences in blood TCPy pharmacokinetics following ethanol and nicotine pretreatments in both CPF dose groups, which showed higher TCPy peak concentrations and increased blood TCPy AUC in ethanol and nicotine groups over CPF-only (~1.8- and 3.8-fold at 1 and 5 mg CPF doses, respectively). Brain acetylcholinesterase (AChE) activities from both ethanol and nicotine-treated groups showed substantially less inhibition following repeated 5 mg CPF/kg dosing compared to CPF-only controls (96 ± 13 and 66 ± 7% of naïve at 4 hr post-last CPF dosing, respectively). Inhibition of brain AChE activities was minimal in both 1 mg CPF/kg/day dosing groups, but a similar trend indicating less inhibition following ethanol/nicotine pretreatment was apparent. No differences were observed in plasma ChE activities due to the combined alcohol and nicotine treatments. In vitro, CPF

  17. BATMAN--an R package for the automated quantification of metabolites from nuclear magnetic resonance spectra using a Bayesian model.

    Science.gov (United States)

    Hao, Jie; Astle, William; De Iorio, Maria; Ebbels, Timothy M D

    2012-08-01

    Nuclear Magnetic Resonance (NMR) spectra are widely used in metabolomics to obtain metabolite profiles in complex biological mixtures. Common methods used to assign and estimate concentrations of metabolites involve either an expert manual peak fitting or extra pre-processing steps, such as peak alignment and binning. Peak fitting is very time consuming and is subject to human error. Conversely, alignment and binning can introduce artefacts and limit immediate biological interpretation of models. We present the Bayesian automated metabolite analyser for NMR spectra (BATMAN), an R package that deconvolutes peaks from one-dimensional NMR spectra, automatically assigns them to specific metabolites from a target list and obtains concentration estimates. The Bayesian model incorporates information on characteristic peak patterns of metabolites and is able to account for shifts in the position of peaks commonly seen in NMR spectra of biological samples. It applies a Markov chain Monte Carlo algorithm to sample from a joint posterior distribution of the model parameters and obtains concentration estimates with reduced error compared with conventional numerical integration and comparable to manual deconvolution by experienced spectroscopists. http://www1.imperial.ac.uk/medicine/people/t.ebbels/ t.ebbels@imperial.ac.uk.

  18. [A study of population pharmacokinetics of linezolid in Chinese].

    Science.gov (United States)

    Zhang, L; Bai, N; Liu, Y N; Wang, R

    2016-12-12

    Objective: To study the population pharmacokinetic (PPK) profiles of linezolid in Chinese healthy volunteers and infected patients. Methods: Linezolid 600 mg was administered to 31 Chinese healthy volunteers with a single dose and to 57 infected patients every 12 h for at least 5 doses. High performance liquid chromatography was applied to determine the plasma concentration of linezolid. Nonlinear mixed-effects modeling method was applied to analyze the PPK profiles. Results: For healthy volunteers with single dose of linezolid, 2-compartment with linear elimination model was the most appropriate structural pharmacokinetic model. The population typical value of apparent volume of central compartment was 26.99 L, volume of peripheral compartment was 22.22 L, apparent clearance of central compartment was 7.99 L/h, and clearance of peripheral compartment was 101.28 L/h. For each 1 kg deviation of weight from the mean value, 0.62 L of volume of peripheral compartment was correlated. For Chinese infected patients with multiple doses of linezolid, 1-compartment with linear elimination model was the most appropriate structural pharmacokinetic model. The population typical value of apparent volume was 38.85 L, and apparent clearance was 4.70 L/h. For each 1 kg deviation of weight from the mean value, 0.79 L of volume, as well as 0.04 L/h of clearance were correlated. For each 1 year deviation of age from the mean value, -0.045 L/h of clearance was correlated. Conclusions: The pharmacokinetic profiles of linezolid in Chinese simulate a 2-compartment with linear elimination model when single dose is administrated, and the weight is linearly positive-correlated to volume. While a 1-compartment with linear elimination model is appropriate when multiple doses are administrated, and the weight is linearly positive-correlated to volume and clearance, but the age is linearly negative-correlated to clearance.

  19. Mutant prevention concentration, pharmacokinetic-pharmacodynamic integration, and modeling of enrofloxacin data established in diseased buffalo calves.

