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Sample records for metabolic detoxication drug

  1. The UDP-glucuronosyltransferases of the blood-brain barrier: their role in drug metabolism and detoxication

    Directory of Open Access Journals (Sweden)

    Mohamed eOuzzine

    2014-10-01

    Full Text Available UDP-glucuronosyltransferases (UGTs form a multigenic family of membrane-bound enzymes expressed in various tissues, including brain. They catalyze the formation of β-Dglucuronides from structurally unrelated substances (drugs, other xenobiotics, as well as endogenous compounds by the linkage of glucuronic acid from the high energy donor, UDP-αD-glucuronic acid. In brain, UGTs actively participate to the overall protection of the tissue against the intrusion of potentially harmful lipophilic substances that are metabolized as hydrophilic glucuronides. These metabolites are generally inactive, except for important pharmacologically glucuronides such as morphine-6-glucuronide. UGTs are mainly expressed in endothelial cells and astrocytes of the blood brain barrier. They are also associated to brain interfaces devoid of blood-brain barrier, such as circumventricular organ, pineal gland, pituitary gland and neuro-olfactory tissues. Beside their key-role as a detoxication barrier, UGTs play a role in the steady-state of endogenous compounds, like steroids or dopamine that participate to the function of the brain. UGT isoforms of family 1A, 2A, 2B and 3A are expressed in brain tissues to various levels and are known to present distinct but overlapping substrate specificity. The importance of these enzyme species with regard to the formation of toxic, pharmacologically or physiologically relevant glucuronides in the brain will be discussed.

  2. Drug Metabolism

    Indian Academy of Sciences (India)

    IAS Admin

    Chemistry of Drug Metabolism. Drug metabolism is a chemical process, where enzymes play a crucial role in the conversion of one chemical species to another. The major family of enzymes associated with these metabolic reactions is the cytochrome P450 family. The structural features and functional activity of these ...

  3. Drug Metabolism

    Indian Academy of Sciences (India)

    IAS Admin

    Drug metabolism may be defined as the biochemical modifica- tion of one chemical form to another, occurring usually through ..... Endogenous. Enzyme. Drugs. Cofactor. Glucuronidation. UDP glucoronic. UDP-. Chloramphenicol, acid glucuronosyltransferase morphine, paracetamol, salicylic acid, fenoprofen, desipramine,.

  4. Drug Metabolism

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 19; Issue 3. Drug Metabolism: A Fascinating Link Between Chemistry and Biology. Nikhil Taxak Prasad V Bharatam. General Article Volume 19 Issue 3 March 2014 pp 259-282 ...

  5. Profiles in drug metabolism and toxicology: Richard Tecwyn Williams (1909-1979).

    Science.gov (United States)

    Jones, Alan Wayne

    2015-01-01

    This article pays homage to the life and work of a veritable pioneer in toxicology and drug metabolism, namely a Welshman, Richard Tecwyn Williams, FRS. Professor Williams, or RT as he was known, made major contributions to knowledge about the metabolism and toxicology of drugs and xenobiotics during a scientific career spanning nearly 50 years. Author or coauthor of close to 400 research articles and reviews, including a classic book, entitled Detoxication Mechanisms, Williams and his research school investigated virtually all aspects of drug metabolism, especially conjugations. In particular, the concepts of phase 1 and phase II metabolic pathways were introduced by Williams; the biliary excretion of drugs was extensively studied as were species differences in drug metabolism and detoxication. Besides investigating the metabolism of many pharmaceutical drugs, such as sulfonamides and thalidomide, Williams and his group investigated the disposition and fate in the body of organic pesticides and recreational drugs of abuse, such as amphetamine, methamphetamine and lysergic acid diethylamide (LSD).

  6. Detox fashion supply chain

    CERN Document Server

    2017-01-01

    This first volume on detox fashion discusses various interesting topics including a Toxic-Free Supply Chain for Textiles and Clothing; Environmental Issues in Textiles; Global Regulations, Restrictions & Research; Making the Change: Consumer Adoption of Sustainable Fashion; and Strategies for Detoxing Your Wardrobe. It provides an overview of the chemical-related issues confronting the fashion sector, summarizes global regulations, and discusses how to make the change by changing consumers’ attitude towards adopting sustainable fashion, as well as the best strategies for detoxing our wardrobes.

  7. Are Detox Diets Safe?

    Science.gov (United States)

    ... Your Body Does the Rest Print en español ¿Son seguras las dietas de desintoxicación? What Is a ... including serious eating disorders, heart problems, and even death. Detox supplements can have side effects. Many of ...

  8. Enzymatic Detoxication, Conformational Selection, and the Role of Molten Globule Active Sites*

    Science.gov (United States)

    Honaker, Matthew T.; Acchione, Mauro; Zhang, Wei; Mannervik, Bengt; Atkins, William M.

    2013-01-01

    The role of conformational ensembles in enzymatic reactions remains unclear. Discussion concerning “induced fit” versus “conformational selection” has, however, ignored detoxication enzymes, which exhibit catalytic promiscuity. These enzymes dominate drug metabolism and determine drug-drug interactions. The detoxication enzyme glutathione transferase A1–1 (GSTA1–1), exploits a molten globule-like active site to achieve remarkable catalytic promiscuity wherein the substrate-free conformational ensemble is broad with barrierless transitions between states. A quantitative index of catalytic promiscuity is used to compare engineered variants of GSTA1–1 and the catalytic promiscuity correlates strongly with characteristics of the thermodynamic partition function, for the substrate-free enzymes. Access to chemically disparate transition states is encoded by the substrate-free conformational ensemble. Pre-steady state catalytic data confirm an extension of the conformational selection model, wherein different substrates select different starting conformations. The kinetic liability of the conformational breadth is minimized by a smooth landscape. We propose that “local” molten globule behavior optimizes detoxication enzymes. PMID:23649628

  9. The Role of Human Aldo-Keto Reductases (AKRs in the Metabolic Activation and Detoxication of Polycyclic Aromatic Hydrocarbons: Interconversion of PAH-catechols and PAH o-Quinones

    Directory of Open Access Journals (Sweden)

    Li eZhang

    2012-11-01

    Full Text Available Polycyclic aromatic hydrocarbons (PAH are ubiquitous environmental pollutants. They are procarcinogens requiring metabolic activation to elicit their deleterious effects. Aldo-keto reductases (AKR catalyze the oxidation of proximate carcinogenic PAH trans-dihydrodiols to yield electrophilic and redox-active PAH o-quiniones. AKRs are also found to be capable of reducing PAH o-quinones to form PAH catechols. The interconversion of o-quinones and catechols results in the redox cycling of PAH o-quinones to give rise to the generation of reactive oxygen species and subsequent oxidative DNA damage. On the other hand, PAH catechols can be intercepted through phase II metabolism by which PAH o-quinones could be detoxified and eliminated. The aim of the present review is to summarize the role of human AKRs in the metabolic activation/detoxication of PAH and the relevance of phase II conjugation reactions to human lung carcinogenesis.

  10. Human drug metabolism: an introduction

    National Research Council Canada - National Science Library

    Coleman, Michael D

    2010-01-01

    ..., both under drug pressure and during inhibition. Factors affecting drug metabolism, such as genetic polymorphisms, age and diet are discussed and how metabolism can lead to toxicity is explained. The book concludes with the role of drug metabolism in the commercial development of therapeutic agents as well as the pharmacology of some illicit drugs.

  11. Human drug metabolism: an introduction

    National Research Council Canada - National Science Library

    Coleman, Michael D

    2010-01-01

    ... metabolism and its impact on patient welfare. After underlining the relationship between efficacy, toxicity and drug concentration, the book then considers how metabolizing systems operate and how they impact upon drug concentration...

  12. Human drug metabolism: an introduction

    National Research Council Canada - National Science Library

    Coleman, Michael D

    2010-01-01

    Human Drug Metabolism, An Introduction, Second Edition provides an accessible introduction to the subject and will be particularly invaluable to those who already have some understanding of the life sciences...

  13. Drug treatment of metabolic syndrome.

    Science.gov (United States)

    Altabas, Velimir

    2013-08-01

    The metabolic syndrome is a constellation of risk factors for cardiovascular diseases including: abdominal obesity, a decreased ability to metabolize glucose (increased blood glucose levels and/or presence of insulin resistance), dyslipidemia, and hypertension. Patients who have developed this syndrome have been shown to be at an increased risk of developing cardiovascular disease and/or type 2 diabetes. Genetic factors and the environment both are important in the development of the metabolic syndrome, influencing all single components of this syndrome. The goals of therapy are to treat the underlying cause of the syndrome, to reduce morbidity, and to prevent complications, including premature death. Lifestyle modification is the preferred first-step treatment of the metabolic syndrome. There is no single effective drug treatment affecting all components of the syndrome equally known yet. However, each component of metabolic syndrome has independent goals to be achieved, so miscellaneous types of drugs are used in the treatment of this syndrome, including weight losing drugs, antidiabetics, antihypertensives, antilipemic and anticlothing drugs etc. This article provides a brief insight into contemporary drug treatment of components the metabolic syndrome.

  14. Food addiction: detox and abstinence reinterpreted?

    Science.gov (United States)

    Shriner, Richard L

    2013-10-01

    The senior patient and/or the geriatrician are confronted with a confusing literature describing how patients interested in combating metabolic syndrome, diabesity (diabetes plus obesity) or simple obesity might best proceed. The present paper gives a brief outline of the basic disease processes that underlie metabolic pro-inflammation, including how one might go about devising the most potent and practical detoxification from such metabolic compromise. The role that dietary restriction plays in pro-inflammatory detoxification (detox), including how a modified fast (selective food abstinence) is incorporated into this process, is developed. The unique aspects of geriatric bariatric medicine are elucidated, including the concepts of sarcopenia and the obesity paradox. Important caveats involving the senior seeking weight loss are offered. By the end of the paper, the reader will have a greater appreciation for the challenges and opportunities that lie ahead for geriatric patients who wish to overcome food addiction and reverse pro-inflammatory states of ill-heath. This includes the toxic metabolic processes that create obesity complicated by type 2 diabetes mellitus (T2DM) which collectively we call diabesity. In that regard, diabesity is often the central pathology that leads to the evolution of the metabolic syndrome. The paper also affords the reader a solid review of the neurometabolic processes that effectuate anorexigenic versus orexigenic inputs to obesity that drive food addiction. We argue that these processes lead to either weight gain or weight loss by a tripartite system involving metabolic, addictive and relational levels of organismal functioning. Recalibrating the way we negotiate these three levels of daily functioning often determines success or failure in terms of overcoming metabolic syndrome and food addiction. Copyright © 2013 Elsevier Inc. All rights reserved.

  15. Impact of a Detox Diet paradigm in Weight Management

    Directory of Open Access Journals (Sweden)

    Marie Therese Khalil

    2017-11-01

    Full Text Available Research Question: The main Research Question concerns the attitudes of the respondents about the “detox” diet. The term detoxification as a concept is not considered as new but its application has known a drift starting from religious point of view in terms of purification and redemption to therapeutically characteristic in treating alcohol or drug addiction until its new relevance in treating obesity and reducing fat. This new paradigm has been used in health and wellness centres by dieticians and practitioners to overcome the failure of traditional diet programs. Purpose: The purpose of the study is to define, present and qualify the “detox” concept or paradigm and to investigate the attitudes of the respondents towards the “detox” concept as a diet method. Method: Participants in the study are divided into two groups; the group that already used “detox” and the group that have not yet used “detox” diet. The two groups are asked the same questions which are designed to measure their attitudes regarding “detox” diet. For this purpose, a quantitative analysis is conducted using descriptive statistical non-parametric method Chi-Square. Results: There is no significant difference of attitudes toward a detox diet between the users and non-users of it (p >0.05. The results of the study show that detox diet is not something appealing for the ones who went through it although they admit that it is an effective method to lose weight and get healthy. The same approach sounds to be seductive for the patients who didn’t try it before in order to get healthy without specifying the right time to follow such diet. Organization: The results of the study emphasises the need of organizations who provide “detox” diet, to present it to the potential customers and to point out its positive effects on the health of the people, who use it. Society: Study results emphasise the social responsibility of the providers of “detox” and

  16. Gender Differences in Emergency Department Visits and Detox Referrals for Illicit and Nonmedical Use of Opioids

    Directory of Open Access Journals (Sweden)

    Hyeon-Ju Ryoo

    2016-05-01

    Full Text Available Introduction: Visits to the emergency department (ED for use of illicit drugs and opioids have increased in the past decade. In the ED, little is known about how gender may play a role in drug-related visits and referrals to treatment. This study performs gender-based comparison analyses of drug-related ED visits nationwide. Methods: We performed a cross-sectional analysis with data collected from 2004 to 2011 by the Drug Abuse Warning Network (DAWN. All data were coded to capture major drug categories and opioids. We used logistic regression models to find associations between gender and odds of referral to treatment programs. A second set of models were controlled for patient “seeking detox,” or patient explicitly requesting for detox referral. Results: Of the 27.9 million ED visits related to drug use in the DAWN database, visits by men were 2.69 times more likely to involve illicit drugs than visits by women (95% CI [2.56, 2.80]. Men were more likely than women to be referred to detox programs for any illicit drugs (OR 1.12, 95% CI [1.02-1.22], for each of the major illicit drugs (e.g., cocaine: OR 1.27, 95% CI [1.15-1.40], and for prescription opioids (OR 1.30, 95% CI [1.17-1.43]. This significant association prevailed after controlling for “seeking detox.” Conclusion: Women are less likely to receive referrals to detox programs than men when presenting to the ED regardless of whether they are “seeking detox.” Future research may help determine the cause for this gender-based difference and its significance for healthcare costs and health outcomes.

  17. Cytochrome b(5) shifts oxidation of the anticancer drug ellipticine by cytochromes P450 1A1 and 1A2 from its detoxication to activation, thereby modulating its pharmacological efficacy.

    Science.gov (United States)

    Kotrbová, Věra; Mrázová, Barbora; Moserová, Michaela; Martínek, Václav; Hodek, Petr; Hudeček, Jiří; Frei, Eva; Stiborová, Marie

    2011-09-15

    Ellipticine is a pro-drug, whose activation is dependent on its oxidation by cytochromes P450 (CYP) and peroxidases. Cytochrome b(5) alters the ratio of ellipticine metabolites formed by isolated reconstituted CYP1A1 and 1A2, favoring formation of 12-hydroxy- and 13-hydroxyellipticine metabolites implicated in ellipticine-DNA adduct formation, at the expense of 9-hydroxy- and 7-hydroxyellipticine that are detoxication products. Cytochrome b(5) enhances the production of 12-hydroxy and 13-hydroxyellipticine. The change in metabolite ratio results in an increased formation of covalent ellipticine-DNA adducts, one of the DNA-damaging mechanisms of ellipticine antitumor action. This finding explains previous apparent discrepancies found with isolated enzymes and in vivo, where CYP1A enzymatic activation correlated with ellipticine-DNA-adduct levels while isolated CYP1A1 or 1A2 in reconstituted systems were much less effective than CYP3A4. The effect of cytochrome b(5) might be even more pronounced in vivo, since, as we show here, ellipticine increases levels of cytochrome b(5) in rat liver. Our results demonstrate that both the native 3D structure of cytochrome b(5) and the presence of the heme as an electron transfer agent in this protein enable a shift in ellipticine metabolites formed by CYP1A1/2. Copyright © 2011 Elsevier Inc. All rights reserved.

  18. A detoxication route for acetaldehyde: metabolism of diacetyl, acetoin, and 2,3-butanediol in liver homogenate and perfused liver of rats.

    Science.gov (United States)

    Otsuka, M; Mine, T; Ohuchi, K; Ohmori, S

    1996-02-01

    The metabolism of diacetyl (2,3-butanedione), acetoin (3-hydroxy-2-butanone), and 2,3-butanediol, which are metabolites of acetaldehyde was quantitatively investigated using rat liver homogenate, liver perfusion, and in vivo experiments. Diacetyl and acetoin were reduced to 2,3-butanediol in these experiments, but acetoin and 2,3-butanediol were scarcely oxidized to diacetyl, indicating that the reduction reaction to 2,3-butanediol from diacetyl occurs actively in rat liver. The formation of acetoin from diacetyl required either NADH or NADPH as a reductant, while the reduction of acetoin to 2,3-butanediol required NADH. Acetoin and 2,3-butanediol were more readily accumulated than diacetyl in brain tissue.

  19. Predicting drug metabolism: Concepts and challenges

    OpenAIRE

    Testa, B.; Balmat, A.-L; Long, Anthony

    2017-01-01

    The paper begins with a discussion of the needs and goals of metabolic predictions in early drug research. Major difficulties toward this objective are examined, mainly the various substrate and product selectivities characteristic of drug metabolism. In a second part, we classify and summarize the major in silico methods used to predict drug metabolism. A discrimination is thus made between "local ”and "global ”systems. In the last part of the paper, the program METEOR is presented and evalu...

  20. Human drug metabolism: an introduction

    National Research Council Canada - National Science Library

    Coleman, Michael D

    2010-01-01

    .... Completely revised and updated throughout, the new edition focuses only on essential chemical detail and includes patient case histories to illustrate the clinical consequences of changes in drug...

  1. Pharmacokinetics and drug metabolism in the elderly.

    Science.gov (United States)

    Klotz, Ulrich

    2009-01-01

    Aging involves progressive impairments in the functional reserve of multiple organs, which might also affect drug metabolism and pharmacokinetics. In addition, the elderly population will develop multiple diseases and, consequently, often has to take several drugs. As the hepatic first-pass effect of highly cleared drugs could be reduced (due to decreases in liver mass and perfusion), the bioavailability of some drugs can be increased in the elderly. Significant changes in body composition occur with advancing age. Lipophilic drugs may have an increased volume of distribution (Vd) with a prolonged half-life, and water-soluble drugs tend to have a smaller Vd. In the elderly, hepatic drug clearance of some drugs can be reduced by up to 30% and CYP-mediated phase I reactions are more likely to be impaired than phase II metabolism, which is relatively preserved in the elderly. Concerning the most important CYP3A4 studies with human liver microsomes and clinical studies with the validated probe, midazolam, it is indicated that there are no significant differences in CYP3A4 activity between young and old populations. Finally, renal excretion is decreased (up to 50%) in about two thirds of elderly subjects, but confounding factors such as hypertension and coronary heart disease account also for a decline in kidney function. In conclusion, age-related physiological and pharmacokinetic changes as well as the presence of comorbidity and polypharmacy will complicate drug therapy in the elderly.