    Science.gov (United States)

    Ramalingam, B; Sidhu, P K; Kaur, G; Venkatachalam, D; Rampal, S

    2015-12-01

    The pharmacokinetic-pharmacodynamic (PK/PD) modeling of enrofloxacin data using mutant prevention concentration (MPC) of enrofloxacin was conducted in febrile buffalo calves to optimize dosage regimen and to prevent the emergence of antimicrobial resistance. The serum peak concentration (Cmax ), terminal half-life (t1/2 K10) , apparent volume of distribution (Vd(area) /F), and mean residence time (MRT) of enrofloxacin were 1.40 ± 0.27 μg/mL, 7.96 ± 0.86 h, 7.74 ± 1.26 L/kg, and 11.57 ± 1.01 h, respectively, following drug administration at dosage 12 mg/kg by intramuscular route. The minimum inhibitory concentration (MIC), minimum bactericidal concentration, and MPC of enrofloxacin against Pasteurella multocida were 0.055, 0.060, and 1.45 μg/mL, respectively. Modeling of ex vivo growth inhibition data to the sigmoid Emax equation provided AUC24 h /MIC values to produce effects of bacteriostatic (33 h), bactericidal (39 h), and bacterial eradication (41 h). The estimated daily dosage of enrofloxacin in febrile buffalo calves was 3.5 and 8.4 mg/kg against P. multocida/pathogens having MIC90 ≤0.125 and 0.30 μg/mL, respectively, based on the determined AUC24 h /MIC values by modeling PK/PD data. The lipopolysaccharide-induced fever had no direct effect on the antibacterial activity of the enrofloxacin and alterations in PK of the drug, and its metabolite will be beneficial for its use to treat infectious diseases caused by sensitive pathogens in buffalo species. In addition, in vitro MPC data in conjunction with in vivo PK data indicated that clinically it would be easier to eradicate less susceptible strains of P. multocida in diseased calves. © 2015 John Wiley & Sons Ltd.

  20. Pharmacokinetic of 3 H-deacetylasperulosidic acid in mice

    Directory of Open Access Journals (Sweden)

    Simla Basar-Maurer

    2016-08-01

    Full Text Available Background: An investigation was conducted to determine the fate of the iridoid derivative deacetylasperulosidic acid (DAA after oral application to mice. Methods: DAA was extracted from Morinda citrifolia leaf and purified by preparative HPLC. The identity was verified by MS and NMR spectroscopy. A sample of DAA was radioactively labelled with tritium and applied to mice by gavage. The pharmacokinetic of the radioactivity was investigated in blood, organs, urine and feces. Metabolites were isolated in blood and urine by HPLC and identified by LC-MS. In vitro incubation of DAA with mouse duodenum and liver homogenate and human fecal bacteria was performed and possible metabolites were separated by HPLC. Results: DAA was rapidly absorbed and excreted mainly via the kidneys with a half-life of 30 minutes. Radioactivity was present in all organs with highest concentrations in kidney and liver. Almost 100% of the radioactivity isolated from urine and organs could be identified as unchanged DAA. Additionally, no metabolism could be observed after in vitro incubation of DAA with mouse small intestine or liver homogenate. However, a total breakdown of the molecule was observed after incubation of DAA with human intestinal bacteria. Conclusion: The absorption and excretion of glycosides such as DAA in mammals without hydrolysis is a potential defense mechanism of animals against the toxicity of these compounds.

  1. Investigation of clinical pharmacokinetic variability of an opioid antagonist through physiologically based absorption modeling.

    Science.gov (United States)

    Ding, Xuan; He, Minxia; Kulkarni, Rajesh; Patel, Nita; Zhang, Xiaoyu

    2013-08-01

    Identifying the source of inter- and/or intrasubject variability in pharmacokinetics (PK) provides fundamental information in understanding the pharmacokinetics-pharmacodynamics relationship of a drug and project its efficacy and safety in clinical populations. This identification process can be challenging given that a large number of potential causes could lead to PK variability. Here we present an integrated approach of physiologically based absorption modeling to investigate the root cause of unexpectedly high PK variability of a Phase I clinical trial drug. LY2196044 exhibited high intersubject variability in the absorption phase of plasma concentration-time profiles in humans. This could not be explained by in vitro measurements of drug properties and excellent bioavailability with low variability observed in preclinical species. GastroPlus™ modeling suggested that the compound's optimal solubility and permeability characteristics would enable rapid and complete absorption in preclinical species and in humans. However, simulations of human plasma concentration-time profiles indicated that despite sufficient solubility and rapid dissolution of LY2196044 in humans, permeability and/or transit in the gastrointestinal (GI) tract may have been negatively affected. It was concluded that clinical PK variability was potentially due to the drug's antagonism on opioid receptors that affected its transit and absorption in the GI tract. Copyright © 2013 Wiley Periodicals, Inc.

  2. Prediction of the Pharmacokinetic Parameters of Triptolide in Rats Based on Endogenous Molecules in Pre-Dose Baseline Serum

    Science.gov (United States)

    Aa, Jiye; Zheng, Tian; Shi, Jian; Li, Mengjie; Wang, Xinwen; Zhao, Chunyan; Xiao, Wenjing; Yu, Xiaoyi; Sun, Runbin; Gu, Rongrong; Zhou, Jun; Wu, Liang; Hao, Gang; Zhu, Xuanxuan; Wang, Guangji

    2012-01-01

    Background Individual variances usually affect drug metabolism and disposition, and hence result in either ineffectiveness or toxicity of a drug. In addition to genetic polymorphism, the multiple confounding factors of lifestyles, such as dietary preferences, contribute partially to individual variances. However, the difficulty of quantifying individual diversity greatly challenges the realization of individualized drug therapy. This study aims at quantitative evaluating the association between individual variances and the pharmacokinetics. Methodology/Principal Findings Molecules in pre-dose baseline serum were profiled using gas chromatography mass spectrometry to represent the individual variances of the model rats provided with high fat diets (HFD), routine chows and calorie restricted (CR) chows. Triptolide and its metabolites were determined using high performance liquid chromatography mass spectrometry. Metabonomic and pharmacokinetic data revealed that rats treated with the varied diets had distinctly different metabolic patterns and showed differential Cmax values, AUC and drug metabolism after oral administration of triptolide. Rats with fatty chows had the lowest Cmax and AUC values and the highest percentage of triptolide metabolic transformation, while rats with CR chows had the highest Cmax and AUC values and the least percentage of triptolide transformation. Multivariate linear regression revealed that in baseline serum, the concentrations of creatinine and glutamic acid, which is the precursor of GSH, were linearly negatively correlated to Cmax and AUC values. The glutamic acid and creatinine in baseline serum were suggested as the potential markers to represent individual diversity and as predictors of the disposal and pharmacokinetics of triptolide. Conclusions/Significance These results highlight the robust potential of metabonomics in characterizing individual variances and identifying relevant markers that have the potential to facilitate

  3. Transplacental pharmacokinetics of diclofenac in perfused human placenta.

    Science.gov (United States)

    Shintaku, Kyohei; Hori, Satoko; Tsujimoto, Masayuki; Nagata, Hideaki; Satoh, Shoji; Tsukimori, Kiyomi; Nakano, Hitoo; Fujii, Tomoyuki; Taketani, Yuji; Ohtani, Hisakazu; Sawada, Yasufumi

    2009-05-01

    The aims of this study were to evaluate the transplacental transfer properties of diclofenac and to determine the effect of L-lactic acid on the transplacental transfer of diclofenac. The maternal and fetal vessels of human placenta were perfused in a single-pass mode with a solution containing diclofenac and antipyrine. The transplacental pharmacokinetic model was fitted to the time profiles of the drug concentrations in the effluent and placenta to obtain transplacental pharmacokinetic parameters. In addition, chloride ion in the perfusate was partially replaced with L-lactic acid to see the change in the transplacental transfer properties of diclofenac. The TPT(ss) value (ratio of the rate of amount transferred across the placenta to that infused in the steady state) of diclofenac was 2.22%, which was approximately one-third that of antipyrine and was significantly reduced in the presence of L-lactic acid. The transplacental pharmacokinetic model could adequately explain the transplacental transfer of diclofenac with influx clearances from maternal and fetal perfusates to placental tissue of 0.276 and 0.0345 ml/min/g cotyledon and efflux rate constants from placental tissue to maternal and fetal perfusates of 0.406 and 0.0337 min(-1), respectively. By taking into account protein binding, the placental tissue/plasma concentration ratio in humans for diclofenac was estimated to be 0.108 ml/g of cotyledon and was smaller than that of antipyrine. In conclusion, human placental perfusion and transplacental pharmacokinetic modeling allowed us to determine the transplacental transfer properties of diclofenac quantitatively. Diclofenac may share transplacental transfer system(s) with L-lactic acid.

  4. PARENT NURTURE MODEL IN SHAPING BEHAVIOR OF ADOLESCENCE 12-15 AGES

    Directory of Open Access Journals (Sweden)

    Dimas Hadi Prayoga

    2017-02-01

    Full Text Available Introduction: The deviation problem of smoking activity an adolescent is come to anxious level for parents, teachers, and society. The correlation between parents nurture model and smoking activity of adolescent needs to be examined further. The purpose of this study was to analyze the correlation between parents nurture model with smoking activity of adolescent (12-15 years old. Method: This was correlational research with cross sectional approach. The sample were 84 adolescent (12-15 years old at MTs Mojosari Nganjuk. The independent variables was parents nurture model and the dependent variable was adolescent smoking activity. Data were collected by using questionnare, then examined by using chi square with the level of significant α=0,05. Result: Statistical analysis had showed the low correlation between permissive parents nurture model with smoking activity of adolescent (12-15 years old at MTs Mojosari Nganjuk (p=0,049; r = 0,210 and no correlation between democratic nurture model (p=0,554 and authoritative nurture model (p=0,418 with smoking activity of adolescent (12-15 years old at MTs Mojosari Nganjuk, but only permissive model which correlate with smoking activity. The permissive parents with no control and demand caused adolescent to be feeling unimpeded to do smoking activity since there is no warning and punishment from the parents. Discussion: So that, School nurses should provide health promotion to parents in making appropriate parenting in adolescence. Parents should have the right parenting provided in accordance with the age and development of adolescents because appropriate parenting will have a positive impact on adolescent behavior. Further research on parenting questionnaires must be checked for cross-compatibility between questionnaire answers given adolescent and parents to know the truth in filling out the questionnaire. The differences in this study compared to previous studies is the researcher doing research in