  2. Study of Drug Metabolism by Xanthine Oxidase

    Directory of Open Access Journals (Sweden)

    Lizhou Sun

    2012-04-01

    Full Text Available In this work, we report the studies of drug metabolism by xanthine oxidase (XOD with electrochemical techniques. Firstly, a pair of stable, well-defined and quasi-reversible oxidation/reduction peaks is obtained with the formal potential at −413.1 mV (vs. SCE after embedding XOD in salmon sperm DNA membrane on the surface of pyrolytic graphite electrode. Then, a new steady peak can be observed at −730 mV (vs. SCE upon the addition of 6-mercaptopurine (6-MP to the electrochemical system, indicating the metabolism of 6-MP by XOD. Furthermore, the chronoamperometric response shows that the current of the catalytic peak located at −730 mV increases with addition of 6-MP in a concentration-dependent manner, and the increase of the chronoamperometric current can be inhibited by an XOD inhibitor, quercetin. Therefore, our results prove that XOD/DNA modified electrode can be efficiently used to study the metabolism of 6-MP, which may provide a convenient approach for in vitro studies on enzyme-catalyzed drug metabolism.

  3. Can vaccines interact with drug metabolism?

    Science.gov (United States)

    Pellegrino, Paolo; Clementi, Emilio; Capuano, Annalisa; Radice, Sonia

    2015-02-01

    Vaccines are safe and efficacious in reducing the burden of several serious infections affecting children and adults. Due to their efficacy, vaccines are often administered in patients with chronic diseases, likely to be under poly-therapy. Because of several case reports indicating changes in drug metabolism after vaccination, the hypothesis of an interaction between vaccines and specific drugs has been put forward. These interactions are conceivably of great concern, especially in patients treated with molecules characterised by a narrow therapeutic index. Herein, we review and systematise the available evidence on vaccine-drug interactions. The picture that emerges indicates that reduction in the activity of specific CYPs following vaccination may occur, most likely via interferon γ overproduction, and for specific drugs such as anticonvulsivant and theophylline may have significant clinical relevance. Clinical interaction between vaccines and drugs that are metabolised by cytochromes uninfluenced by INFγ levels, such as warfarin, are instead unlikely to happen. Further studies are however needed to gain a complete picture of vaccine-drug interactions and define their relevance in terms of possible negative clinical impact. Copyright © 2014 Elsevier Ltd. All rights reserved.

  4. 21 CFR 862.3360 - Drug metabolizing enzyme genotyping system.

    Science.gov (United States)

    2010-04-01

    ....3360 Section 862.3360 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... Test Systems § 862.3360 Drug metabolizing enzyme genotyping system. (a) Identification. A drug metabolizing enzyme genotyping system is a device intended for use in testing deoxyribonucleic acid (DNA...

  5. Important role of proinflammatory cytokines/other endogenous substances in drug-induced hepatotoxicity: depression of drug metabolism during infections/inflammation states, and genetic polymorphisms of drug-metabolizing enzymes/cytokines may markedly contribute to this pathology.

    Science.gov (United States)

    Prandota, Joseph

    2005-01-01

    Analysis of literature data on drug-induced hepatotoxicity reveals that often upper respiratory febrile illnesses and/or inflammation states precede liver injury/diseases related to administration of drugs or hepatotoxicity associated with administration of therapeutic doses of acetaminophen in some genetically predisposed subjects. The goals of this paper are to review the potential role of alterations in the balance between TH1 cells producing cytokines associated with a cell-mediated response and TH2 cells associated with an antibody response, as well as other endogenous substances, eg, growth factors, leading to a shift in immune response to one that may participate in the liver cells injury during administration of certain drugs, especially in subjects with genetic polymorphisms in drug-metabolizing enzymes. The papers cited in this review were selected to illustrate specific issue related to how profuse and dysregulated production of cytokines, growth factors, and/or other endogenous substances during viral/bacterial infections and inflammation states play a role in the development of drug-induced liver injury. Several cases of liver injury related to administration of drugs appear to be initiated or intensified by upper respiratory febrile illnesses and/or inflammation states, which stimulate sometimes dysregulated production of interferon gamma and/or other proinflammatory cytokines/growth factors. This, in turn, results in down-regulation of various induced and constitutive isoforms of cytochromes P-450, and other enzymes involved in the metabolism of several exogenous (eg, drugs) and endogenous lipophilic (eg, steroids) substances, thus having an important impact on the alterations in bioactivation and detoxication processes in the body and on the balance between production, utilization, and elimination of endogenous bioproducts of these reactions. Activation of systemic host defense mechanisms results in down-regulation of various enzymes involved in

  6. Biological control and management of the detoxication wastewater treatment technologies

    Directory of Open Access Journals (Sweden)

    Topalova Yana

    2007-01-01

    Full Text Available Detoxication technologies require the combination of theoretical and practical knowledge of xenobiotic biodegradation, wastewater treatment technologies, and management rules. The purpose of this complicated combination is to propose specialized strategies for detoxication, based on lab- and pilot-scale modeling. These strategies include preliminary created algorithms for preventing the risk of water pollution and sediments. The technologies and algorithms are essentially important outcome, applied in the textile, pharmaceutical, cosmetic, woodtreating, and oiltreating industries. In this paper four rehabilitation technologies for pretreatment of water contaminated by pentachlorophenol (PCP have been developed in the frame of the European and Bulgarian National projects. Emphasize is put on the biological systems and their potential of detoxication management. The light and transmission electron microscopy of the reconstructed activated sludges the microbial, kinetic and enzymological indicators are presented and approved as critical points in the biocontrol.

  7. PXR antagonists and implication in drug metabolism

    Science.gov (United States)

    Mani, Sridhar; Dou, Wei; Redinbo, Matthew R.

    2013-01-01

    Adopted orphan nuclear receptor (NR), pregnane X receptor (PXR), plays a central role in the regulation of xeno- and endobiotic metabolism. Since the discovery of the functional role of PXR in 1998, there is evolving evidence for the role of PXR agonists in abrogating metabolic pathophysiology (e.g., cholestasis, hypercholesterolemia, and inflammation). However, more recently, it is clear that PXR is also an important mediator of adverse xeno- (e.g., enhances acetaminophen toxicity) and endobiotic (e.g., hepatic steatosis) metabolic phenotypes. Moreover, in cancer therapeutics, PXR activation can induce drug resistance, and there is growing evidence for tissue-specific enhancement of the malignant phenotype. Thus, in these instances, there may be a role for PXR antagonists. However, as opposed to the discovery efforts for PXR agonists, there are only a few antagonists described. The mode of action of these antagonists (e.g., sulforaphane) remains less clear. Our laboratory efforts have focused on this question. Since the original discovery of azoles analogs as PXR antagonists, we have preliminarily defined an important PXR antagonist pharmacophore and developed less-toxic PXR antagonists. In this review, we describe our published and unpublished findings on recent structure-function studies involving the azole chemical scaffold. Further work in the future is needed to fully define potent, more-selective PXR antagonists that may be useful in clinical application. PMID:23330542

  8. Interplay of drug metabolizing enzymes with cellular transporters.

    Science.gov (United States)

    Böhmdorfer, Michaela; Maier-Salamon, Alexandra; Riha, Juliane; Brenner, Stefan; Höferl, Martina; Jäger, Walter

    2014-11-01

    Many endogenous and xenobiotic substances and their metabolites are substrates for drug metabolizing enzymes and cellular transporters. These proteins may not only contribute to bioavailability of molecules but also to uptake into organs and, consequently, to overall elimination. The coordinated action of uptake transporters, metabolizing enzymes, and efflux pumps, therefore, is a precondition for detoxification and elimination of drugs. As the understanding of the underlying mechanisms is important to predict alterations in drug disposal, adverse drug reactions and, finally, drug-drug interactions, this review illustrates the interplay between selected uptake/efflux transporters and phase I/II metabolizing enzymes.

  9. Metabolic engineering of microorganisms: general strategies and drug production.

    Science.gov (United States)

    Lee, Sang Yup; Kim, Hyun Uk; Park, Jin Hwan; Park, Jong Myung; Kim, Tae Yong

    2009-01-01

    Many drugs and drug precursors found in natural organisms are rather difficult to synthesize chemically and to extract in large amounts. Metabolic engineering is playing an increasingly important role in the production of these drugs and drug precursors. This is typically achieved by establishing new metabolic pathways leading to the product formation, and enforcing or removing the existing metabolic pathways toward enhanced product formation. Recent advances in system biology and synthetic biology are allowing us to perform metabolic engineering at the whole cell level, thus enabling optimal design of a microorganism for the efficient production of drugs and drug precursors. In this review, we describe the general strategies for the metabolic engineering of microorganisms for the production of drugs and drug precursors. As successful examples of metabolic engineering, the approaches taken toward strain development for the production of artemisinin, an antimalarial drug, and benzylisoquinoline alkaloids, a family of antibacterial and anticancer drugs, are described in detail. Also, systems metabolic engineering of Escherichia coli for the production of L-valine, an important drug precursor, is showcased as an important strategy of future metabolic engineering effort.

  10. Drug-Induced Metabolic Acidosis [version 1; referees: 3 approved

    Directory of Open Access Journals (Sweden)

    Amy Quynh Trang Pham

    2015-12-01

    Full Text Available Metabolic acidosis could emerge from diseases disrupting acid-base equilibrium or from drugs that induce similar derangements. Occurrences are usually accompanied by comorbid conditions of drug-induced metabolic acidosis, and clinical outcomes may range from mild to fatal. It is imperative that clinicians not only are fully aware of the list of drugs that may lead to metabolic acidosis but also understand the underlying pathogenic mechanisms. In this review, we categorized drug-induced metabolic acidosis in terms of pathophysiological mechanisms, as well as individual drugs’ characteristics.

  11. Sex Differences in the Expression of Hepatic Drug Metabolizing Enzymes

    OpenAIRE

    Waxman, David J.; Holloway, Minita G.

    2009-01-01

    Sex differences in pharmacokinetics and pharmacodynamics characterize many drugs and contribute to individual differences in drug efficacy and toxicity. Sex-based differences in drug metabolism are the primary cause of sex-dependent pharmacokinetics and reflect underlying sex differences in the expression of hepatic enzymes active in the metabolism of drugs, steroids, fatty acids and environmental chemicals, including cytochromes P450 (P450s), sulfotransferases, glutat...

  12. Links between nutrition, drug abuse, and the metabolic syndrome.

    Science.gov (United States)

    Virmani, Ashraf; Binienda, Zbigniew; Ali, Syed; Gaetani, Franco

    2006-08-01

    Nutritional deficiency in combination with drug abuse may increase risk of developing the metabolic syndrome by augmenting cell damage, excitotoxicity, reducing energy production, and lowering the antioxidant potential of the cells. We have reviewed here the following points: effects of drugs of abuse on nutrition and brain metabolism; effects of nutrition on actions of the drugs of abuse; drug abuse and probability of developing metabolic syndrome; role of genetic vulnerability in nutrition/drug abuse and brain damage; and the role of neuroprotective supplements in drug abuse. Nutrition education is an essential component of substance abuse treatment programs and can enhance substance abuse treatment outcomes. The strategies available, in particular the nutritional approach to protect the drug abusers from the metabolic syndrome and other diseases are discussed.

  13. Quantum Mechanics/Molecular Mechanics Modeling of Drug Metabolism

    DEFF Research Database (Denmark)

    Lonsdale, Richard; Fort, Rachel M; Rydberg, Patrik

    2016-01-01

    The mechanism of cytochrome P450(CYP)-catalyzed hydroxylation of primary amines is currently unclear and is relevant to drug metabolism; previous small model calculations have suggested two possible mechanisms: direct N-oxidation and H-abstraction/rebound. We have modeled the N-hydroxylation of (R...... are useful for understanding drug metabolism....

  14. Fast prediction of cytochrome P450 mediated drug metabolism

    DEFF Research Database (Denmark)

    Rydberg, Patrik Åke Anders; Poongavanam, Vasanthanathan; Oostenbrink, Chris

    2009-01-01

    Cytochrome P450 mediated metabolism of drugs is one of the major determinants of their kinetic profile, and prediction of this metabolism is therefore highly relevant during the drug discovery and development process. A new rule-based method, based on results from density functional theory...

  15. Nutritional conditioning : The effect of fasting on drug metabolism

    NARCIS (Netherlands)

    Lammers, L.A.

    2018-01-01

    The studies described in this thesis focus on the effect of fasting, as nutritional modulator, on drug metabolism. Drug metabolism varies considerably between and within patients, which may result in treatment failure or, conversely, in untoward side effects. Many factors contribute to the

  16. Barriers to Accessing Detox Facilities, Substance Use Treatment, and Residential Services among Women Impacted by Commercial Sexual Exploitation & Trafficking.

    Science.gov (United States)

    Gerassi, Lara B

    2017-10-06

    More than 50% of women entering substance use treatment in the U.S. reported having traded sex for money or drugs. Women's participation in addiction treatment and related services is essential to their recovery and increased safety, stabilization, and quality of life. This paper's aim is to explore the barriers related to accessing detox facilities and essential services including substance use treatment and residential services for women impacted by commercial sexual exploitation (CSE). Data are drawn from a larger, community-based, grounded theory study. In-depth interview data were collected from 30 adult women who traded sex as adults (through maximum variation and snowball sampling), as well as 20 service providers who come into contact with adult women who trade sex (through nominations and purposive sampling). Finding suggest that women often encountered sobriety requirements, which created barriers to accessing addiction treatment or residential services. Some organizations' policies required evicting women if they were caught using, which created additional challenges for women who relapsed. Women wanted to avoid becoming "dopesick" on the streets or at home, which partially contributed to them needing to maintain their addiction. Consequently, some returned to sex trading, thus increasing their risk of trafficking. Some women engaged in creative strategies, such as claiming they were suicidal, in order to access the detox facilities in hospitals. Some women indicated they were only able to detox when they were forced to do so in jail or prison, often without medical assistance. Implications to improve health care delivery for this population are discussed.

  17. In vitro methods to study intestinal drug metabolism

    NARCIS (Netherlands)

    van de Kerkhof, Esther G.; de Graaf, Inge A. M.; Groothuis, Geny M. M.

    2007-01-01

    Although the liver has long been thought to play the major role in drug metabolism, also the metabolic capacity of the intestine is more and more recognized. In vivo studies eventually pointed out not only the significance of first-pass metabolism by the intestinal wall for the bioavailability of

  18. Detox does not know what it was storing

    International Nuclear Information System (INIS)

    Benka, M.

    2006-01-01

    There are still doubts about what actually burned during the fire at the warehouses of Detox, a company which processes oils and solvents. Last week company representatives published a list of materials that was supposed to be stored in Rimavska Sobota. But they still refuse to publish information on what substances burned during the fire in Bratislava. The police published information that in Rimavska Sobota traces of radionuclides were burned. But the volumes were not harmful. One thing is sure, no such substance can be found on the lists supplied by Detox. Executive Officer of the company, Lorant Vojcek, in his first reaction claimed that he did not know about it and that he first had to discuss the matter with the police. Shortly afterwards the company issued a statement stating that 'the volumes of radionuclides were so low that the final report would decide whether they were present in the warehouse or not. (author)

  19. Chimeric mice with humanized liver: Application in drug metabolism and pharmacokinetics studies for drug discovery.

    Science.gov (United States)

    Naritomi, Yoichi; Sanoh, Seigo; Ohta, Shigeru

    2018-02-01

    Predicting human drug metabolism and pharmacokinetics (PK) is key to drug discovery. In particular, it is important to predict human PK, metabolite profiles and drug-drug interactions (DDIs). Various methods have been used for such predictions, including in vitro metabolic studies using human biological samples, such as hepatic microsomes and hepatocytes, and in vivo studies using experimental animals. However, prediction studies using these methods are often inconclusive due to discrepancies between in vitro and in vivo results, and interspecies differences in drug metabolism. Further, the prediction methods have changed from qualitative to quantitative to solve these issues. Chimeric mice with humanized liver have been developed, in which mouse liver cells are mostly replaced with human hepatocytes. Since human drug metabolizing enzymes are expressed in the liver of these mice, they are regarded as suitable models for mimicking the drug metabolism and PK observed in humans; therefore, these mice are useful for predicting human drug metabolism and PK. In this review, we discuss the current state, issues, and future directions of predicting human drug metabolism and PK using chimeric mice with humanized liver in drug discovery. Copyright © 2017 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

  20. Predicting drug metabolism by cytochrome P450 2C9

    DEFF Research Database (Denmark)

    Rydberg, Patrik; Olsen, Lars

    2012-01-01

    By the use of knowledge gained through modeling of drug metabolism mediated by the cytochrome P450 2D6 and 3A4 isoforms, we constructed a 2D-based model for site-of-metabolism prediction for the cytochrome P450 2C9 isoform. The similarities and differences between the models for the 2C9 and 2D6...

  1. Significance and challenges of stereoselectivity assessing methods in drug metabolism

    Directory of Open Access Journals (Sweden)

    Zhuowei Shen

    2016-02-01

    Full Text Available Stereoselectivity in drug metabolism can not only influence the pharmacological activities, tolerability, safety, and bioavailability of drugs directly, but also cause different kinds of drug–drug interactions. Thus, assessing stereoselectivity in drug metabolism is of great significance for pharmaceutical research and development (R&D and rational use in clinic. Although there are various methods available for assessing stereoselectivity in drug metabolism, many of them have shortcomings. The indirect method of chromatographic methods can only be applicable to specific samples with functional groups to be derivatized or form complex with a chiral selector, while the direct method achieved by chiral stationary phases (CSPs is expensive. As a detector of chromatographic methods, mass spectrometry (MS is highly sensitive and specific, whereas the matrix interference is still a challenge to overcome. In addition, the use of nuclear magnetic resonance (NMR and immunoassay in chiral analysis are worth noting. This review presents several typical examples of drug stereoselective metabolism and provides a literature-based evaluation on current chiral analytical techniques to show the significance and challenges of stereoselectivity assessing methods in drug metabolism.

  2. TLR2 Controls Intestinal Carcinogen Detoxication by CYP1A1

    DEFF Research Database (Denmark)

    Do, Khoa; Fink, Lisbeth Nielsen; Jensen, Thomas Elbenhardt

    2012-01-01

    of ligands for TLR2 of bacterial origin seems to be crucial for detoxication of luminal carcinogens by CYP1A1 in the intestine. This unprecedented finding indicates a complex interplay between the immune system of the host and intestinal bacteria with detoxication mechanisms. This highlights the relevance...

  3. In Vitro Drug Metabolism by Human Carboxylesterase 1

    DEFF Research Database (Denmark)

    Thomsen, Ragnar; Rasmussen, Henrik B; Linnet, Kristian

    2014-01-01

    Carboxylesterase 1 (CES1) is the major hydrolase in human liver. The enzyme is involved in the metabolism of several important therapeutic agents, drugs of abuse, and endogenous compounds. However, no studies have described the role of human CES1 in the activation of two commonly prescribed...... a panel of therapeutic drugs and drugs of abuse to assess their inhibition of the hydrolysis of p-nitrophenyl acetate by recombinant CES1 and human liver microsomes. The screening assay confirmed several known inhibitors of CES1 and identified two previously unreported inhibitors: the dihydropyridine...... calcium antagonist, isradipine, and the immunosuppressive agent, tacrolimus. CES1 plays a role in the metabolism of several drugs used in the treatment of common conditions, including hypertension, congestive heart failure, and diabetes mellitus; thus, there is a potential for clinically relevant drug-drug...

  4. Digitalisation and digitalis detoxication in the elderly.

    Science.gov (United States)

    Caird, F I; Kennedy, R D

    1977-02-01

    Twenty-three elderly patients with normal renal function were studied during digitalisation for cardiac failure or atrial fibrillation. Mean serum digoxin concentrations were in the therapeutic range from the fourth day in seven patients given digoxin 0.25 mg daily, from the second day in seven patients given 0.5 mg followed by 0.25 mg daily, and from the first day in nine patients given 0.75 mg followed by 0.25 mg daily. Toxic effects were not encountered in any patient. Serial measurement of serum digoxin concentrations in six patients recovering from digitalis intoxication, all of whom had severe renal impairment, allowed calculation of serum half-times (62 to 189 hours), and elimination constants (9 to 27% per day). The apparent volumes of distribution of digoxin were around 300 litres, and the apparent body contents of the drugs around 20-25 mug/kg body weight. Differences between these figures and those determined by others for younger patients seem mainly to reflect the consequences of renal impairment. If reasonable assumptions are made for fractional absorption, volume of distribution, and elimination constant, serum digoxin levels during digitalisation can be predicted, and are found to agree well with those observed.

  5. New analytical strategies in studying drug metabolism.

    Science.gov (United States)

    Staack, Roland F; Hopfgartner, Gérard

    2007-08-01

    Identification and elucidation of the structures of metabolites play major roles in drug discovery and in the development of pharmaceutical compounds. These studies are also important in toxicology or doping control with either pharmaceuticals or illicit drugs. This review focuses on: new analytical strategies used to identify potential metabolites in biological matrices with and without radiolabeled drugs; use of software for metabolite profiling; interpretation of product spectra; profiling of reactive metabolites; development of new approaches for generation of metabolites; and detection of metabolites with increased sensitivity and simplicity. Most of the new strategies involve mass spectrometry (MS) combined with liquid chromatography (LC).

  6. Intrinsic and Antipsychotic Drug-Induced Metabolic Dysfunction in Schizophrenia

    Directory of Open Access Journals (Sweden)

    Zachary Freyberg

    2017-07-01

    Full Text Available For decades, there have been observations demonstrating significant metabolic disturbances in people with schizophrenia including clinically relevant weight gain, hypertension, and disturbances in glucose and lipid homeostasis. Many of these findings pre-date the use of antipsychotic drugs (APDs which on their own are also strongly associated with metabolic side effects. The combination of APD-induced metabolic changes and common adverse environmental factors associated with schizophrenia have made it difficult to determine the specific contributions of each to the overall metabolic picture. Data from drug-naïve patients, both from the pre-APD era and more recently, suggest that there may be an intrinsic metabolic risk associated with schizophrenia. Nevertheless, these findings remain controversial due to significant clinical variability in both psychiatric and metabolic symptoms throughout patients' disease courses. Here, we provide an extensive review of classic and more recent literature describing the metabolic phenotype associated with schizophrenia. We also suggest potential mechanistic links between signaling pathways associated with schizophrenia and metabolic dysfunction. We propose that, beyond its symptomatology in the central nervous system, schizophrenia is also characterized by pathophysiology in other organ systems directly related to metabolic control.

  7. Bioanalysis, metabolism & clinical pharmacology of antiretroviral drugs

    NARCIS (Netherlands)

    Heine, R. ter

    2009-01-01

    The aims of all studies described in this thesis were to develop new bioanalytical and more patient friendly methods for studying the clinical pharmacology of antiretroviral drugs and to ultimately improve antiretroviral treatment.

  8. Cunninghamella Biotransformation--Similarities to Human Drug Metabolism and Its Relevance for the Drug Discovery Process.

    Science.gov (United States)

    Piska, Kamil; Żelaszczyk, Dorota; Jamrozik, Marek; Kubowicz-Kwaśny, Paulina; Pękala, Elżbieta

    2016-01-01

    Studies of drug metabolism are one of the most significant issues in the process of drug development, its introduction to the market and also in treatment. Even the most promising molecule may show undesirable metabolic properties that would disqualify it as a potential drug. Therefore, such studies are conducted in the early phases of drug discovery and development process. Cunninghamella is a filamentous fungus known for its catalytic properties, which mimics mammalian drug metabolism. It has been proven that C. elegans carries at least one gene coding for a CYP enzyme closely related to the CYP51 family. The transformation profile of xenobiotics in Cunninghamella spp. spans a number of reactions catalyzed by different mammalian CYP isoforms. This paper presents detailed data on similar biotransformation drug products in humans and Cunninghamella spp. and covers the most important aspects of preparative biosynthesis of metabolites, since this model allows to obtain metabolites in sufficient quantities to conduct the further detailed investigations, as quantification, structure analysis and pharmacological activity and toxicity testing. The metabolic activity of three mostly used Cunninghamella species in obtaining hydroxylated, dealkylated and oxidated metabolites of different drugs confirmed its convergence with human biotransformation. Though it cannot replace the standard methods, it can provide support in the field of biotransformation and identifying metabolic soft spots of new chemicals and in predicting possible metabolic pathways. Another aspect is the biosynthesis of metabolites. In this respect, techniques using Cunninghamella spp. seem to be competitive to the chemical methods currently used.

  9. Acute Metabolic Changes Associated With Analgesic Drugs

    DEFF Research Database (Denmark)

    Hansen, Tine Maria; Olesen, Anne Estrup; Simonsen, Carsten Wiberg

    2016-01-01

    BACKGROUND AND PURPOSE: Magnetic resonance spectroscopy (MRS) is used to measure brain metabolites. Limited data exist on the analgesic-induced spectroscopy response. This was an explorative study with the aims to investigate the central effects of two analgesic drugs, an opioid and a selective...

  10. Disposition and Metabolism of Investigational New Drugs.

    Science.gov (United States)

    1982-09-01

    and Trans- fer of Raw Data for Disposition, Metabolic Profile, and Phar- macokinetics of Mefloquine -SC1, WR-142490-EC1 in the Monkey," July 21, 1980...Studies on DL-Erythro-a- (2-Piperidyl)-2,8-Bis (Tri- fluoromethyl)-4-Quinoline Methanol Hydrochloride, Mefloquine - SHC1, WR-142490"HC1 in the Rat...DL-Erythro--(2-Piperidyl)-2,8-Bis (Trifluoro- Umethyl)-4-Quinolinemethanol Hydrochloride, Mefloquine *ld, WR-142490-HCI in the Monkey," July 21, 1980

  11. Antilipolytic drug boosts glucose metabolism in prostate cancer

    DEFF Research Database (Denmark)

    Andersen, Kim Francis; Divilov, Vadim; Koziorowski, Jacek

    2013-01-01

    The antilipolytic drug Acipimox reduces free fatty acid (FFA) levels in the blood stream. We examined the effect of reduced FFAs on glucose metabolism in androgen-dependent (CWR22Rv1) and androgen-independent (PC3) prostate cancer (PCa) xenografts.......The antilipolytic drug Acipimox reduces free fatty acid (FFA) levels in the blood stream. We examined the effect of reduced FFAs on glucose metabolism in androgen-dependent (CWR22Rv1) and androgen-independent (PC3) prostate cancer (PCa) xenografts....

  12. Predicting selective drug targets in cancer through metabolic networks

    Science.gov (United States)

    Folger, Ori; Jerby, Livnat; Frezza, Christian; Gottlieb, Eyal; Ruppin, Eytan; Shlomi, Tomer

    2011-01-01

    The interest in studying metabolic alterations in cancer and their potential role as novel targets for therapy has been rejuvenated in recent years. Here, we report the development of the first genome-scale network model of cancer metabolism, validated by correctly identifying genes essential for cellular proliferation in cancer cell lines. The model predicts 52 cytostatic drug targets, of which 40% are targeted by known, approved or experimental anticancer drugs, and the rest are new. It further predicts combinations of synthetic lethal drug targets, whose synergy is validated using available drug efficacy and gene expression measurements across the NCI-60 cancer cell line collection. Finally, potential selective treatments for specific cancers that depend on cancer type-specific downregulation of gene expression and somatic mutations are compiled. PMID:21694718

  13. Design and impact of bundled payment for detox and follow-up care.

    Science.gov (United States)

    Quinn, Amity E; Hodgkin, Dominic; Perloff, Jennifer N; Stewart, Maureen T; Brolin, Mary; Lane, Nancy; Horgan, Constance M

    2017-11-01

    Recent payment reforms promote movement from fee-for-service to alternative payment models that shift financial risk from payers to providers, incentivizing providers to manage patients' utilization. Bundled payment, an episode-based fixed payment that includes the prices of a group of services that would typically treat an episode of care, is expanding in the United States. Bundled payment has been recommended as a way to pay for comprehensive SUD treatment and has the potential to improve treatment engagement after detox, which could reduce detox readmissions, improve health outcomes, and reduce medical care costs. However, if moving to bundled payment creates large losses for some providers, it may not be sustainable. The objective of this study was to design the first bundled payment for detox and follow-up care and to estimate its impact on provider revenues. Massachusetts Medicaid beneficiaries' behavioral health, medical, and pharmacy claims from July 2010-April 2013 were used to build and test a detox bundled payment for continuously enrolled adults (N=5521). A risk adjustment model was developed using general linear modeling to predict beneficiaries' episode costs. The projected payments to each provider from the risk adjustment analysis were compared to the observed baseline costs to determine the potential impact of a detox bundled payment reform on organizational revenues. This was modeled in two ways: first assuming no change in behavior and then assuming a supply-side cost sharing behavioral response of a 10% reduction in detox readmissions and an increase of one individual counseling and one group counseling session. The mean total 90-day detox episode cost was $3743. Nearly 70% of the total mean cost consists of the index detox, psychiatric inpatient care, and short-term residential care. Risk mitigation, including risk adjustment, substantially reduced the variation of the mean episode cost. There are opportunities for organizations to gain revenue

  14. Use of density functional theory in drug metabolism studies

    DEFF Research Database (Denmark)

    Rydberg, Patrik; Jørgensen, Flemming Steen; Olsen, Lars

    2014-01-01

    INTRODUCTION: The cytochrome P450 enzymes (CYPs) metabolize many drug compounds. They catalyze a wide variety of reactions, and potentially, a large number of different metabolites can be generated. Density functional theory (DFT) has, over the past decade, been shown to be a powerful tool...

  15. Drug discovery strategies in the field of tumor energy metabolism: Limitations by metabolic flexibility and metabolic resistance to chemotherapy.

    Science.gov (United States)

    Amoedo, N D; Obre, E; Rossignol, R

    2017-08-01

    The search for new drugs capable of blocking the metabolic vulnerabilities of human tumors has now entered the clinical evaluation stage, but several projects already failed in phase I or phase II. In particular, very promising in vitro studies could not be translated in vivo at preclinical stage and beyond. This was the case for most glycolysis inhibitors that demonstrated systemic toxicity. A more recent example is the inhibition of glutamine catabolism in lung adenocarcinoma that failed in vivo despite a strong addiction of several cancer cell lines to glutamine in vitro. Such contradictory findings raised several questions concerning the optimization of drug discovery strategies in the field of cancer metabolism. For instance, the cell culture models in 2D or 3D might already show strong limitations to mimic the tumor micro- and macro-environment. The microenvironment of tumors is composed of cancer cells of variegated metabolic profiles, supporting local metabolic exchanges and symbiosis, but also of immune cells and stroma that further interact with and reshape cancer cell metabolism. The macroenvironment includes the different tissues of the organism, capable of exchanging signals and fueling the tumor 'a distance'. Moreover, most metabolic targets were identified from their increased expression in tumor transcriptomic studies, or from targeted analyses looking at the metabolic impact of particular oncogenes or tumor suppressors on selected metabolic pathways. Still, very few targets were identified from in vivo analyses of tumor metabolism in patients because such studies are difficult and adequate imaging methods are only currently being developed for that purpose. For instance, perfusion of patients with [ 13 C]-glucose allows deciphering the metabolomics of tumors and opens a new area in the search for effective targets. Metabolic imaging with positron emission tomography and other techniques that do not involve [ 13 C] can also be used to evaluate tumor

  16. Are detox diets an effective strategy for obesity and oxidation management in the short term?

    Directory of Open Access Journals (Sweden)

    Ismael San Mauro Martín

    2017-09-01

    Full Text Available Introduction: Detox diets are popular dieting strategies that claim to facilitate toxin elimination and weight loss, thereby promoting health and well-being. Objective: To examine whether detox diets affect antioxidant markers in blood and body composition. Methods: 14 participants were randomly divided into two groups: a Group 1/Detox diet: followed an exclusive detox diet based on juices for three days, followed by a hypocaloric diet for 4 days; and b Group 2/Mediterranean diet: followed a hypocaloric Mediterranean diet for 7 days. Results: there were statistically significant differences, in both groups, between the basal and final data in all study variables, except for test PAT. Weight, BMI, total fat, muscle and dROM decreased, while body water increased slightly. Weight loss and body fat were higher in group 2 (Mediterranean diet than in group 1 (detox diet. The percentage of body water and the level of reactive oxygen metabolites increased. There was greater loss of musculature and water. In group 1, a decrease in the level of reactive oxygen metabolites was observed. However, there was a lower decrease in the body's antioxidant response, in group 1 than in group 2. Conclusion: There are reports which support that detox diets are useful for health promotion and weight loss; however, some preliminary studies suggest that certain nutritional components possess detoxification properties; we did not meet such a conclusion in our study.

  17. Intracellular thiols: involvement in drug metabolism and radiation response

    International Nuclear Information System (INIS)

    Astor, M.

    1983-01-01

    Nitro compunds are activated by coupled enzyme reactions to oxygen reactive intermediates leading to the formation of peroxide, under aerobic conditions, and to the depletion of thiols, under anaerobic conditions. Some nitro compounds as substrates for glutathione-S-transferase, show peroxide production without prior thiol removal. Other drugs reacting spontaneouly with glutathione also produce peroxide. Glutathione plays an important role in the metabolism of the nitrocompounds either by directly reacting with them or their reduced intermediates such as the nitroso, nitro and hydroxyl radical. In the case of misonidazole, protection against their cytotoxic effects can be achieved by the addition of exogenous thiols such as glutathione or cysteamine. Results indicate that oxygen and peroxide electrodes provide convenient means for measuring the products of metabolic activation of nitro compounds. Mechanisms are proposed whereby protein, nonprotein and glutathione thiols can interact with drug radicals or with DNA radicals. 60 references, 14 figures, 5 tables

  18. The use of stable isotopes in drug metabolism studies.

    Science.gov (United States)

    Abramson, F P

    2001-06-01

    Although there is a long history of stable isotopes use in drug metabolism research, it is appropriate to evaluate them in pregnancy drug studies in which safety takes highest priority. It is well established through a number of human and animal experiments that stable isotopes themselves rarely generate additional toxicities beyond the molecules to which they are attached. For the analysis of stable isotopes involved in metabolism studies, mass spectrometry plays the predominant role. Several mass spectrometry-based techniques now exist that enable the selective quantitative detection of stable isotopes with better sensitivity and better retention of chromatographic resolution than do in-line radioactivity monitors for 14C. Even mass balance studies can be performed by using stable isotopes, a type of experiment that still predominantly uses radioisotopes. Some of the newest developments in the use of stable isotopes involve biopolymers, in which fully isotope-labeled species can be generated from cells grown in isotopically labeled growth media. Having shown safety, sensitivity, specificity, and versatility, stable isotopes should play an important role in drug metabolism studies in pregnancy.

  19. Flavonoids as modulators of metabolic enzymes and drug transporters.

    Science.gov (United States)

    Miron, Anca; Aprotosoaie, Ana Clara; Trifan, Adriana; Xiao, Jianbo

    2017-06-01

    Flavonoids, natural compounds found in plants and in plant-derived foods and beverages, have been extensively studied with regard to their capacity to modulate metabolic enzymes and drug transporters. In vitro, flavonoids predominantly inhibit the major phase I drug-metabolizing enzyme CYP450 3A4 and the enzymes responsible for the bioactivation of procarcinogens (CYP1 enzymes) and upregulate the enzymes involved in carcinogen detoxification (UDP-glucuronosyltransferases, glutathione S-transferases (GSTs)). Flavonoids have been reported to inhibit ATP-binding cassette (ABC) transporters (multidrug resistance (MDR)-associated proteins, breast cancer-resistance protein) that contribute to the development of MDR. P-glycoprotein, an ABC transporter that limits drug bioavailability and also induces MDR, was differently modulated by flavonoids. Flavonoids and their phase II metabolites (sulfates, glucuronides) inhibit organic anion transporters involved in the tubular uptake of nephrotoxic compounds. In vivo studies have partially confirmed in vitro findings, suggesting that the mechanisms underlying the modulatory effects of flavonoids are complex and difficult to predict in vivo. Data summarized in this review strongly support the view that flavonoids are promising candidates for the enhancement of oral drug bioavailability, chemoprevention, and reversal of MDR. © 2017 New York Academy of Sciences.