  5. Physiologically based pharmacokinetics model for estimating urinary excretion of short half-life nuclides in nuclear medicine

    International Nuclear Information System (INIS)

    Akahane, K.; Kai, M.; Konishi, E.; Kusama, T.; Aoki, Y.

    1995-01-01

    The biokinetic model in ICRP 53 is used for calculating absorbed dose to each organ of a patient in nuclear medicine. The ICRP model is a simple compartment model based on human data; however, the model cannot produce the biokinetics of radiopharmaceuticals under various physiological conditions. On the other hand, a physiologically based pharmacokinetics model (PBPK model) can describe the flow of radiopharmaceuticals as a compartment model for any physiological conditions theoretically. The PBPK model was applied especially for the kidney-bladder dynamics, and similar results obtained compared with the ICRP model. This suggests the possibility of the PBPK model for predicting the biokinetics of radiopharmaceuticals under various physiological conditions. (Author)

  6. Population pharmacokinetic modeling and dosing simulations of nitrogen-scavenging compounds: disposition of glycerol phenylbutyrate and sodium phenylbutyrate in adult and pediatric patients with urea cycle disorders.

    Science.gov (United States)

    Monteleone, Jon P R; Mokhtarani, M; Diaz, G A; Rhead, W; Lichter-Konecki, U; Berry, S A; Lemons, C; Dickinson, K; Coakley, D; Lee, B; Scharschmidt, B F

    2013-07-01

    Sodium phenylbutyrate and glycerol phenylbutyrate mediate waste nitrogen excretion in the form of urinary phenylacetylglutamine (PAGN) in patients with urea cycle disorders (UCDs); rare genetic disorders characterized by impaired urea synthesis and hyperammonemia. Sodium phenylbutyrate is approved for UCD treatment; the development of glycerol phenylbutyrate afforded the opportunity to characterize the pharmacokinetics (PK) of both compounds. A population PK model was developed using data from four Phase II/III trials that collectively enrolled patients ages 2 months to 72 years. Dose simulations were performed with particular attention to phenylacetic acid (PAA), which has been associated with adverse events in non-UCD populations. The final model described metabolite levels in plasma and urine for both drugs and was characterized by (a) partial presystemic metabolism of phenylbutyric acid (PBA) to PAA and/or PAGN, (b) slower PBA absorption and greater presystemic conversion with glycerol phenylbutyrate, (c) similar systemic disposition with saturable conversion of PAA to PAGN for both drugs, and (d) body surface area (BSA) as a significant covariate accounting for age-related PK differences. Dose simulations demonstrated similar PAA exposure following mole-equivalent PBA dosing of both drugs and greater PAA exposure in younger patients based on BSA. © The Author(s) 2013.

  7. Quantitation of promethazine and metabolites in urine samples using on-line solid-phase extraction and column-switching

    Science.gov (United States)

    Song, Q.; Putcha, L.; Harm, D. L. (Principal Investigator)

    2001-01-01

    A chromatographic method for the quantitation of promethazine (PMZ) and its three metabolites in urine employing on-line solid-phase extraction and column-switching has been developed. The column-switching system described here uses an extraction column for the purification of PMZ and its metabolites from a urine matrix. The extraneous matrix interference was removed by flushing the extraction column with a gradient elution. The analytes of interest were then eluted onto an analytical column for further chromatographic separation using a mobile phase of greater solvent strength. This method is specific and sensitive with a range of 3.75-1400 ng/ml for PMZ and 2.5-1400 ng/ml for the metabolites promethazine sulfoxide, monodesmethyl promethazine sulfoxide and monodesmethyl promethazine. The lower limits of quantitation (LLOQ) were 3.75 ng/ml with less than 6.2% C.V. for PMZ and 2.50 ng/ml with less than 11.5% C.V. for metabolites based on a signal-to-noise ratio of 10:1 or greater. The accuracy and precision were within +/- 11.8% in bias and not greater than 5.5% C.V. in intra- and inter-assay precision for PMZ and metabolites. Method robustness was investigated using a Plackett-Burman experimental design. The applicability of the analytical method for pharmacokinetic studies in humans is illustrated.