  20. Drug metabolism in early infancy: opioids as an illustration.

    Science.gov (United States)

    Van Donge, Tamara; Mian, Paola; Tibboel, Dick; Van Den Anker, John; Allegaert, Karel

    2018-03-01

    Drug dosing in infants frequently depends on body weight as a crude indicator for maturation. Fentanyl (metabolized by Cytochrome P450 3A4) and morphine (glucuronidated by UDP-glucuronosyltransferase-2B7) served as model drugs to provide insight in maturation patterns of these enzymes and provide understanding of the impact of non-maturational factors to optimize dosing in infants. Areas covered: Systematic searches on metabolism and population pharmacokinetic (Pop-PK) models for fentanyl and morphine were performed. Pre- and post-model selection criteria were applied to assess and evaluate the validity of these models. It was observed that maturational changes have been rather well investigated, be it with variability in the maturational function estimates. The same holds true for Pop-PK models, where non-maturational covariates have also been reported (pharmacogenetics, disease state or external influences), although less incorporated in the PK models and with limited knowledge on mechanisms involved. Expert opinion: PK models for fentanyl and morphine are currently available. Consequently, we suggest that researchers should not continue to develop new models, but should investigate whether collected data fit in already existing models and provide additional value concerning the impact of (non)-maturational factors like drug-drug interactions or pharmacogenetics.

  1. Metabolic drug interactions - the impact of prescribed drug regimens on the medication safety.

    NARCIS (Netherlands)

    Fialova, D.; Vrbensky, K.; Topinkova, E.; Vlcek, J.; Soerbye, L.W.; Wagner, C.; Bernabei, R.

    2005-01-01

    Background and objective: Risk/benefit profile of prescribed drug regimens is unkown. Over 60% of commonly used medications interact on metabolic pathways (cytochrom P450 (CYP450), uridyl-glucuronyl tranferasis (UGT I, II) and P-glycoprotein (PGP) transport). Using an up-to-date knowledge on

  2. Electrochemical and enzymatic synthesis of oxidative drug metabolites for metabolism studies : Exploring selectivity and yield

    NARCIS (Netherlands)

    Gül, Turan

    2017-01-01

    Metabolism studies of drug molecules play a crucial role in drug discovery and development since the early detection of possibly toxic drug metabolites can save time and money. During the metabolic biotransformation process, oxidation of a drug molecule is catalyzed by specific enzymes which can

  3. Associations of Drug Lipophilicity and Extent of Metabolism with Drug-Induced Liver Injury.

    Science.gov (United States)

    McEuen, Kristin; Borlak, Jürgen; Tong, Weida; Chen, Minjun

    2017-06-22

    Drug-induced liver injury (DILI), although rare, is a frequent cause of adverse drug reactions resulting in warnings and withdrawals of numerous medications. Despite the research community's best efforts, current testing strategies aimed at identifying hepatotoxic drugs prior to human trials are not sufficiently powered to predict the complex mechanisms leading to DILI. In our previous studies, we demonstrated lipophilicity and dose to be associated with increased DILI risk and, and in our latest work, we factored reactive metabolites into the algorithm to predict DILI. Given the inconsistency in determining the potential for drugs to cause DILI, the present study comprehensively assesses the relationship between DILI risk and lipophilicity and the extent of metabolism using a large published dataset of 1036 Food and Drug Administration (FDA)-approved drugs by considering five independent DILI annotations. We found that lipophilicity and the extent of metabolism alone were associated with increased risk for DILI. Moreover, when analyzed in combination with high daily dose (≥100 mg), lipophilicity was statistically significantly associated with the risk of DILI across all datasets ( p < 0.05). Similarly, the combination of extensive hepatic metabolism (≥50%) and high daily dose (≥100 mg) was also strongly associated with an increased risk of DILI among all datasets analyzed ( p < 0.05). Our results suggest that both lipophilicity and the extent of hepatic metabolism can be considered important risk factors for DILI in humans, and that this relationship to DILI risk is much stronger when considered in combination with dose. The proposed paradigm allows the convergence of different published annotations to a more uniform assessment.

  4. Effect of the anticarcinogenic drug 6-mercaptopurine on mineral metabolism

    International Nuclear Information System (INIS)

    Amemiya, K.

    1987-01-01

    The effect of 6-mercaptopurine (6-MP) on mineral metabolism was investigated using rats and mice. A single 6-mercaptopurine injection in pregnant rats on day 11 of gestation proved to be highly teratogenic. At term, fetuses from 6-MP injected dams had lower livers zinc concentrations than non-injected or vehicle injected controls while dams showed no differences in liver zinc. Fetuses from dams injected with 6-MP and fed supplemental levels of zinc had a lower frequency of malformations and had higher hepatic zinc concentrations than fetuses from dams fed less zinc with drug injection. Non-pregnant mice injected with 6-MP had higher zinc concentrations compared to controls. In addition, iron, copper and calcium concentrations were higher in the livers of 6-MP injected mice than in controls, indicating that the drug affected several elements. Hepatic concentrations of metallothionein (MT) were also elevated in 6-MP injected mice, suggesting that the change in zinc concentrations associated with drug administration was the result of a drug induction of MT. Dams injected with 6-MP on day 13 of pregnancy had livers which retained more of an absorbed dose of 65 zinc than non-injected dams. Plasma from these drug injected dams also retained less of the absorbed dose than control dams. In contrast, day 14 from dams injected with 6-MP, retained less of an absorbed dose than control embryos

  5. NMR spectroscopy applied to the eye: Drugs and metabolic studies

    International Nuclear Information System (INIS)

    Saether, Oddbjoern

    2005-01-01

    NMR spectroscopy has been extensively applied in biomedical research during the last decades. It has proved to be an analytical tool of great value. From being mainly used in chemistry, technological developments have expanded the application of NMR spectroscopy to a great wealth of disciplines. With this method, biochemical information can be obtained by analysing tissue extracts. Moreover, NMR spectroscopy is increasingly employed for pharmacokinetic studies and analysis of biofluids. Technological progress has provided increased sensitivity and resolution in the spectra, which enable even more of the complexity of biological samples to be elucidated. With the implementation of high-resolution magic angle spinning (HR-MAS) NMR spectroscopy in biomedicine, intact tissue samples or biopsies can be investigated. Thus, NMR spectroscopy has an ever-increasing impact in metabolic screening of human samples and in animal models, and methods are also increasingly realised in vivo. The present work, NMR spectroscopy applied to eye research, consists of two main parts. Firstly, the feasibility to monitor fluorinated ophthalmic drugs directly in the eye was assessed. Secondly, HR-MAS H1 NMR spectroscopy was applied for metabolic profiling of the anterior eye segment, specifically to analyse metabolic changes in intact corneal and lenticular samples after cataractogenic insults. This work included metabonomics with the application of pattern recognition methods to analyse HR-MAS spectra of eye tissues. Optimisation strategies were explored for F19 NMR detection of fluorinated drugs in a phantom eye. S/N gains in F19 NMR spectroscopy were achieved by implementing time-share H1 decoupling at 2.35 T. The method is advantageous for compounds displaying broad spectral coupling patterns, though detection of drugs at concentrations encountered in the anterior eye segment after topical application was not feasible. Higher magnetic fields and technological improvements could enable

  6. NMR spectroscopy applied to the eye: Drugs and metabolic studies

    Energy Technology Data Exchange (ETDEWEB)

    Saether, Oddbjoern

    2005-07-01

    NMR spectroscopy has been extensively applied in biomedical research during the last decades. It has proved to be an analytical tool of great value. From being mainly used in chemistry, technological developments have expanded the application of NMR spectroscopy to a great wealth of disciplines. With this method, biochemical information can be obtained by analysing tissue extracts. Moreover, NMR spectroscopy is increasingly employed for pharmacokinetic studies and analysis of biofluids. Technological progress has provided increased sensitivity and resolution in the spectra, which enable even more of the complexity of biological samples to be elucidated. With the implementation of high-resolution magic angle spinning (HR-MAS) NMR spectroscopy in biomedicine, intact tissue samples or biopsies can be investigated. Thus, NMR spectroscopy has an ever-increasing impact in metabolic screening of human samples and in animal models, and methods are also increasingly realised in vivo. The present work, NMR spectroscopy applied to eye research, consists of two main parts. Firstly, the feasibility to monitor fluorinated ophthalmic drugs directly in the eye was assessed. Secondly, HR-MAS H1 NMR spectroscopy was applied for metabolic profiling of the anterior eye segment, specifically to analyse metabolic changes in intact corneal and lenticular samples after cataractogenic insults. This work included metabonomics with the application of pattern recognition methods to analyse HR-MAS spectra of eye tissues. Optimisation strategies were explored for F19 NMR detection of fluorinated drugs in a phantom eye. S/N gains in F19 NMR spectroscopy were achieved by implementing time-share H1 decoupling at 2.35 T. The method is advantageous for compounds displaying broad spectral coupling patterns, though detection of drugs at concentrations encountered in the anterior eye segment after topical application was not feasible. Higher magnetic fields and technological improvements could enable

  7. Pharmacogenomic and clinical data link non-pharmacokinetic metabolic dysregulation to drug side effect pathogenesis

    DEFF Research Database (Denmark)

    Zielinski, Daniel C.; Filipp, F. V.; Bordbar, A.

    2015-01-01

    Drug side effects cause a significant clinical and economic burden. However, mechanisms of drug action underlying side effect pathogenesis remain largely unknown. Here, we integrate pharmacogenomic and clinical data with a human metabolic network and find that non-pharmacokinetic metabolic pathways...... the relationships between the cellular response to drugs, genetic variation of patients and cell metabolism may help managing side effects by personalizing drug prescriptions and nutritional intervention strategies....

  8. Expression and Regulation of Drug Transporters and Metabolizing Enzymes in the Human Gastrointestinal Tract.

    Science.gov (United States)

    Drozdzik, M; Oswald, S

    2016-01-01

    Orally administered drugs must pass through the intestinal wall and then through the liver before reaching systemic circulation. During this process drugs are subjected to different processes that may determine the therapeutic value. The intestinal barrier with active drug metabolizing enzymes and drug transporters in enterocytes plays an important role in the determination of drug bioavailability. Accumulating information demonstrates variable distribution of drug metabolizing enzymes and transporters along the human gastrointestinal tract (GI), that creates specific barrier characteristics in different segments of the GI. In this review, expression of drug metabolizing enzymes and transporters in the healthy and diseased human GI as well as their regulatory aspects: genetic, miRNA, DNA methylation are outlined. The knowledge of unique interplay between drug metabolizing enzymes and transporters in specific segments of the GI tract allows more precise definition of drug release sites within the GI in order to assure more complete bioavailability and prediction of drug interactions.

  9. Recent Advances of Computational Modeling for Predicting Drug Metabolism: A Perspective.

    Science.gov (United States)

    Kar, Supratik; Leszczynski, Jerzy

    2017-01-01

    Absorption, Distribution, Metabolism, Excretion (ADME) properties along with drug induced adverse effects are the major reasons for the late stage failure of drug candidates as well as the cause for the expensive withdrawal of many approved drugs from the market. Considering the adverse effects of drugs, metabolism factor has great importance in medicinal chemistry and clinical pharmacology because it influences the deactivation, activation, detoxification and toxification of drugs. Computational methods are effective approaches to reduce the number of safety issues by analyzing possible links between chemical structures and metabolism followed by adverse effects, as they serve the integration of information on several levels to enhance the reliability of outcomes. In silico profiling of drug metabolism can help progress only those molecules along the discovery chain that is less likely to fail later in the drug discovery process. This positively impacts the very high costs of drug discovery and development. Understanding the science behind computational tools, their opportunities, and limitations is essential to make a true influence on drug discovery at different levels. If applied in a scientifically consequential way, computational tools may improve the capability to identify and evaluate potential drug molecules considering pharmacokinetic properties of drugs. Herein, current trends in computational modeling for predicting drug metabolism are reviewed highlighting new computational tools for drug metabolism prediction followed by reporting large and integrated databases of approved drugs associated with diverse metabolism issues. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  10. Short-term fasting alters cytochrome P450-mediated drug metabolism in humans

    NARCIS (Netherlands)

    Lammers, Laureen A.; Achterbergh, Roos; de Vries, Emmely M.; van Nierop, F. Samuel; Klümpen, Heinz-Josef; Soeters, Maarten R.; Boelen, Anita; Romijn, Johannes A.; Mathôt, Ron A. A.

    2015-01-01

    Experimental studies indicate that short-term fasting alters drug metabolism. However, the effects of short-term fasting on drug metabolism in humans need further investigation. Therefore, the aim of this study was to evaluate the effects of short-term fasting (36 h) on P450-mediated drug

  11. The effect of chronic renal failure on hepatic drug metabolism and drug disposition.

    Science.gov (United States)

    Dreisbach, Albert W; Lertora, Juan J L

    2003-01-01

    There is abundant evidence that chronic renal failure (CRF) and end-stage renal disease (ESRD) alter drug disposition by affecting protein and tissue binding and reducing systemic clearance of renally cleared drugs. What is not fully appreciated is that CRF can significantly reduce nonrenal clearance and alter the bioavailability of drugs predominantly metabolized by the liver. Animal studies in CRF have shown a major down-regulation (40-85%) of hepatic cytochrome P-450 metabolism involving specific isozymes. Phase II reactions such as acetylation and glucuronidation are also involved, with some isozymes showing induction and others inhibition. Hepatic enzymes exhibiting genetic polymorphisms such as N-acetyl-transferase-2 (NAT-2), which is responsible for the rapid and slow acetylator phenotypes, have been shown to be inhibited by ESRD and reversed by transplantation. There is some evidence pointing to the possibility of inhibitory factors circulating in the serum in ESRD patients which may be dialyzable. This review includes all significant animal and clinical studies using the search terms "chronic renal failure,"cytochrome P-450," and "liver metabolism" over the past 10 years obtained from the National Library of Medicine MEDLINE database, including relevant articles back to 1969.

  12. Drug metabolism in human brain: high levels of cytochrome P4503A43 in brain and metabolism of anti-anxiety drug alprazolam to its active metabolite.

    Directory of Open Access Journals (Sweden)

    Varsha Agarwal

    2008-06-01

    Full Text Available Cytochrome P450 (P450 is a super-family of drug metabolizing enzymes. P450 enzymes have dual function; they can metabolize drugs to pharmacologically inactive metabolites facilitating their excretion or biotransform them to pharmacologically active metabolites which may have longer half-life than the parent drug. The variable pharmacological response to psychoactive drugs typically seen in population groups is often not accountable by considering dissimilarities in hepatic metabolism. Metabolism in brain specific nuclei may play a role in pharmacological modulation of drugs acting on the CNS and help explain some of the diverse response to these drugs seen in patient population. P450 enzymes are also present in brain where drug metabolism can take place and modify therapeutic action of drugs at the site of action. We have earlier demonstrated an intrinsic difference in the biotransformation of alprazolam (ALP in brain and liver, relatively more alpha-hydroxy alprazolam (alpha-OHALP is formed in brain as compared to liver. In the present study we show that recombinant CYP3A43 metabolizes ALP to both alpha-OHALP and 4-hydroxy alprazolam (4-OHALP while CYP3A4 metabolizes ALP predominantly to its inactive metabolite, 4-OHALP. The expression of CYP3A43 mRNA in human brain samples correlates with formation of relatively higher levels of alpha-OH ALP indicating that individuals who express higher levels of CYP3A43 in the brain would generate larger amounts of alpha-OHALP. Further, the expression of CYP3A43 was relatively higher in brain as compared to liver across different ethnic populations. Since CYP3A enzymes play a prominent role in the metabolism of drugs, the higher expression of CYP3A43 would generate metabolite profile of drugs differentially in human brain and thus impact the pharmacodynamics of psychoactive drugs at the site of action.

  13. Consequences of psychophysiological stress on cytochrome P450-catalyzed drug metabolism.

    Science.gov (United States)

    Konstandi, Maria; Johnson, Elizabeth O; Lang, Matti A

    2014-09-01

    Most drugs are metabolized in the liver by cytochromes P450 (CYPs). Stress can modify CYP-catalyzed drug metabolism and subsequently, the pharmacokinetic profile of a drug. Current evidence demonstrates a gene-, stress- and species-specific interference in stress-mediated regulation of genes encoding the major drug-metabolizing CYP isozymes. Stress-induced up-regulation of CYPs that metabolize the majority of prescribed drugs can result in their increased metabolism and consequently, in failure of pharmacotherapy. In contrast, stress-induced down-regulation of CYP isozymes, including CYP2E1 and CYP2B1/2, potentially reduces metabolism of several toxicants and specific drugs-substrates resulting in increased levels and altered toxicity. The primary stress effectors, the adrenergic receptor-linked pathways and glucocorticoids, play primary and distinct roles in stress-mediated regulation of CYPs. Evidence demonstrates that stress regulates major drug metabolizing CYP isozymes, suggesting that stress should be considered to ensure pharmacotherapy efficacy and minimize drug toxicity. A detailed understanding of the molecular events underlying the stress-dependent regulation of drug metabolizing CYPs is crucial both for the design of new drugs and for physiology-based pharmacokinetic and pharmacodynamic modeling. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. Sirtuins: Novel targets for metabolic disease in drug development

    International Nuclear Information System (INIS)

    Jiang Weijian

    2008-01-01

    Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases such as type 2 diabetes. SIRT1, an NAD + -dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produces beneficial effects on glucose homeostasis and insulin sensitivity. Activation of SIRT1 leads to enhanced activity of multiple proteins, including peroxisome proliferator-activated receptor coactivator-1α (PGC-1α) and FOXO which helps to mediate some of the in vitro and in vivo effects of sirtuins. Resveratrol, a polyphenolic SIRT1 activator, mimics the effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance. In this review, we summarize recent research advances in unveiling the molecular mechanisms that underpin sirtuin as therapeutic candidates and discuss the possibility of using resveratrol as potential drug for treatment of diabetes

  15. Effect of drugs used in psychoses on cerebral dopamine metabolism

    Science.gov (United States)

    O'Keeffe, Ruth; Sharman, D. F.; Vogt, Marthe

    1970-01-01

    1. Chlorpromazine 15 mg/kg, given daily to cats for 2 weeks, produced a rise in homovanillic acid (HVA) content of the caudate nucleus, whereas the same dose of thioridazine lacked this effect. Of these two drugs, only chlorpromazine causes a high incidence of drug-induced Parkinsonism in man. 2. In the mouse, chlorpromazine, thioridazine and haloperidol increased striatal concentrations of HVA and accelerated the disappearance of dopamine (DA) after inhibition of catecholamine synthesis with α-methyltyrosine. Low doses of the three compounds increased, whereas high doses reduced, the concentration of DA in the striatum. In their effects on the DA metabolism of the mouse, chlorpromazine and thioridazine had the same potency, but haloperidol was between 10 and 100 times more active than the other two drugs. In producing hypothermia and sedation, the three compounds were equiactive. 3. Oxypertine, another drug apt to produce Parkinsonism in man, caused a severe reduction in striatal DA and hypothalamic noradrenaline (NA). Though the clinical signs produced in the mouse were indistinguishable from those seen after the same dose of chlorpromazine, the biochemical changes in the brain were thus quite different. 4. Though all the drugs used caused temporary motor disabilities in animals, these bore no resemblance to human Parkinsonism, even when treatment was continued for 7 weeks or more as it was in cats and monkeys. The latter were treated with chlorpromazine 7·5 mg/kg daily, a dose chosen to avoid loss of weight and which may have been too small to produce toxic side-effects. It caused no changes in striatal DA turnover. 5. Even at the high dose of 50 mg/kg, phenoxybenzamine did not increase DA turnover in mouse brain, but it sedated the mice as did the tranquillizers. 6. Atropine sulphate, 25 mg/kg, reduced the HVA content of mouse striatum and partially antagonized the rise in HVA produced by phenothiazines. The effect was surmountable. Possible modes of action

  16. Uses and limits of radiotracers in the study of drugs and xenobiotics metabolism

    International Nuclear Information System (INIS)

    Cohen, Y.