  8. Metabolites from inhalation of aerosolized S-8 synthetic jet fuel in rats.

    Science.gov (United States)

    Tremblay, Raphael T; Martin, Sheppard A; Fisher, Jeffrey W

    2011-01-01

    Alternative fuels are being considered for civilian and military uses. One of these is S-8, a replacement jet fuel synthesized using the Fischer-Tropsch process, which contains no aromatic compounds and is mainly composed of straight and branched alkanes. Metabolites of S-8 fuel in laboratory animals have not been identified. The goal of this study was to identify metabolic products from exposure to aerosolized S-8 and a designed straight-chain alkane/polyaromatic mixture (decane, undecane, dodecane, tridecane, tetradecane, pentadecane, naphthalene, and 2-methylnaphthalene) in male Fischer 344 rats. Collected blood and tissue samples were analyzed for 70 straight and branched alcohols and ketones ranging from 7 to 15 carbons. No fuel metabolites were observed in the blood, lungs, brain, and fat following S-8 exposure. Metabolites were detected in the liver, urine, and feces. Most of the metabolites were 2- and 3-position alcohols and ketones of prominent hydrocarbons with very few 1- or 4-position metabolites. Following exposure to the alkane mixture, metabolites were observed in the blood, liver, and lungs. Interestingly, heavy metabolites (3-tridecanone, 2-tridecanol, and 2-tetradecanol) were observed only in the lung tissues possibly indicating that metabolism occurred in the lungs. With the exception of these heavy metabolites, the metabolic profiles observed in this study are consistent with previous studies reporting on the metabolism of individual alkanes. Further work is needed to determine the potential metabolic interactions of parent, primary, and secondary metabolites and identify more polar metabolites. Some metabolites may have potential use as biomarkers of exposure to fuels.

  9. Solanum tuberosum and Lycopersicon esculentum Leaf Extracts and Single Metabolites Affect Development and Reproduction of Drosophila melanogaster.

    Science.gov (United States)

    Ventrella, Emanuela; Adamski, Zbigniew; Chudzińska, Ewa; Miądowicz-Kobielska, Mariola; Marciniak, Paweł; Büyükgüzel, Ender; Büyükgüzel, Kemal; Erdem, Meltem; Falabella, Patrizia; Scrano, Laura; Bufo, Sabino Aurelio

    2016-01-01

    Glycoalkaloids are secondary metabolites commonly found in Solanaceae plants. They have anti-bacterial, anti-fungal and insecticidal activities. In the present study we examine the effects of potato and tomato leaf extracts and their main components, the glycoalkaloids α-solanine, α-chaconine and α-tomatine, on development and reproduction of Drosophila melanogaster wild-type flies at different stages. Parental generation was exposed to five different concentrations of tested substances. The effects were examined also on the next, non-exposed generation. In the first (exposed) generation, addition of each extract reduced the number of organisms reaching the pupal and imaginal stages. Parent insects exposed to extracts and metabolites individually applied showed faster development. However, the effect was weaker in case of single metabolites than in case of exposure to extracts. An increase of developmental rate was also observed in the next, non-exposed generation. The imagoes of both generations exposed to extracts and pure metabolites showed some anomalies in body size and malformations, such as deformed wings and abdomens, smaller black abdominal zone. Our results further support the current idea that Solanaceae can be an impressive source of molecules, which could efficaciously be used in crop protection, as natural extract or in formulation of single pure metabolites in sustainable agriculture.

  10. Solanum tuberosum and Lycopersicon esculentum Leaf Extracts and Single Metabolites Affect Development and Reproduction of Drosophila melanogaster.

    Directory of Open Access Journals (Sweden)

    Emanuela Ventrella

    Full Text Available Glycoalkaloids are secondary metabolites commonly found in Solanaceae plants. They have anti-bacterial, anti-fungal and insecticidal activities. In the present study we examine the effects of potato and tomato leaf extracts and their main components, the glycoalkaloids α-solanine, α-chaconine and α-tomatine, on development and reproduction of Drosophila melanogaster wild-type flies at different stages. Parental generation was exposed to five different concentrations of tested substances. The effects were examined also on the next, non-exposed generation. In the first (exposed generation, addition of each extract reduced the number of organisms reaching the pupal and imaginal stages. Parent insects exposed to extracts and metabolites individually applied showed faster development. However, the effect was weaker in case of single metabolites than in case of exposure to extracts. An increase of developmental rate was also observed in the next, non-exposed generation. The imagoes of both generations exposed to extracts and pure metabolites showed some anomalies in body size and malformations, such as deformed wings and abdomens, smaller black abdominal zone. Our results further support the current idea that Solanaceae can be an impressive source of molecules, which could efficaciously be used in crop protection, as natural extract or in formulation of single pure metabolites in sustainable agriculture.

  11. Quantitative analysis of elevation of serum creatinine via renal transporter inhibition by trimethoprim in healthy subjects using physiologically-based pharmacokinetic model.