    1980-01-01

    This review deals with scientific papers issued in 1977-1978, on labelling of drugs and xenobiotics and their metabolism. It is divided in five parts: site of label; in vivo metabolism in animals and human beings; in vitro metabolism on tissue slices, cells culture, microsomes, membrane receptors; metabolism of xenobiotics: nutrients, food additives, detergents, plastics and fabrics; discussion. Metabolic studies, nowadays, associate radiotracers, stable isotopes with high performing procedures for analytical separation [fr

  17. Individualization of treatments with drugs metabolized by CES1: combining genetics and metabolomics

    DEFF Research Database (Denmark)

    Rasmussen, Henrik B.; Bjerre, Ditte; Linnet, Kristian

    2015-01-01

    in individualizing the treatment with these drugs. The present review addresses the issue of individualized treatment with drugs metabolized by CES1. It describes the composition of the gene encoding CES1, reports variants of this gene with focus upon those with a potential effect on drug metabolism and provides......CES1 is involved in the hydrolysis of ester group-containing xenobiotic and endobiotic compounds including several essential and commonly used drugs. The individual variation in the efficacy and tolerability of many drugs metabolized by CES1 is considerable. Hence, there is a large interest...... an overview of the protein structure of this enzyme bringing notice to mechanisms involved in the regulation of enzyme activity. Subsequently, the review highlights drugs metabolized by CES1 and argues that individual differences in the pharmacokinetics of these drugs play an important role in determining...

  18. Chemical reaction vector embeddings: towards predicting drug metabolism in the human gut microbiome.

    Science.gov (United States)

    Mallory, Emily K; Acharya, Ambika; Rensi, Stefano E; Turnbaugh, Peter J; Bright, Roselie A; Altman, Russ B

    2018-01-01

    Bacteria in the human gut have the ability to activate, inactivate, and reactivate drugs with both intended and unintended effects. For example, the drug digoxin is reduced to the inactive metabolite dihydrodigoxin by the gut Actinobacterium E. lenta, and patients colonized with high levels of drug metabolizing strains may have limited response to the drug. Understanding the complete space of drugs that are metabolized by the human gut microbiome is critical for predicting bacteria-drug relationships and their effects on individual patient response. Discovery and validation of drug metabolism via bacterial enzymes has yielded >50 drugs after nearly a century of experimental research. However, there are limited computational tools for screening drugs for potential metabolism by the gut microbiome. We developed a pipeline for comparing and characterizing chemical transformations using continuous vector representations of molecular structure learned using unsupervised representation learning. We applied this pipeline to chemical reaction data from MetaCyc to characterize the utility of vector representations for chemical reaction transformations. After clustering molecular and reaction vectors, we performed enrichment analyses and queries to characterize the space. We detected enriched enzyme names, Gene Ontology terms, and Enzyme Consortium (EC) classes within reaction clusters. In addition, we queried reactions against drug-metabolite transformations known to be metabolized by the human gut microbiome. The top results for these known drug transformations contained similar substructure modifications to the original drug pair. This work enables high throughput screening of drugs and their resulting metabolites against chemical reactions common to gut bacteria.

  19. Drug Metabolizing Enzyme and Transporter Gene Variation, Nicotine Metabolism, Prospective Abstinence, and Cigarette Consumption

    Science.gov (United States)

    Bergen, Andrew W.; Michel, Martha; Nishita, Denise; Krasnow, Ruth; Javitz, Harold S.; Conneely, Karen N.; Lessov-Schlaggar, Christina N.; Hops, Hyman; Zhu, Andy Z. X.; Baurley, James W.; McClure, Jennifer B.; Hall, Sharon M.; Baker, Timothy B.; Conti, David V.; Benowitz, Neal L.; Lerman, Caryn; Tyndale, Rachel F.; Swan, Gary E.

    2015-01-01

    The Nicotine Metabolite Ratio (NMR, ratio of trans-3’-hydroxycotinine and cotinine), has previously been associated with CYP2A6 activity, response to smoking cessation treatments, and cigarette consumption. We searched for drug metabolizing enzyme and transporter (DMET) gene variation associated with the NMR and prospective abstinence in 2,946 participants of laboratory studies of nicotine metabolism and of clinical trials of smoking cessation therapies. Stage I was a meta-analysis of the association of 507 common single nucleotide polymorphisms (SNPs) at 173 DMET genes with the NMR in 449 participants of two laboratory studies. Nominally significant associations were identified in ten genes after adjustment for intragenic SNPs; CYP2A6 and two CYP2A6 SNPs attained experiment-wide significance adjusted for correlated SNPs (CYP2A6 PACT=4.1E-7, rs4803381 PACT=4.5E-5, rs1137115, PACT=1.2E-3). Stage II was mega-regression analyses of 10 DMET SNPs with pretreatment NMR and prospective abstinence in up to 2,497 participants from eight trials. rs4803381 and rs1137115 SNPs were associated with pretreatment NMR at genome-wide significance. In post-hoc analyses of CYP2A6 SNPs, we observed nominally significant association with: abstinence in one pharmacotherapy arm; cigarette consumption among all trial participants; and lung cancer in four case:control studies. CYP2A6 minor alleles were associated with reduced NMR, CPD, and lung cancer risk. We confirmed the major role that CYP2A6 plays in nicotine metabolism, and made novel findings with respect to genome-wide significance and associations with CPD, abstinence and lung cancer risk. Additional multivariate analyses with patient variables and genetic modeling will improve prediction of nicotine metabolism, disease risk and smoking cessation treatment prognosis. PMID:26132489

  20. Drug Metabolizing Enzyme and Transporter Gene Variation, Nicotine Metabolism, Prospective Abstinence, and Cigarette Consumption.

    Directory of Open Access Journals (Sweden)

    Andrew W Bergen

    Full Text Available The Nicotine Metabolite Ratio (NMR, ratio of trans-3'-hydroxycotinine and cotinine, has previously been associated with CYP2A6 activity, response to smoking cessation treatments, and cigarette consumption. We searched for drug metabolizing enzyme and transporter (DMET gene variation associated with the NMR and prospective abstinence in 2,946 participants of laboratory studies of nicotine metabolism and of clinical trials of smoking cessation therapies. Stage I was a meta-analysis of the association of 507 common single nucleotide polymorphisms (SNPs at 173 DMET genes with the NMR in 449 participants of two laboratory studies. Nominally significant associations were identified in ten genes after adjustment for intragenic SNPs; CYP2A6 and two CYP2A6 SNPs attained experiment-wide significance adjusted for correlated SNPs (CYP2A6 PACT=4.1E-7, rs4803381 PACT=4.5E-5, rs1137115, PACT=1.2E-3. Stage II was mega-regression analyses of 10 DMET SNPs with pretreatment NMR and prospective abstinence in up to 2,497 participants from eight trials. rs4803381 and rs1137115 SNPs were associated with pretreatment NMR at genome-wide significance. In post-hoc analyses of CYP2A6 SNPs, we observed nominally significant association with: abstinence in one pharmacotherapy arm; cigarette consumption among all trial participants; and lung cancer in four case:control studies. CYP2A6 minor alleles were associated with reduced NMR, CPD, and lung cancer risk. We confirmed the major role that CYP2A6 plays in nicotine metabolism, and made novel findings with respect to genome-wide significance and associations with CPD, abstinence and lung cancer risk. Additional multivariate analyses with patient variables and genetic modeling will improve prediction of nicotine metabolism, disease risk and smoking cessation treatment prognosis.

  1. Metabolic and redox barriers in the skin exposed to drugs and xenobiotics.

    Science.gov (United States)

    Korkina, Liudmila

    2016-01-01

    Growing exposure of human skin to environmental and occupational hazards, to numerous skin care/beauty products, and to topical drugs led to a biomedical concern regarding sustainability of cutaneous chemical defence that is essential for protection against intoxication. Since skin is the largest extra-hepatic drug/xenobiotic metabolising organ where redox-dependent metabolic pathways prevail, in this review, publications on metabolic processes leading to redox imbalance (oxidative stress) and its autocrine/endocrine impact to cutaneous drug/xenobiotic metabolism were scrutinised. Chemical and photo-chemical skin barriers contain metabolic and redox compartments: their protective and homeostatic functions. The review will examine the striking similarity of adaptive responses to exogenous chemical/photo-chemical stressors and endogenous toxins in cutaneous metabolic and redox system; the role(s) of xenobiotics/drugs and phase II enzymes in the endogenous antioxidant defence and maintenance of redox balance; redox regulation of interactions between metabolic and inflammatory responses in skin cells; skin diseases sharing metabolic and redox problems (contact dermatitis, lupus erythematosus, and vitiligo) Due to exceptional the redox dependence of cutaneous metabolic pathways and interaction of redox active metabolites/exogenous antioxidants with drug/xenobiotic metabolism, metabolic tests of topical xenobiotics/drugs should be combined with appropriate redox analyses and performed on 3D human skin models.

  2. Antihypertensive drugs metabolism: an update to pharmacokinetic profiles and computational approaches.

    Science.gov (United States)

    Zisaki, Aikaterini; Miskovic, Ljubisa; Hatzimanikatis, Vassily

    2015-01-01

    Drug discovery and development is a high-risk enterprise that requires significant investments in capital, time and scientific expertise. The studies of xenobiotic metabolism remain as one of the main topics in the research and development of drugs, cosmetics and nutritional supplements. Antihypertensive drugs are used for the treatment of high blood pressure, which is one the most frequent symptoms of the patients that undergo cardiovascular diseases such as myocardial infraction and strokes. In current cardiovascular disease pharmacology, four drug clusters - Angiotensin Converting Enzyme Inhibitors, Beta-Blockers, Calcium Channel Blockers and Diuretics - cover the major therapeutic characteristics of the most antihypertensive drugs. The pharmacokinetic and specifically the metabolic profile of the antihypertensive agents are intensively studied because of the broad inter-individual variability on plasma concentrations and the diversity on the efficacy response especially due to the P450 dependent metabolic status they present. Several computational methods have been developed with the aim to: (i) model and better understand the human drug metabolism; and (ii) enhance the experimental investigation of the metabolism of small xenobiotic molecules. The main predictive tools these methods employ are rule-based approaches, quantitative structure metabolism/activity relationships and docking approaches. This review paper provides detailed metabolic profiles of the major clusters of antihypertensive agents, including their metabolites and their metabolizing enzymes, and it also provides specific information concerning the computational approaches that have been used to predict the metabolic profile of several antihypertensive drugs.

  3. Genetic analysis of drug metabolizing phase-I enzymes CYP3A4 in ...

    Indian Academy of Sciences (India)

    LIJUN LIU

    CYP3A4*5 and CYP3A4*18 are the predominant mutations affecting the metabolism of certain drugs in Chinese people. Tibetans are minority in China and have huge differences in the genetic structure, physiology, diet and lifestyle com- pared with the Han population. These variable factors may affect the drug metabolism.

  4. Metabolic and Endocrine Side Effects of Atypical Antipsychotic Drugs in Children and Adolescents

    Directory of Open Access Journals (Sweden)

    Aysegul Tahiroglu

    2011-03-01

    Full Text Available omorbid psychiatric disorders, frequent hospitalization, multiple outpatient treatment, prior history of hypertension, obesity and lipid dysregulation are associated with higher risk of metabolic syndrome in children. Side effects of antipsychotic drugs and their management have recently become a major subject of research due to enhanced antipsychotic drug usage in child and adolescents. Prevention strategies are usually preferred to secondary or tertiary strategies in the management of metabolic syndrome associated with antipsychotic drugs. Clinicians should present multidisciplinary approach to endocrine and metabolic side effects due to antipsychotic use in pediatric patient groups and avoid multiple drug use in such patients. In this paper, we briefly reviewed metabolic side effects of second generation antipsychotic drugs in child and adolescent population, possible mechanisms of susceptibility to metabolic syndrome and pharmacological and non pharmacological treatment approach to prevention of weight gain.

  5. The Conduct of Drug Metabolism Studies Considered Good Practice (II): In Vitro Experiments

    OpenAIRE

    Jia, Lee; Liu, Xiaodong

    2007-01-01

    In vitro drug metabolism studies, which are inexpensive and readily carried out, serve as an adequate screening mechanism to characterize drug metabolites, elucidate their pathways, and make suggestions for further in vivo testing. This publication is a sequel to part I in a series and aims at providing a general framework to guide designs and protocols of the in vitro drug metabolism studies considered good practice in an efficient manner such that it would help researchers avoid common pitf...

  6. Drug metabolizing enzyme systems and their relationship to toxic mechanisms

    International Nuclear Information System (INIS)

    Boyd, M.R.; Ravindranath, V.; Burka, L.T.

    1983-01-01

    The metabolism and toxicity of 3-methylfuran (3-MF) are described. The major product of metabolic activation of 3-MF appears to be disemicarbazones. Cursory description of toxic effects of 3-MF on lung and kidneys are provided. 18 refs

  7. Predicting drug metabolism--an evaluation of the expert system METEOR.

    Science.gov (United States)

    Testa, Bernard; Balmat, Anne-Loyse; Long, Anthony; Judson, Philip

    2005-07-01

    The paper begins with a discussion of the goals of metabolic predictions in early drug research, and some difficulties toward this objective, mainly the various substrate and product selectivities characteristic of drug metabolism. The major in silico approaches to predict drug metabolism are then classified and summarized. A discrimination is, thus, made between 'local' and 'global' systems. In its second part, an evaluation of METEOR, a rule-based expert system used to predict the metabolism of drugs and other xenobiotics, is reported. The published metabolic data of ten substrates were used in this evaluation, the overall results being discussed in terms of correct vs. disputable (i.e., false-positive and false-negative) predictions. The predictions for four representative substrates are presented in detail (Figs. 1-4), illustrating the interest of such an evaluation in identifying where and how predictive rules can be improved.

  8. METABOLISM OF 3 PHARMACOLOGICALLY ACTIVE-DRUGS IN ISOLATED HUMAN AND RAT HEPATOCYTES - ANALYSIS OF INTERSPECIES VARIABILITY AND COMPARISON WITH METABOLISM IN-VIVO

    NARCIS (Netherlands)

    SANDKER, GW; VOS, RME; DELBRESSINE, LPC; SLOOFF, MJH; MEIJER, DKF; GROOTHUIS, GMM

    1. The metabolism of the three drugs (Org GB 94, Org 3770 and Org OD 14) was studied in isolated human and rat hepatocytes. The metabolic profiles in rat and human hepatocytes were compared with the available in vivo data in both species. 2. All three drugs were metabolized extensively under the

  9. The conduct of drug metabolism studies considered good practice (II): in vitro experiments.

    Science.gov (United States)

    Jia, Lee; Liu, Xiaodong

    2007-12-01

    In vitro drug metabolism studies, which are inexpensive and readily carried out, serve as an adequate screening mechanism to characterize drug metabolites, elucidate their pathways, and make suggestions for further in vivo testing. This publication is a sequel to part I in a series and aims at providing a general framework to guide designs and protocols of the in vitro drug metabolism studies considered good practice in an efficient manner such that it would help researchers avoid common pitfalls and misleading results. The in vitro models include hepatic and non-hepatic microsomes, cDNA-expressed recombinant human CYPs expressed in insect cells or human B lymphoblastoid, chemical P450 inhibitors, S9 fraction, hepatocytes and liver slices. Important conditions for conducting the in vitro drug metabolism studies using these models are stated, including relevant concentrations of enzymes, co-factors, inhibitors and test drugs; time of incubation and sampling in order to establish kinetics of reactions; appropriate control settings, buffer selection and method validation. Separate in vitro data should be logically integrated to explain results from animal and human studies and to provide insights into the nature and consequences of in vivo drug metabolism. This article offers technical information and data and addresses scientific rationales and practical skills related to in vitro evaluation of drug metabolism to meet regulatory requirements for drug development.

  10. An ex Vivo Model for Evaluating Blood-Brain Barrier Permeability, Efflux, and Drug Metabolism

    DEFF Research Database (Denmark)

    Hellman, Karin; Aadal Nielsen, Peter; Ek, Fredrik

    2016-01-01

    , risperidone, citalopram, fluoxetine, and haloperidol were studied, and one preselected metabolite for each drug was analyzed, identified, and quantified. Metabolite identification studies of clozapine and midazolam showed that the locust brain was highly metabolically active, and 18 and 14 metabolites...