    Science.gov (United States)

    Nakada, Tomohisa; Kudo, Toshiyuki; Kume, Toshiyuki; Kusuhara, Hiroyuki; Ito, Kiyomi

    2018-02-01

    Serum creatinine (SCr) levels rise during trimethoprim therapy for infectious diseases. This study aimed to investigate whether the elevation of SCr can be quantitatively explained using a physiologically-based pharmacokinetic (PBPK) model incorporating inhibition by trimethoprim on tubular secretion of creatinine via renal transporters such as organic cation transporter 2 (OCT2), OCT3, multidrug and toxin extrusion protein 1 (MATE1), and MATE2-K. Firstly, pharmacokinetic parameters in the PBPK model of trimethoprim were determined to reproduce the blood concentration profile after a single intravenous and oral administration of trimethoprim in healthy subjects. The model was verified with datasets of both cumulative urinary excretions after a single administration and the blood concentration profile after repeated oral administration. The pharmacokinetic model of creatinine consisted of the creatinine synthesis rate, distribution volume, and creatinine clearance (CL cre ), including tubular secretion via each transporter. When combining the models for trimethoprim and creatinine, the predicted increments in SCr from baseline were 29.0%, 39.5%, and 25.8% at trimethoprim dosages of 5 mg/kg (b.i.d.), 5 mg/kg (q.i.d.), and 200 mg (b.i.d.), respectively, which were comparable with the observed values. The present model analysis enabled us to quantitatively explain increments in SCr during trimethoprim treatment by its inhibition of renal transporters. Copyright © 2017 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

  12. Pharmacokinetics and metabolism of olerciamide A from Portulaca oleracea L. in rats by UHPLC-UV and UHPLC-ESI-Q-TOF/MS.

    Science.gov (United States)

    Ying, Zheming; Li, Cuiyu; Gao, Mingzhe; Ying, Xixiang; Yang, Guanlin

    2018-02-01

    The aim of this study was to elucidate the pharmacokinetics of olerciamide A in rats after oral and intravenous administration of Portulaca oleracea L. extract by a simple and rapid ultra high-performance liquid chromatography method with bergapten as internal standard. The pharmacokinetic results indicated that olerciamide A was rapidly distributed with a time to peak concentration of 30 min after oral administration and presented a low oral absolute bioavailability of 4.57%. The metabolism of olerciamide A in rats was also investigated using ultra-high-performance liquid chromatography electrospray coupled with quadrupole-time of flight mass spectrometry to elucidate the reason for the low absolute bioavailability of olerciamide A and seven metabolites of oleraciamide A were found in rat plasma and urine. Copyright © 2017 John Wiley & Sons, Ltd.

  13. [Diagnostic value of quantitative pharmacokinetic parameters and relative quantitative pharmacokinetic parameters in breast lesions with dynamic contrast-enhanced MRI].

    Science.gov (United States)

    Sun, T T; Liu, W H; Zhang, Y Q; Li, L H; Wang, R; Ye, Y Y

    2017-08-01

    Objective: To explore the differential between the value of dynamic contrast-enhanced MRI quantitative pharmacokinetic parameters and relative pharmacokinetic quantitative parameters in breast lesions. Methods: Retrospective analysis of 255 patients(262 breast lesions) who was obtained by clinical palpation , ultrasound or full-field digital mammography , and then all lessions were pathologically confirmed in Zhongda Hospital, Southeast University from May 2012 to May 2016. A 3.0 T MRI scanner was used to obtain the quantitative MR pharmacokinetic parameters: volume transfer constant (K(trans)), exchange rate constant (k(ep))and extravascular extracellular volume fraction (V(e)). And measured the quantitative pharmacokinetic parameters of normal glands tissues which on the same side of the same level of the lesions; and then calculated the value of relative pharmacokinetic parameters: rK(rans)、rk(ep) and rV(e).To explore the diagnostic value of two pharmacokinetic parameters in differential diagnosis of benign and malignant breast lesions using receiver operating curves and model of logistic regression. Results: (1)There were significant differences between benign lesions and malignant lesions in K(trans) and k(ep) ( t =15.489, 15.022, respectively, P 0.05). The areas under the ROC curve(AUC)of K(trans), k(ep) and V(e) between malignant and benign lesions were 0.933, 0.948 and 0.387, the sensitivity of K(trans), k(ep) and V(e) were 77.1%, 85.0%, 51.0% , and the specificity of K(trans), k(ep) and V(e) were 96.3%, 93.6%, 60.8% for the differential diagnosis of breast lesions if taken the maximum Youden's index as cut-off. (2)There were significant differences between benign lesions and malignant lesions in rK(trans), rk(ep) and rV(e) ( t =14.177, 11.726, 2.477, respectively, P quantitative pharmacokinetic parameters and the prediction probability of relative quantitative pharmacokinetic parameters( Z =0.867, P =0.195). Conclusion: There was no significant

  14. Absorption and disposition of LY127210, an orally effective hypotensive agent, in laboratory animals

    International Nuclear Information System (INIS)

    Turner, J.C.; White, J.F.; Sullivan, H.R.

    1986-01-01

    The disposition, pharmacokinetics, and metabolic fate of LY127210, 7,8-dimethoxy-(1H)-3-benzazepin-2-amine hydrochloride, have been studied in mice, rats, dogs and monkeys. Pharmacokinetic and bioavailability studies in dogs and monkeys showed it to be well absorbed orally with maximum plasma levels of drug obtained within 4 hr. Following administration of 14 C-LY127210, the plasma half-lives of parent and radiocarbon in rat were 11 hr and 45 hr (β-phase), respectively. In dogs and monkeys parent half-lives were 11 hr (β-phase) and 5.2 hr (monophasic) while half-lives of total radiocarbon were 145 hr (β-phase) and 299 hr (β-phase), respectively. Plasma concentrations of parent compound in rat, dog, and monkey following oral administration accounted for approximately 15% of circulating radiocarbon. Renal excretion was the major route of elimination. The major urinary species was LY127210; metabolic mechanisms included oxidative O-demethylation and deamination, aliphatic oxidation, and reduction. Radiocarbon tissue level studies in rat indicated wide distribution of drug and/or metabolites. Similar studies in monkeys indicated that the half-life of radiocarbon in tissues was equal to or greater than that in plasma and red blood cells. The long half-life of radiocarbon in blood was due to irreversible dose dependent binding of drug and/or metabolites to plasma albumin and to cellular hemoglobin

  15. [Study on differences between pharmacokinetics and chromatopharmacodynamics for Chinese materia medica formulae].

    Science.gov (United States)

    He, Fuyuan; Deng, Kaiwen; Zou, Huan; Qiu, Yun; Chen, Feng; Zhou, Honghao

    2011-01-01

    To study on the differences between chromatopharmacokinetics (pharmacokinetics with fingerprint chromatography) and chromatopharmacodynamics (pharmacodynamics with fingerprint chromatography) of Chinese materia medica formulae to answer the question whether the pharmacokinetic parameters of multiple composites can be utilized to guide the medication of multiple composites. On the base of established four chromatopharmacology (pharmacology with chromatographic fingerprint), the pharmacokinetics, and pharmacodynamics were analyzed comparably on their mathematical model and parameter definition. On the basis of quantitative pharmacology, the function expressions and total statistical parameters, such as total zero moment, total first moment, total second moment of the pharmacokinetics, and pharmacodynamics were analyzed to the common expressions and elucidated results for single and multiple components in Chinese materia medica formulae. Total quantitative pharmacokinetic, i.e., chromatopharmacokinetic parameter were decided by each component pharmacokinetic parameters, whereas the total quantitative pharmacodynamic, i.e., chromatopharmacodynamic parameter were decided by both of pharmacokinetic and pharmacodynamic parameters of each components. The pharmacokinetic parameters were corresponded to pharmacodynamic parameters with an existing stable effective coefficient when the constitutive ratio of each composite was a constant. The effects of Chinese materia medica were all controlled by pharmacokinetic and pharmacodynamic coefficient. It is a special case that the pharmacokinetic parameter could independently guide the clinical medication for single component whereas the chromatopharmacokinetic parameters are not applied to the multiple drug combination system, and not be used to solve problems of chromatopharmacokinetic of Chinese materia medica formulae.

  16. Application of Physiologically Based Pharmacokinetic Models in Chemical Risk Assessment

    Directory of Open Access Journals (Sweden)

    Moiz Mumtaz

    2012-01-01

    Full Text Available Post-exposure risk assessment of chemical and environmental stressors is a public health challenge. Linking exposure to health outcomes is a 4-step process: exposure assessment, hazard identification, dose response assessment, and risk characterization. This process is increasingly adopting “in silico” tools such as physiologically based pharmacokinetic (PBPK models to fine-tune exposure assessments and determine internal doses in target organs/tissues. Many excellent PBPK models have been developed. But most, because of their scientific sophistication, have found limited field application—health assessors rarely use them. Over the years, government agencies, stakeholders/partners, and the scientific community have attempted to use these models or their underlying principles in combination with other practical procedures. During the past two decades, through cooperative agreements and contracts at several research and higher education institutions, ATSDR funded translational research has encouraged the use of various types of models. Such collaborative efforts have led to the development and use of transparent and user-friendly models. The “human PBPK model toolkit” is one such project. While not necessarily state of the art, this toolkit is sufficiently accurate for screening purposes. Highlighted in this paper are some selected examples of environmental and occupational exposure assessments of chemicals and their mixtures.

  17. Parental Expression of Disappointment: Should It Be a Factor in Hoffman's Model of Parental Discipline?

    Science.gov (United States)

    Patrick, Renee B.; Gibbs, John C.