  11. 75 FR 13559 - Endocrinologic and Metabolic Drugs Advisory Committee; Notice of Meeting

    Science.gov (United States)

    2010-03-22

    ... growth hormone releasing hormone (GHRH). The proposed indication (use) for EGRIFTA in this application is...: Endocrinologic and Metabolic Drugs Advisory Committee. General Function of the Committee: To provide advice and...

  12. [Design and analyze mathematical algorithms of intestinal absorption and metabolism of multicomponent drug].

    Science.gov (United States)

    Dong, Ling; Xiang, Jia-Mei; Wang, Yun; Wu, Rui-Guang; Tang, Ming-Min; Sun, Mo-Han

    2014-12-01

    Evaluation of the permeability mainly focuses on intestinal absorption in biopharmaceutics classification system (BCS). It is more complicated that the absorption and metabolism under multicomponent environment in biopharmaceutics classification system of Chinese materia medica (CMMBCS) compared with single component environment, which needs suitable mathematical models to be described. Therefore, with full consideration of existing single component mathematical algorithm combining with the characteristics of intestinal absorption and metabolism, we explored and designed a new mathematical algorithm of intestinal absorption and metabolism of multicomponent drug. Then we put forward a new coefficient, P (influence), the relative change rate of the single component's intestinal absorption and metabolism under multicomponent environment compared with single component environment, which described the influences of intestinal absorption and metabolism of the component under multicomponent environment. Moreover, P (influence) highlights the distinctive characteristics of multicomponent drug's intestinal absorption and metabolism, and lays the foundation for the construction of CMMBCS.

  13. The effect of chronic renal failure on drug metabolism and transport.

    Science.gov (United States)

    Dreisbach, Albert W; Lertora, Juan J L

    2008-08-01

    Chronic renal failure (CRF) has been shown to significantly reduce the nonrenal clearance and alter bioavailability of drugs predominantly metabolized by the liver and intestine. The purpose of this article is to review all significant animal and clinical studies dealing with the effect of CRF on drug metabolism and transport. A search of the National Library of Medicine PubMed was done with terms such as chronic renal failure, cytochrome P450 [CYP], liver metabolism, efflux drug transport and uptake transport, including relevant articles back to 1969. Animal studies in CRF have shown a significant downregulation (40-85%) of hepatic and intestinal CYP metabolism. High levels of parathyroid hormone, cytokines and uremic toxins have been shown to reduce CYP activity. Phase II reactions and drug transporters such as P-glycoprotein and organic anion transporting polypeptide are also affected. CRF alters intestinal, renal and hepatic drug metabolism and transport producing a clinically significant impact on drug disposition and increasing the risk for adverse drug reactions.

  14. Electrochemical Oxidation by Square-Wave Potential Pulses in the Imitation of Oxidative Drug Metabolism

    NARCIS (Netherlands)

    Nouri-Nigjeh, Eslam; Permentier, Hjalmar P.; Bischoff, Rainer; Bruins, Andries P.

    2011-01-01

    Electrochemistry combined with mass spectrometry (EC-MS) is an emerging analytical technique in the imitation of oxidative drug metabolism at the early stages of new drug development. Here, we present the benefits of electrochemical oxidation by square-wave potential pulses for the oxidation of

  15. Drug metabolism in older people--a key consideration in achieving optimal outcomes with medicines.

    Science.gov (United States)

    McLachlan, Andrew J; Pont, Lisa G

    2012-02-01

    Hepatic clearance plays a key role in determining the systemic exposure of drugs and metabolites, which in turn has a major effect on variability in the beneficial and adverse effects of medicines. Aging results in a number of significant changes in the human liver including reductions in liver blood flow, size, drug-metabolizing enzyme content, and pseudocapillarization. Drug metabolism is also influenced by comorbid disease, frailty, concomitant medicines, and (epi)genetics. These changes have the potential to alter the hepatic clearance of drugs but need to be interpreted in the context of the pharmacokinetic (and pharmacodynamic) characteristics of the drug of interest. There is growing evidence that the age-related changes in the liver not only result in a decrease in the hepatic clearance of unbound drug but also influence variability in response to medicines in older people.

  16. Discovery and therapeutic potential of drugs that shift energy metabolism from mitochondrial respiration to glycolysis

    Science.gov (United States)

    Gohil, Vishal M.; Sheth, Sunil A.; Nilsson, Roland; Wojtovich, Andrew P.; Lee, Jeong Hyun; Perocchi, Fabiana; Chen, William; Clish, Clary B.; Ayata, Cenk; Brookes, Paul S.; Mootha, Vamsi K.

    2010-01-01

    Most cells can dynamically shift their relative reliance on glycolytic versus oxidative metabolism in response to nutrient availability, during development, and in disease. Studies in model systems have shown that re-directing energy metabolism from respiration to glycolysis can suppress oxidative damage and cell death in ischemic injury. At present we have a limited set of drugs that safely toggle energy metabolism in humans. Here, we introduce a quantitative, nutrient sensitized screening strategy that can identify such compounds based on their ability to selectively impair growth and viability of cells grown in galactose versus glucose. We identify several FDA approved agents never before linked to energy metabolism, including meclizine, which blunts cellular respiration via a mechanism distinct from canonical inhibitors. We further show that meclizine pretreatment confers cardioprotection and neuroprotection against ischemia-reperfusion injury in murine models. Nutrient-sensitized screening may offer a useful framework for understanding gene function and drug action within the context of energy metabolism. PMID:20160716

  17. Current knowledge of microRNA-mediated regulation of drug metabolism in humans.

    Science.gov (United States)

    Nakano, Masataka; Nakajima, Miki

    2018-05-02

    Understanding the factors causing inter- and intra-individual differences in drug metabolism potencies is required for the practice of personalized or precision medicine, as well as for the promotion of efficient drug development. The expression of drug-metabolizing enzymes is controlled by transcriptional regulation by nuclear receptors and transcriptional factors, epigenetic regulation, such as DNA methylation and histone acetylation, and post-translational modification. In addition to such regulation mechanisms, recent studies revealed that microRNAs (miRNAs), endogenous ~22-nucleotide non-coding RNAs that regulate gene expression through the translational repression and degradation of mRNAs, significantly contribute to post-transcriptional regulation of drug-metabolizing enzymes. Areas covered: This review summarizes the current knowledge regarding miRNAs-dependent regulation of drug-metabolizing enzymes and transcriptional factors and its physiological and clinical significance. We also describe recent advances in miRNA-dependent regulation research, showing that the presence of pseudogenes, single-nucleotide polymorphisms, and RNA editing affects miRNA targeting. Expert opinion: It is unwavering fact that miRNAs are critical factors causing inter- and intra-individual differences in the expression of drug-metabolizing enzymes. Consideration of miRNA-dependent regulation would be a helpful tool for optimizing personalized and precision medicine.

  18. Importance of Tourism Paradox, Tourism Equinox and Tourism Detox for Urban Environments

    Directory of Open Access Journals (Sweden)

    Arikan Irfan

    2016-12-01

    Full Text Available When looking at the increase of tourism in a destination, it can be said that tourism is a valuable part of the economy. The proposal offered by today’s competitive paradigm: that higher the number of tourists visiting a city, the higher the income, sounds good at first. The increased number of tourist arrivals gives the appearance of increasing desirability of the city. Parallel with the increased tourism activities, new buildings, new lifestyles, foreign capital and new socio-economic relationships appear rapidly and replace the traditional ones. However, there will be a huge amount of social, cultural, economic and environmental problems faced by the local people as well as the tourists the city. Tourism paradox is the name given to the phenomenon where tourism industry destroys natural and cultural environment in a destination that is necessary for tourism activities. On the other hand the balance, which does not change and disturbs the social and economic relations at the destination is called “tourism equinox”. Therefore, spatial reorganization and urban regeneration play a crucial role for the marketing of cities and this transformation action affects all infrastructure facilities, restorations of old buildings, reorganization of historical zones, and revitalizing the architectural style of the cities. New projects and approaches to solve the problems caused by the growth of urban populations and to establish healthy sustainable tourism destinations are becoming more important than ever. Tourism detox is a treatment that is intended to remove harmful substances from these destinations. This paper investigates the influence of tourism paradox and tourism equinox on urban environments in relation to tourism activities and the protection of natural and cultural resources with the help of tourism detox. It primarily relies on qualitative research to understand the main futures of tourism paradox, equinox and detox taking the physical

  19. RESEARCH ON DETOXICATION OF SOILS POLLUTED WITH ARSENIUM AND DEVELOPMENT OF NEW SORBING MATERIALS

    Directory of Open Access Journals (Sweden)

    L.V. Kireycheva

    2012-06-01

    Full Text Available Arsenium being a hazardous substance is harmful for plants, animals and people. Having been applied to the soil arsenium is partly transformed as the result of interaction with the soil minerals. It may enter plants, animals as well as human body through the feed circuit. Nowadays issue of the anthropogenic impact diminishing as well as environmentally friendly farm production obtaining in the polluted soils becomes more and more urgent. Therefore development of soil detoxication techniques using natural sorbing materials is challenging and timely.

  20. Regulation of drug-metabolizing enzymes in infectious and inflammatory disease: implications for biologics-small molecule drug interactions.

    Science.gov (United States)

    Mallick, Pankajini; Taneja, Guncha; Moorthy, Bhagavatula; Ghose, Romi

    2017-06-01

    Drug-metabolizing enzymes (DMEs) are primarily down-regulated during infectious and inflammatory diseases, leading to disruption in the metabolism of small molecule drugs (smds), which are increasingly being prescribed therapeutically in combination with biologics for a number of chronic diseases. The biologics may exert pro- or anti-inflammatory effect, which may in turn affect the expression/activity of DMEs. Thus, patients with infectious/inflammatory diseases undergoing biologic/smd treatment can have complex changes in DMEs due to combined effects of the disease and treatment. Areas covered: We will discuss clinical biologics-SMD interaction and regulation of DMEs during infection and inflammatory diseases. Mechanistic studies will be discussed and consequences on biologic-small molecule combination therapy on disease outcome due to changes in drug metabolism will be highlighted. Expert opinion: The involvement of immunomodulatory mediators in biologic-SMDs is well known. Regulatory guidelines recommend appropriate in vitro or in vivo assessments for possible interactions. The role of cytokines in biologic-SMDs has been documented. However, the mechanisms of drug-drug interactions is much more complex, and is probably multi-factorial. Studies aimed at understanding the mechanism by which biologics effect the DMEs during inflammation/infection are clinically important.

  1. Cytochrome P450s: mechanisms and biological implications in drug metabolism and its interaction with oxidative stress.

    Science.gov (United States)

    Bhattacharyya, Sudip; Sinha, Krishnendu; Sil, Parames C

    2014-01-01

    Cytochrome monooxygenases P450 enzymes (CYPs) are terminal oxidases, belonging to the multi-gene family of heme-thiolate enzymes and located in multiple sites of ER, cytosol and mitochondria. CYPs act as catalysts in drugs metabolism. This review highlights the mitochondrial and microsomal CYPs metabolic functions, CYPs mediated ROS generation and its feedback, bioactivation of drugs and related hypersensitivity, metabolic disposition as well as the therapeutic approaches. CYPs mediated drugs bioactivation may trigger oxidative stress and cause pathophysiology. Almost all drugs show some adverse reactions at high doses or accidental overdoses. Drugs lead to hypersensitivity reactions while metabolic predisposition to drug hypersensitivity exaggerates it. Mostly different intermediate bioactive products of CYPs mediated drug metabolism is the principal issue in this respect. On the other hand, CYPs are the main source of ROS. Their generation and feedback are of major concern of this review. Besides drug metabolism, CYPs also contribute significantly to carcinogen metabolism. Ultimately other enzymes in drug metabolism and antioxidant therapy are indispensible. Importance of this field: In a global sense, understanding of exact mechanism can facilitate pharmaceutical industries' challenge of developing drugs without toxicity. Ultimate message: This review would accentuate the recent advances in molecular mechanism of CYPs mediated drug metabolism and complex cross-talks between various restorative novel strategies evolved by CYPs to sustain the redox balance and limit the source of oxidative stress.

  2. Adrenal metabolism of mitotane and related compounds

    International Nuclear Information System (INIS)

    Djanegara, T.K.S.

    1989-01-01

    Mitotane (o,p'-DDD; 1-[2-chlorophenyl]-1-[4-chlorophenyl]-2,2-dichloroethane) has been used in the treatment of Cushing's syndrome due to adrenal hyperfunction and it the drug of choice for adrenocortical carcinoma. The object of this investigation is to study the biotransformation of o,p'-DDD and p,p'-DDD in dogs and bovine adrenal cortex to explain its selective toxicity and mechanism of action. The in vitro biotransformation of 14 C-labeled o,p'-DDD and p,p'-DDD by dog and bovine adrenal cortex as studied. Of the cortex subcellular fractions, the cytosol fraction was found to be the most active in metabolizing the substrates, followed by the mitochondrial fraction. This metabolism including that in cytosolic fractions, did not take place with boiled enzyme preparations and required an NADPH generating system. This study has been directed towards establishing the metabolic activation mechanism which may account for the adrenocorticolytic effect of mitotane in contrast to detoxication by the liver. HPLC and TLC metabolic profiles have been generated from incubations of bovine and dog adrenal cortex homogenates and their subfractions for 14 C-labeled p,p'-DDD, o,p'-DDD and its monochloroethylene derivative, o,p'-DDMU

  3. Effects of resveratrol on drug- and carcinogen-metabolizing enzymes, implications for cancer prevention.

    Science.gov (United States)

    Guthrie, Ariane R; Chow, H-H Sherry; Martinez, Jessica A

    2017-02-01

    Resveratrol is a polyphenol found in grape skins and peanuts that has demonstrated many health benefits including protection against aging, cardiovascular and metabolic disease, neurological decline, and cancer. The anticancer properties of resveratrol have been attributed to a variety of mechanisms, including its general inhibition of phase I metabolism and induction of phase II metabolism. The effects of resveratrol on these enzymes, however, are still unclear, as in vitro evidence often contrasts with animal studies and clinical trials. Reasons for these variances could include the low bioavailability of resveratrol and the effects of resveratrol metabolites. Due to resveratrol's interactions with drug-metabolizing enzymes and drug transporters, individuals concurrently taking pharmacological doses of resveratrol with other supplements or medications could potentially experience nutrient-drug interactions. This review summarizes the known effects of resveratrol and its main metabolites on drug metabolism in order to help characterize which populations might benefit from resveratrol for the prevention of cancer, as well as those that may need to avoid supplementation due to potential drug interactions.

  4. Metabolic Side-Effects of the Novel Second-Generation Antipsychotic Drugs Asenapine and Iloperidone: A Comparison with Olanzapine

    OpenAIRE

    Boyda, Heidi N.; Procyshyn, Ric M.; Pang, Catherine C. Y.; Hawkes, Erin; Wong, Daniel; Jin, Chen Helen; Honer, William G.; Barr, Alasdair M.

    2013-01-01

    Background The second generation antipsychotic (SGA) drugs are widely used in psychiatry due to their clinical efficacy and low incidence of neurological side-effects. However, many drugs in this class cause deleterious metabolic side-effects. Animal models accurately predict metabolic side-effects for SGAs with known clinical metabolic liability. We therefore used preclinical models to evaluate the metabolic side-effects of glucose intolerance and insulin resistance with the novel SGAs asena...

  5. Mechanistic and structural insight into promiscuity based metabolism of cardiac drug digoxin by gut microbial enzyme.

    Science.gov (United States)

    Kumar, Kundan; Jaiswal, Shubham K; Dhoke, Gaurao V; Srivastava, Gopal N; Sharma, Ashok K; Sharma, Vineet K

    2017-12-23

    The recent advances in microbiome studies have revealed the role of gut microbiota in altering the pharmacological properties of oral drugs, which contributes to patient-response variation and undesired effect of the drug molecule. These studies are essential to guide us for achieving the desired efficacy and pharmacological activity of the existing drug molecule or for discovering novel and more effective therapeutics. However, one of the main limitations is the lack of atomistic details on the binding and metabolism of these drug molecules by gut-microbial enzymes. Therefore, in this study, for a well-known and important FDA-approved cardiac glycoside drug, digoxin, we report the atomistic details and energy economics for its binding and metabolism by the Cgr2 protein of Eggerthela lenta DSM 2243. It was observed that the binding pocket of digoxin to Cgr2 primarily involved the negatively charged polar amino acids and a few non-polar hydrophobic residues. The drug digoxin was found to bind Cgr2 at the same binding site as that of fumarate, which is the proposed natural substrate. However, digoxin showed a much lower binding energy (17.75 ±2 Kcal mol -1 ) than the binding energy (42.17 ±2 Kcal mol -1 ) of fumarate. This study provides mechanistic insights into the structural and promiscuity-based metabolism of widely used cardiac drug digoxin and presents a methodology, which could be useful to confirm the promiscuity-based metabolism of other orally administrated drugs by gut microbial enzymes and also help in designing strategies for improving the efficacy of the drugs. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  6. Structural specificity of mucosal-cell transport and metabolism of peptide drugs: implication for oral peptide drug delivery

    Science.gov (United States)

    Bai, J. P.; Amidon, G. L.

    1992-01-01

    The brush border membrane of intestinal mucosal cells contains a peptide carrier system with rather broad substrate specificity and various endo- and exopeptidase activities. Small peptide (di-/tripeptide)-type drugs with or without an N-terminal alpha-amino group, including beta-lactam antibiotics and angiotensin-converting enzyme (ACE) inhibitors, are transported by the peptide transporter. Polypeptide drugs are hydrolyzed by brush border membrane proteolytic enzymes to di-/tripeptides and amino acids. Therefore, while the intestinal brush border membrane has a carrier system facilitating the absorption of di-/tripeptide drugs, it is a major barrier limiting oral availability of polypeptide drugs. In this paper, the specificity of peptide transport and metabolism in the intestinal brush border membrane is reviewed.

  7. Redox-based Epigenetic status in Drug Addiction: Potential mediator of drug-induced gene priming phenomenon and use of metabolic intervention for symptomatic treatment in drug addiction.

    Directory of Open Access Journals (Sweden)

    Malav Suchin Trivedi

    2015-01-01

    Full Text Available Alcohol and other drugs of abuse, including psychostimulants and opioids, can induce epigenetic changes: a contributing factor for drug addiction, tolerance and associated withdrawal symptoms. DNA methylation is the major epigenetic mechanism and it is one of more than 200 methylation reactions supported by methyl donor S-adenosylmethionine (SAM. The levels of SAM are controlled by cellular redox status via the folate and vitamin B12-dependent enzyme methionine synthase (MS, for example; under oxidative conditions MS is inhibited, diverting its substrate homocysteine (HCY to the transsulfuration pathway. Alcohol, dopamine and morphine, can alter intracellular levels of glutathione (GSH-based cellular redox status, subsequently affecting S-adenosylmethionine (SAM levels and DNA methylation status. In this discussion, we compile this and other existing evidence in a coherent manner to present a novel hypothesis implicating the involvement of redox-based epigenetic changes in drug addiction. Next, we also discuss how gene priming phenomenon can contribute to maintenance of redox and methylation status homeostasis under various stimuli including drugs of abuse. Lastly, based on our hypothesis and some preliminary evidence, we discuss a mechanistic explanation for use of metabolic interventions / redox-replenishers as symptomatic treatment of alcohol addiction and associated withdrawal symptoms. Hence, the current review article strengthens the hypothesis that neuronal metabolism has a critical bidirectional coupling with epigenetic changes in drug addiction and we support this claim via exemplifying the link between redox-based metabolic changes and resultant epigenetic consequences under the effect of drugs of abuse.

  8. Increasing of organism radioresistance by MR-33 metabolic drug

    International Nuclear Information System (INIS)

    Kalinina, E.V.; Novichkova, M.D.; Chirkova, E.M.; Koppel', M.A.; Komissarova, I.V.

    1999-01-01

    Using acute radiation injury model and mother-embryo system the radioprotective effect is studied of original metabolic preparation MR-33 (L-glutamine acid + glycine + cysteine) the characteristic feature of which is the ability to increase the intracellular level of glutathione (GSH) and GSH-depending system. Rats-males and pregnant females were used for experiments as well as volunteers. It is shown that the MR-33 increase adult and embryo radioresistance in case of γ-irradiation using 60 Co source [ru

  9. Forensic relevance of glucuronidation in phase-II-metabolism of alcohols and drugs.

    Science.gov (United States)

    Kaeferstein, Herbert

    2009-04-01

    Forensic toxicology means detecting toxic or pharmacologically active substances in body fluids and organs and the evaluation and judgement of the respective results. In the legal judgement, not only the taken in active drugs, but also their metabolites are to be included. Regarding metabolism one distinguishes phase-I- and phase-II-metabolism. In the phase-I-metabolism, active substances are converted by oxidation, reduction or hydrolysis, but influencing the polarity of more lipophilic substances often not decisively. The pharmacological activity is often preserved or even increased. In phase-II-metabolism a highly hydrophilic substance--mostly glucuronic acid--is coupled to the active substances or the respective phase-I-metabolites. This reaction step decisively increases hydrophilicity of lipophilic substances, thus enhancing renal elimination and often also abolishing pharmacologically and/or toxicologically effects. Nevertheless the interaction of different drugs and alcohols in glucuronidation and the glucuronides of phase-II-metabolism still do not play a substantial role in the forensic-toxicological analysis and interpretation of results so far. However, in vitro investigations since 1999 in our lab show that such interactions are not unlikely. For valid interpretation of complex cases in the future it may become necessary not only to quantify drugs and the phase-I-metabolites but also the phase-II-metabolites and discuss possible interactions in the metabolism.

  10. The fibrate drug gemfibrozil disrupts lipoprotein metabolism in rainbow trout

    International Nuclear Information System (INIS)

    Prindiville, John S.; Mennigen, Jan A.; Zamora, Jake M.; Moon, Thomas W.; Weber, Jean-Michel

    2011-01-01

    Gemfibrozil (GEM) is a fibrate drug consistently found in effluents from sewage treatment plants. This study characterizes the pharmacological effects of GEM on the plasma lipoproteins of rainbow trout (Oncorhynchus mykiss). Our goals were to quantify the impact of the drug on: 1) lipid constituents of lipoproteins (phospholipids (PL), triacylglycerol (TAG), and cholesterol), 2) lipoprotein classes (high, low and very low density lipoproteins), and 3) fatty acid composition of lipoproteins. Potential mechanisms of GEM action were investigated by measuring lipoprotein lipase activity (LPL) and the hepatic gene expression of LPL and of the peroxisome proliferator-activated receptor (PPAR) α, β, and γ isoforms. GEM treatment resulted in decreased plasma lipoprotein levels (- 29%) and a reduced size of all lipoprotein classes (lower PL:TAG ratios). However, the increase in HDL-cholesterol elicited by GEM in humans failed to be observed in trout. Therefore, HDL-cholesterol cannot be used to assess the impact of the drug on fish. GEM also modified lipoprotein composition by reducing the abundance of long-chain n-3 fatty acids, thereby potentially reducing the nutritional quality of exposed fish. The relative gene expression of LPL was increased, but the activity of the enzyme was not, and we found no evidence for the activation of PPAR pathways. The depressing effects of GEM on fish lipoproteins demonstrated here may be a concern in view of the widespread presence of fibrates in aquatic environments. Work is needed to test whether exposure to environmental concentrations of these drugs jeopardizes the capacity of fish for reproduction, temperature acclimation or migratory behaviors.

  11. Reactions and enzymes in the metabolism of drugs and other xenobiotics.

    Science.gov (United States)

    Testa, Bernard; Pedretti, Alessandro; Vistoli, Giulio

    2012-06-01

    In this article, we offer an overview of the compared quantitative importance of biotransformation reactions in the metabolism of drugs and other xenobiotics, based on a meta-analysis of current research interests. Also, we assess the relative significance the enzyme (super)families or categories catalysing these reactions. We put the facts unveiled by the analysis into a drug discovery context and draw some implications. The results confirm the primary role of cytochrome P450-catalysed oxidations and UDP-glucuronosyl-catalysed glucuronidations, but they also document the marked significance of several other reactions. Thus, there is a need for several drug discovery scientists to better grasp the variety of drug metabolism reactions and enzymes and their consequences. Copyright © 2012 Elsevier Ltd. All rights reserved.

  12. A metabolic network approach for the identification and prioritization of antimicrobial drug targets.

    Science.gov (United States)

    Chavali, Arvind K; D'Auria, Kevin M; Hewlett, Erik L; Pearson, Richard D; Papin, Jason A

    2012-03-01

    For many infectious diseases, novel treatment options are needed in order to address problems with cost, toxicity and resistance to current drugs. Systems biology tools can be used to gain valuable insight into pathogenic processes and aid in expediting drug discovery. In the past decade, constraint-based modeling of genome-scale metabolic networks has become widely used. Focusing on pathogen metabolic networks, we review in silico strategies used to identify effective drug targets and highlight recent successes as well as limitations associated with such computational analyses. We further discuss how accounting for the host environment and even targeting the host may offer new therapeutic options. These systems-level approaches are beginning to provide novel avenues for drug targeting against infectious agents. Copyright © 2011 Elsevier Ltd. All rights reserved.

  13. Genome-scale metabolic models as platforms for identification of novel genes as antimicrobial drug targets.

    Science.gov (United States)

    Mienda, Bashir Sajo; Salihu, Rabiu; Adamu, Aliyu; Idris, Shehu

    2018-03-01

    The growing number of multidrug-resistant pathogenic bacteria is becoming a world leading challenge for the scientific community and for public health. However, advances in high-throughput technologies and whole-genome sequencing of bacterial pathogens make the construction of bacterial genome-scale metabolic models (GEMs) increasingly realistic. The use of GEMs as an alternative platforms will expedite identification of novel unconditionally essential genes and enzymes of target organisms with existing and forthcoming GEMs. This approach will follow the existing protocol for construction of high-quality GEMs, which could ultimately reduce the time, cost and labor-intensive processes involved in identification of novel antimicrobial drug targets in drug discovery pipelines. We discuss the current impact of existing GEMs of selected multidrug-resistant pathogenic bacteria for identification of novel antimicrobial drug targets and the challenges of closing the gap between genome-scale metabolic modeling and conventional experimental trial-and-error approaches in drug discovery pipelines.

  14. Metabolic acidosis with a high anion: A drug-drug interaction between paracetamol and flucloxacillin

    NARCIS (Netherlands)

    Jessurun, N.T.; Van Hunse, F.; Van Puijenbroek, E.

    2015-01-01

    Background: Five-oxoproline is a product of disordered glutathione metabolism in the gamma glutamyl cycle: glutathione deficiency removes the feedback inhibition resulting in the formation of γ -glutamylcysteine and elevated concentrations of γ -glutamylcysteine leading to the formation of

  15. Effects of uremic toxins on transport and metabolism of different biopharmaceutics drug disposition classification system xenobiotics.

    Science.gov (United States)

    Reyes, Maribel; Benet, Leslie Z

    2011-09-01

    Chronic kidney disease (CKD) is recognized to cause pharmacokinetic changes in renally excreted drugs; however, pharmacokinetic changes are also reported for drugs that are nonrenally eliminated. Few studies have investigated how uremic toxins may affect drug transporters and metabolizing enzymes and how these may result in pharmacokinetic/metabolic changes in CKD. Here, we investigated the effects of uremic toxins and human uremic serum on the transport of the prototypical transporter substrate [(3) H]-estrone sulfate and three Biopharmaceutics Drug Disposition Classification System (BDDCS) drugs, propranolol, losartan, and eprosartan. We observed a significant decrease in [(3) H]-estrone sulfate, losartan, and eprosartan uptake with some uremic toxins in both transfected cells and rat hepatocytes. The uptake of losartan was decreased in rat and human hepatocytes (28% and 48%, respectively) in the presence of hemodialysis (HD) serum. Time-course studies of losartan showed a 27%, 65%, and 68% increase in area under the curve (AUC) in the presence of HD serum, rifampin, and sulfaphenazole, respectively. Intracellular losartan AUC decreased significantly in the treatment groups, and the metabolite AUC decreased by 41% and 26% in rifampin- and sulfaphenazole-treated group, respectively. The intracellular AUC of eprosartan increased 190% in the presence of HD serum. These studies indicate that the uremic toxins contained in HD serum play an important role in drug disposition through drug transporters, and that there would be differential effects depending on the BDDCS classification of the drug. Copyright © 2011 Wiley-Liss, Inc.

  16. Controllability in cancer metabolic networks according to drug targets as driver nodes.

    Science.gov (United States)

    Asgari, Yazdan; Salehzadeh-Yazdi, Ali; Schreiber, Falk; Masoudi-Nejad, Ali

    2013-01-01

    Networks are employed to represent many nonlinear complex systems in the real world. The topological aspects and relationships between the structure and function of biological networks have been widely studied in the past few decades. However dynamic and control features of complex networks have not been widely researched, in comparison to topological network features. In this study, we explore the relationship between network controllability, topological parameters, and network medicine (metabolic drug targets). Considering the assumption that targets of approved anticancer metabolic drugs are driver nodes (which control cancer metabolic networks), we have applied topological analysis to genome-scale metabolic models of 15 normal and corresponding cancer cell types. The results show that besides primary network parameters, more complex network metrics such as motifs and clusters may also be appropriate for controlling the systems providing the controllability relationship between topological parameters and drug targets. Consequently, this study reveals the possibilities of following a set of driver nodes in network clusters instead of considering them individually according to their centralities. This outcome suggests considering distributed control systems instead of nodal control for cancer metabolic networks, leading to a new strategy in the field of network medicine.

  17. Deletion of 30 murine cytochrome p450 genes results in viable mice with compromised drug metabolism.

    Science.gov (United States)

    Scheer, Nico; McLaughlin, Lesley A; Rode, Anja; Macleod, A Kenneth; Henderson, Colin J; Wolf, C Roland

    2014-06-01

    In humans, 75% of all drugs are metabolized by the cytochrome P450-dependent monooxygenase system. Enzymes encoded by the CYP2C, CYP2D, and CYP3A gene clusters account for ∼80% of this activity. There are profound species differences in the multiplicity of cytochrome P450 enzymes, and the use of mouse models to predict pathways of drug metabolism is further complicated by overlapping substrate specificity between enzymes from different gene families. To establish the role of the hepatic and extrahepatic P450 system in drug and foreign chemical disposition, drug efficacy, and toxicity, we created a unique mouse model in which 30 cytochrome P450 genes from the Cyp2c, Cyp2d, and Cyp3a gene clusters have been deleted. Remarkably, despite a wide range of putative important endogenous functions, Cyp2c/2d/3a KO mice were viable and fertile, demonstrating that these genes have evolved primarily as detoxification enzymes. Although there was no overt phenotype, detailed examination showed Cyp2c/2d/3a KO mice had a smaller body size (15%) and larger livers (20%). Changes in hepatic morphology and a decreased blood glucose (30%) were also noted. A five-drug cocktail of cytochrome P450 isozyme probe substrates were used to evaluate changes in drug pharmacokinetics; marked changes were observed in either the pharmacokinetics or metabolites formed from Cyp2c, Cyp2d, and Cyp3a substrates, whereas the metabolism of the Cyp1a substrate caffeine was unchanged. Thus, Cyp2c/2d/3a KO mice provide a powerful model to study the in vivo role of the P450 system in drug metabolism and efficacy, as well as in chemical toxicity.

  18. Characterization of drug-metabolizing enzymes CYP2C9, CYP2C19 ...

    Indian Academy of Sciences (India)

    We believe that this is the first work that reports these variants among those populations. The cytochrome P450 enzymes (CYPs) are a subfamily of hemoproteins, playing a critical role in the metabolism of many drugs. Several genetic polymorphisms which depend on ethnic groups can alter CYP activity and then affect the.

  19. Cryopreservation of precision-cut tissue slices for application in drug metabolism research

    NARCIS (Netherlands)

    de Graaf, I.A.M.; Koster, H

    Cryopreservation of tissue slices greatly facilitates their use in drug metabolism research, leading to efficient use of human organ material and a decrease of laboratory animal use. In the present review, various mechanisms of cryopreservation such as equilibrium slow freezing, rapid freezing and

  20. Host-Microbe Co-metabolism Dictates Cancer Drug Efficacy in C. elegans.

    Science.gov (United States)

    Scott, Timothy A; Quintaneiro, Leonor M; Norvaisas, Povilas; Lui, Prudence P; Wilson, Matthew P; Leung, Kit-Yi; Herrera-Dominguez, Lucia; Sudiwala, Sonia; Pessia, Alberto; Clayton, Peter T; Bryson, Kevin; Velagapudi, Vidya; Mills, Philippa B; Typas, Athanasios; Greene, Nicholas D E; Cabreiro, Filipe

    2017-04-20

    Fluoropyrimidines are the first-line treatment for colorectal cancer, but their efficacy is highly variable between patients. We queried whether gut microbes, a known source of inter-individual variability, impacted drug efficacy. Combining two tractable genetic models, the bacterium E. coli and the nematode C. elegans, we performed three-way high-throughput screens that unraveled the complexity underlying host-microbe-drug interactions. We report that microbes can bolster or suppress the effects of fluoropyrimidines through metabolic drug interconversion involving bacterial vitamin B 6 , B 9 , and ribonucleotide metabolism. Also, disturbances in bacterial deoxynucleotide pools amplify 5-FU-induced autophagy and cell death in host cells, an effect regulated by the nucleoside diphosphate kinase ndk-1. Our data suggest a two-way bacterial mediation of fluoropyrimidine effects on host metabolism, which contributes to drug efficacy. These findings highlight the potential therapeutic power of manipulating intestinal microbiota to ensure host metabolic health and treat disease. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  1. Microsomal drug-metabolizing enzymes in the olive baboon (papio anabis)

    DEFF Research Database (Denmark)

    Autrup, Herman; Thurlow, Brenda J.; Wakhisi, Johnston

    1975-01-01

    1.1. The activity of microsomal drug-metabolizing enzymes—azo reductase, nitroreductase, p-hydroxylation, N-demethylation, O-demethylation, NADPH cytochrome c reductase and cytochrome P P-450—in the olive baboon are lower than in other animal species, e.g. mouse, rat, guinea-pig. 2. 2. The level...

  2. 75 FR 2875 - Endocrinologic and Metabolic Drugs Advisory Committee; Notice of Meeting

    Science.gov (United States)

    2010-01-19

    ... analogue (a chemical compound that resembles another compound in structure) of growth hormone releasing hormone (GHRH). The proposed indication (use) for EGRIFTA in this application is to induce and maintain a...: Endocrinologic and Metabolic Drugs Advisory Committee. General Function of the Committee: To provide advice and...

  3. 131I metabolism in the study of antithyroid drug

    International Nuclear Information System (INIS)

    Gagliardi, R.P.; Santalla de Pirovano, M. del C.; Kramar de Valmaggia, E.P.; Valsecchi, R.; Pisarev, Mario; Altschuler, Noe

    1977-11-01

    The main purpose of the present report was to study the action of antithyroid drugs on different parameters of thyroid activity utilizing 131 I, in the offsprings of rats treated during pregnancy and the perinatal period. Both PTU and MMI caused alterations in growth and thyroid activity, but they were more dramatic with the former. A significative increase in 131 I thyroid uptake and in circulating radioactivity was observed. When % uptake was expressed as a function of thyroidal and body weights, a significative decrease was noticed. The ratio T/S and the percentage of labelled iodothyronines in pancreatin digests were also decreased. Neuromuscular maturation was evaluated, by means of the test of Schapiro. A group of animals treated with PTU plus T 4 had a significant delay, reaching normal developement later than the controls or those treated with MMI. (author) [es

  4. Tea consumption modulates hepatic drug metabolizing enzymes in Wistar rats.

    Science.gov (United States)

    Maliakal, P P; Coville, P F; Wanwimolruk, S

    2001-04-01

    The antioxidant, antimutagenic and anticarcinogenic activities of green tea and its polyphenols have been reported. As bioactivation of the precarcinogens and detoxification of ultimate carcinogens are mainly carried out by hepatic metabolizing enzymes, we have investigated the modulation of these enzyme activities subsequent to tea consumption in rats. Female Wistar rats were divided into eight groups (n = 5). Six groups were given aqueous solutions (2%, w/v) of six different teas (New Zealand green tea, Australian green tea, Java green tea, Dragon green tea, Gunpowder green tea or English Breakfast black tea) as the sole source of fluid. One group was given a standard green tea extract (0.5%, w/v) while the control group had free access to water. At the end of four-weeks treatment, different cytochrome P450 (CYP) isoform and phase II enzyme activities were determined by incubation of the liver microsomes or cytosols with appropriate substrates. CYP 1A2 activity was markedly increased in all the tea treatment groups (P Java green tea-treatment groups. Cytosolic glutathione-S-transferase activity was significantly increased (PJava green tea-treatment groups. The microsomal UDP-glucuronosyl transferase activity remained unchanged or was moderately increased in most of the groups. The balance between the phase I carcinogen-activating enzymes and the phase II detoxifying enzymes could be important in determining the risk of developing chemically-induced cancer.