    2007-01-01

    The authors addressed whether parental expression of disappointment should be included as a distinct factor in M. L. Hoffman's (2000) well-established typology of parenting styles (induction, love withdrawal, power assertion). Hoffman's 3-factor model, along with a more inclusive 4-factor model (induction, love withdrawal, power assertion, and…

  18. Pharmacokinetics and Safety of Momelotinib in Subjects With Hepatic or Renal Impairment.

    Science.gov (United States)

    Xin, Yan; Kawashima, Jun; Weng, Winnie; Kwan, Ellen; Tarnowski, Thomas; Silverman, Jeffrey A

    2018-04-01

    Momelotinib is a Janus kinase 1/2 inhibitor in clinical development for the treatment of myelofibrosis. Two phase 1 open-label, parallel-group, adaptive studies were conducted to evaluate the pharmacokinetics of a single 200-mg oral dose of momelotinib in subjects with hepatic or renal impairment compared with healthy matched control subjects with normal hepatic or renal function. Plasma pharmacokinetics of momelotinib and its major active metabolite, M21, were evaluated, and geometric least-squares mean ratios (GMRs) and associated 90% confidence intervals (CIs) for impaired versus each control group were calculated for plasma exposures (area under concentration-time curve from time 0 to ∞ [AUC ∞ ] and maximum concentration) of momelotinib and M21. There was no clinically significant difference in plasma exposures of momelotinib and M21 between subjects with moderate or severe renal impairment or moderate hepatic impairment and healthy control subjects. Compared with healthy control subjects, momelotinib AUC ∞ was increased (GMR, 197%; 90%CI, 129%-301%), and M21 AUC ∞ was decreased (GMR, 52%; 90%CI, 34%-79%) in subjects with severe hepatic impairment. The safety profile following a single dose of momelotinib was similar between subjects with hepatic or renal dysfunction and healthy control subjects. These pharmacokinetic and safety results indicate that dose adjustment is not necessary for momelotinib in patients with renal impairment or mild to moderate hepatic impairment. In patients with severe hepatic impairment, however, the dose of momelotinib should be reduced. © 2017, The American College of Clinical Pharmacology.

  19. Plasma and cerebrospinal fluid pharmacokinetics of flurbiprofen in children

    Science.gov (United States)

    Kumpulainen, Elina; Välitalo, Pyry; Kokki, Merja; Lehtonen, Marko; Hooker, Andrew; Ranta, Veli-Pekka; Kokki, Hannu

    2010-01-01

    AIMS This study was designed to characterize paediatric pharmacokinetics and central nervous system exposure of flurbiprofen. METHODS The pharmacokinetics of flurbiprofen were studied in 64 healthy children aged 3 months to 13 years, undergoing surgery with spinal anaesthesia. Children were administered preoperatively a single dose of flurbiprofen intravenously as prodrug (n = 27) or by mouth as syrup (n = 37). A single cerebrospinal fluid (CSF) sample (n = 60) was collected at the induction of anaesthesia, and plasma samples (n = 304) before, during and after the operation (up to 20 h after administration). A population pharmacokinetic model was built using the NONMEM software package. RESULTS Flurbiprofen concentrations in plasma were well described by a three compartment model. The apparent bioavailability of oral flurbiprofen syrup was 81%. The estimated clearance (CL) was 0.96 l h−1 70 kg−1. Age did not affect the clearance after weight had been included as a covariate. The estimated volume of distribution at steady state (Vss) was 8.1 l 70 kg−1. Flurbiprofen permeated into the CSF, reaching concentrations that were seven-fold higher compared with unbound plasma concentrations. CONCLUSIONS Flurbiprofen pharmacokinetics can be described using only weight as a covariate in children above 6 months, while more research is needed in neonates and in younger infants. PMID:20840447

  20. Modelling concentration-analgesia relationships for morphine to evaluate experimental pain models

    DEFF Research Database (Denmark)

    Sverrisdóttir, Eva; Foster, David John Richard; Upton, Richard Neil

    2015-01-01

    The aim of this study was to develop population pharmacokinetic-pharmacodynamic models for morphine in experimental pain induced by skin heat and muscle pressure, and to evaluate the experimental pain models with regard to assessment of morphine pharmacodynamics. In a randomized, double......-blind, placebo-controlled, crossover study, 39 healthy volunteers received an oral dose of 30 mg morphine hydrochloride or placebo. Non-linear mixed effects modelling was used to describe the plasma concentrations of morphine and metabolites, and the analgesic effect of morphine on experimental pain in skin...... and muscle. Baseline pain metrics varied between individuals and occasions, and were described with interindividual and interoccasion variability. Placebo-response did not change with time. For both pain metrics, morphine effect was proportional to baseline pain and was described with a linear model...