  5. Gerakan Transnasional dan Kebijakan : Strategi Advokasi Greenpeace Detox Campaign on Fashion di Tiongkok

    Directory of Open Access Journals (Sweden)

    Puti Parameswari

    2016-08-01

    Full Text Available This study aims to understand the power of NGOs through advocacy campaign strategies to change the behavior or policies of other actors. This study analyzed Greenpeace advocacy on Detox Campaign on Fashion in China, in the period of 2011 to 2013. The main advocacy strategies used by  Greenpeace is campaign—include information politics, leverage politics, symbolic politics and accountability politics. This research also analyzed the relations between Greenpeace as NGO and targeted actors, namely global brand fashion, global society and state actors, China. This study found that the campaign strategy success in influencing targeted actors to change their behavior and policies regard to the issue of water pollution in China.

  6. Innovative methods to study human intestinal drug metabolism in vitro : Precision-cut slices compared with Ussing chamber preparations

    NARCIS (Netherlands)

    van de Kerkhof, Esther G.; Ungell, Anna-Lena B.; Sjoberg, Asa K.; de Jager, Marina H.; Hilgendorf, Constanze; de Graaf, Inge A. M.; Groothuis, Geny M. M.

    2006-01-01

    Predictive in vitro methods to investigate drug metabolism in the human intestine using intact tissue are of high importance. Therefore, we studied the metabolic activity of human small intestinal and colon slices and compared it with the metabolic activity of the same human intestinal segments

  7. On-chip electromembrane extraction for monitoring drug metabolism in real time by electrospray ionization mass spectrometry

    DEFF Research Database (Denmark)

    Petersen, Nickolaj J.; Pedersen, Jacob Sønderby; Poulsen, Nicklas Nørgård

    2012-01-01

    the in vitro metabolism of amitriptyline in real time. There was no need to stop the metabolisms by protein precipitation as in conventional metabolic studies, since the EME selectively extracted the drug and metabolites from the reaction solution comprised of rat liver microsomes in buffer. Compositional...

  8. Metabolic switching of drug pathways as a consequence of deuterium substitution

    International Nuclear Information System (INIS)

    Horning, M.G.; Haegele, K.D.; Sommer, K.R.; Nowlin, J.; Stafford, M.

    1975-01-01

    An investigation was made of the metabolism of deuterated analogs of caffeine (1-CD 3 -caffeine and 7-CD 3 -caffeine) and antipyrine (N-CD 3 -antipyrine and 3-CD 3 -antipyrine) because both caffeine and antipyrine are metabolized by multiple alternate pathways. Since it is well established that carbon-deuterium bonds are more stable than carbon-hydrogen bonds, it was postulated that oxidation of the CD 3 group would be depressed and that metabolism of the labeled compounds would be shifted to another pathway that did not involve cleavage of a carbon-deuterium bond. Metabolic switching of drug pathways was observed in vivo for both of the caffeine analogs and was observed both in vivo and in vitro for 3-CD 3 -antipyrine

  9. Drug-drug interaction and doping, part 1: an in vitro study on the effect of non-prohibited drugs on the phase I metabolic profile of toremifene.

    Science.gov (United States)

    Mazzarino, Monica; de la Torre, Xavier; Fiacco, Ilaria; Palermo, Amelia; Botrè, Francesco

    2014-05-01

    The present study was designed to provide preliminary information on the potential impact of metabolic drug-drug interaction on the effectiveness of doping control strategies currently followed by the anti-doping laboratories to detect the intake of banned agents. In vitro assays based on the use of human liver microsomes and recombinant CYP isoforms were designed and performed to characterize the phase I metabolic profile of the prohibited agent toremifene, selected as a prototype drug of the class of selective oestrogen receptor modulators, both in the absence and in the presence of medicaments (fluconazole, ketoconazole, itraconazole, miconazole, cimetidine, ranitidine, fluoxetine, paroxetine, nefazodone) not included in the World Anti-Doping Agency list of prohibited substances and methods and frequently administered to athletes. The results show that the in vitro model developed in this study was adequate to simulate the in vivo metabolism of toremifene, confirming the results obtained in previous studies. Furthermore, our data also show that ketoconazole, itraconazole, miconazole and nefazodone cause a marked modification in the production of the metabolic products (i.e. hydroxylated and carboxylated metabolites) normally selected by the anti-doping laboratories as target analytes to detect toremifene intake; moderate variations were registered in the presence of fluconazole, paroxetine and fluoxetine; while no significant modifications were measured in the presence of ranitidine and cimetidine. This evidence imposes that the potential effect of drug-drug interactions is duly taken into account in anti-doping analysis, also for a broader significance of the analytical results. Copyright © 2014 John Wiley & Sons, Ltd.

  10. Lack of effect of spinal anesthesia on drug metabolism

    International Nuclear Information System (INIS)

    Whelan, E.; Wood, A.J.; Shay, S.; Wood, M.

    1989-01-01

    The effect of spinal anesthesia on drug disposition was determined in six dogs with chronically implanted vascular catheters using propranolol as a model compound. On the first study day, 40 mg of unlabeled propranolol and 200 microCi of [3H]propranolol were injected into the portal and femoral veins respectively. Arterial blood samples were taken for 4 hr for measurement of plasma concentrations of labeled and unlabeled propranolol by high-pressure liquid chromatography (HPLC) and of [3H]propranolol by liquid scintillation counting of the HPLC eluant corresponding to each propranolol peak. Twenty-four hr later, spinal anesthesia was induced with tetracaine (mean dose 20.7 +/- 0.6 mg) with low sacral to midthoracic levels and the propranolol infusions and sampling were then repeated. Spinal anesthesia had no significant effect on either the intrinsic clearance of propranolol (2.01 +/- 0.75 L/min before and 1.9 +/- 0.7 L/min during spinal anesthesia), or on mean hepatic plasma flow (2.01 +/- 0.5 L/min before and 1.93 +/- 0.5 L/min during spinal anesthesia). The systemic clearance and elimination half-life of propranolol were also unchanged by spinal anesthesia (0.9 +/- 0.23 L/min on the first day, 0.7 +/- 0.1 L/min during spinal anesthesia; and 101 +/- 21 min on the first day, 115 +/- 16 min during spinal anesthesia, respectively). The volume of distribution (Vd) of propranolol was similarly unaffected by spinal anesthesia

  11. The metabolic and toxicological considerations for immunosuppressive drugs used during pancreas transplantation.

    Science.gov (United States)

    Rangel, Erika B

    2012-12-01

    Pancreas-kidney transplant is an effective treatment for patients with insulin-dependent dabetes and chronic renal failure. Reduction in technical failure loss and early acute rejection rates contributed to prolong pancreas graft survival. However, drug toxicity affects negatively both short- and long-term follow-ups. This article reviews the existing literature and knowledge of the immunosuppressive drugs that are frequently used in pancreas transplant, including calcineurin inhibitors, sirolimus, corticosteroids, and mycophenolate. The article also discusses the short- and long-term adverse effects of these drugs. The article also reports and discusses the most relevant in vitro studies, providing additional information to in vivo findings. Some clinically relevant drug interactions with immunosuppressive drugs are also highlighted. Over- and underimmunosuppression effects will not be addressed. Immunosuppressive regimen after pancreas transplant is very effective and contributed to pancreas allograft survival. However, they present several side effects that are potentiated when drugs are combined. Modifiable and non-modifiable risk factors can aggravate metabolic and toxicological effects of immunosuppressive drugs. It is important to critically analyze the results of clinical studies and investigate new immunosuppressive drugs and/or novel drug combinations. It is equally important to comprehend and interpret experimental data. Therefore, minimization of side effects, based on safe approaches, can prolong pancreas allograft survival.

  12. Drug metabolism and genetic polymorphism in subjects with previous halothane hepatitis

    DEFF Research Database (Denmark)

    Ranek, L; Dalhoff, K; Poulsen, H E

    1993-01-01

    To test the hypothesis that halothane hepatitis is caused by a combination of altered drug metabolism and an immunoallergic disposition, the metabolism of antipyrine, metronidazole, sparteine, phenytoin, and racemic R- and S-mephenytoin was investigated in seven subjects with previous halothane h...... hepatitis do not appear to be different from controls with regard to drug metabolism and HLA tissue type. The possibility of a higher frequency of complement C3 phenotype F and FS needs further investigation....... hepatitis. The HLA tissue types and the complement C3 phenotypes were also determined. The metabolism of antipyrine and metronidazole was within normal range in all subjects, and they were all fast or extensive metabolizers of sparteine, mephenytoin, and phenytoin. HLA tissue types were unremarkable. Five...... of the seven subjects had complement C3 phenotypes F or FS. In the general population phenotype S is the most common, but the difference in complement C3 phenotypes is not statistically significant (p = 0.07). We conclude, although in a limited number of patients, that subjects with previous halothane...

  13. Psychedelic 5-methoxy-N,N-dimethyltryptamine: metabolism, pharmacokinetics, drug interactions, and pharmacological actions.

    Science.gov (United States)

    Shen, Hong-Wu; Jiang, Xi-Ling; Winter, Jerrold C; Yu, Ai-Ming

    2010-10-01

    5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) belongs to a group of naturally-occurring psychoactive indolealkylamine drugs. It acts as a nonselective serotonin (5-HT) agonist and causes many physiological and behavioral changes. 5-MeO-DMT is O-demethylated by polymorphic cytochrome P450 2D6 (CYP2D6) to an active metabolite, bufotenine, while it is mainly inactivated through the deamination pathway mediated by monoamine oxidase A (MAO-A). 5-MeO-DMT is often used with MAO-A inhibitors such as harmaline. Concurrent use of harmaline reduces 5-MeO-DMT deamination metabolism and leads to a prolonged and increased exposure to the parent drug 5-MeO-DMT, as well as the active metabolite bufotenine. Harmaline, 5-MeO-DMT and bufotenine act agonistically on serotonergic systems and may result in hyperserotonergic effects or serotonin toxicity. Interestingly, CYP2D6 also has important contribution to harmaline metabolism, and CYP2D6 genetic polymorphism may cause considerable variability in the metabolism, pharmacokinetics and dynamics of harmaline and its interaction with 5-MeO-DMT. Therefore, this review summarizes recent findings on biotransformation, pharmacokinetics, and pharmacological actions of 5-MeO-DMT. In addition, the pharmacokinetic and pharmacodynamic drug-drug interactions between harmaline and 5-MeO-DMT, potential involvement of CYP2D6 pharmacogenetics, and risks of 5-MeO-DMT intoxication are discussed.

  14. Metabolism of Drugs Used in the Therapy of Seizures: An Analytical Point of View. Part 1.

    Science.gov (United States)

    Mandrioli, Roberto; Mercolini, Laura

    2017-10-16

    Seizures are aetiologically and clinically heterogeneous neurological disorders that are currently treated using a wide array of drugs, belonging to equally heterogeneous chemical classes. Some of them are known as "antiepileptic drugs" (AEDs), due to their main field of use, while others (such as benzodiazepines) are frequently used for other conditions as well as for seizures. Due to their different chemical properties and mechanisms of activity, the metabolic characteristics of anti-seizure drugs can vary widely, also producing big differences in terms of safety, efficacy and therapeutic suitability. Scopus and PubMed databases were searched for the most significant papers centered on metabolism and analysis of the following antiepileptics: carbamazepine, oxcarbazepine, lamotrigine, phenytoin, ethosuximide, gabapentin, vigabatrin, topiramate, levetiracetam and valproic acid. The most important studies on the metabolic characteristics of several AEDs are reported and briefly discussed in this review; moreover, the analytical methods used to determine biological levels of these drugs during therapy are also described and commented upon, and their main characteristics highlighted. Other AEDs, and notes on polypharmacy, will be included in the second part of this series. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  15. The many consequences of chemical- and genetic-based modulation of drug metabolizing enzyme activities.

    Science.gov (United States)

    Paolini, M; Biagi, G L; Cantelli-Forti, G

    1999-01-01

    The induction or inhibition of the metabolizing enzyme activities by a great deal of substances (including drugs) influence their toxicological or pharmacological outcomes as well as that of other xenobiotics or drugs to which human is simultaneously exposed. The dual bioactivating/detoxificating nature of both phase I and phase II enzymes poses such modulation as an unavoidable unhealthy phenomenon. Therefore, the proposed strategies in preventive medicine which foresee boosting or depressing enzymatic effects such as those in the field of cancer chemoprevention, should be carefully reconsidered before their credibility would be compromised. As the phenotypic features, genetic polymorphisms leading to the occurrence of high or low metabolizers in the population, each at high risk to certain forms of toxicity, behave as a sort of "constitutive" enzymatic modulation. Thus, considering the double-edged sword nature (detoxi-toxicant) of these catalysts towards ubiquitous environmental pollutants, the search for individual susceptibility by means of the genotypic analysis represents a very intriguing problem. However, the knowledge of the "overall" metabolic fingerprint associated to the phenotypic analysis in a single person could offer an interesting way to (partially) control human risk by making suitable (well aimed) modifications of determined life-styles (e.g. stop smoking or drinking) or particular dietetic practices (e.g. stop eating high cooked meat or fish) as well as selecting personalised drug adjustments by physicians either in terms of dosage or fitting drug.

  16. Human gut microbiota plays a role in the metabolism of drugs.

    Science.gov (United States)

    Jourova, Lenka; Anzenbacher, Pavel; Anzenbacherova, Eva

    2016-09-01

    The gut microbiome, an aggregate genome of trillions of microorganisms residing in the human gastrointestinal tract, is now known to play a critical role in human health and predisposition to disease. It is also involved in the biotransformation of xenobiotics and several recent studies have shown that the gut microbiota can affect the pharmacokinetics of orally taken drugs with implications for their oral bioavailability. Review of Pubmed, Web of Science and Science Direct databases for the years 1957-2016. Recent studies make it clear that the human gut microbiota can play a major role in the metabolism of xenobiotics and, the stability and oral bioavailability of drugs. Over the past 50 years, more than 30 drugs have been identified as a substrate for intestinal bacteria. Questions concerning the impact of the gut microbiota on drug metabolism, remain unanswered or only partially answered, namely (i) what are the molecular mechanisms and which bacterial species are involved? (ii) What is the impact of host genotype and environmental factors on the composition and function of the gut microbiota, (iii) To what extent is the composition of the intestinal microbiome stable, transmissible, and resilient to perturbation? (iv) Has past exposure to a given drug any impact on future microbial response, and, if so, for how long? Answering such questions should be an integral part of pharmaceutical research and personalised health care.

  17. Recent developments in our understanding of the implications of traditional African medicine on drug metabolism.

    Science.gov (United States)

    Gouws, Chrisna; Hamman, Josias H

    2018-02-01

    The use of traditional herbal medicines has become increasingly popular globally, but in some countries, it is the main or sometimes even the only healthcare service available in the most rural areas. This is especially true for Africa where herbal medicines form a key component of traditional medicinal practices and there is access to a diversity of medicinal plants. Although many benefits have been derived from the use of traditional herbal medicines, many concerns are associated with their use of which herb-drug interactions have been identified to have a rising impact on patient treatment outcome. One type of pharmacokinetic interaction involves the modulation of drug metabolizing enzymes, which may result in enhanced or reduced bioavailability of co-administered drugs. Areas covered: This review highlights the current information available on drug metabolism-associated information with regards to traditional African medicines related to some of the most prevalent diseases burdening the African continent. Expert opinion: It is clear from previous studies that enzyme modulation by traditional African medicines plays a significant role in the pharmacokinetics of some co-administered drugs, but more research is needed to provide detailed information on these interactions, specifically for treatment of prevalent diseases such as tuberculosis and hypertension.

  18. Metabolic network analysis-based identification of antimicrobial drug targets in category A bioterrorism agents.

    Directory of Open Access Journals (Sweden)

    Yong-Yeol Ahn

    Full Text Available The 2001 anthrax mail attacks in the United States demonstrated the potential threat of bioterrorism, hence driving the need to develop sophisticated treatment and diagnostic protocols to counter biological warfare. Here, by performing flux balance analyses on the fully-annotated metabolic networks of multiple, whole genome-sequenced bacterial strains, we have identified a large number of metabolic enzymes as potential drug targets for each of the three Category A-designated bioterrorism agents including Bacillus anthracis, Francisella tularensis and Yersinia pestis. Nine metabolic enzymes- belonging to the coenzyme A, folate, phosphatidyl-ethanolamine and nucleic acid pathways common to all strains across the three distinct genera were identified as targets. Antimicrobial agents against some of these enzymes are available. Thus, a combination of cross species-specific antibiotics and common antimicrobials against shared targets may represent a useful combinatorial therapeutic approach against all Category A bioterrorism agents.

  19. Metabolism of anabolic steroids and their relevance to drug detection in horseracing.

    Science.gov (United States)

    Teale, Philip; Houghton, Edward

    2010-06-01

    The fight against doping in sport using analytical chemistry is a mature area with a history of approximately 100 years in horseracing. In common with human sport, anabolic/androgenic steroids (AASs) are an important group of potential doping agents. Particular issues with their detection are extensive metabolism including both phase I and phase II. A number of the common AASs are also endogenous to the equine. A further issue is the large number of synthetic steroids produced as pharmaceutical products or as 'designer' drugs intended to avoid detection or for the human supplement market. An understanding of the metabolism of AASs is vital to the development of effective detection methods for equine sport. The aim of this paper is to review current knowledge of the metabolism of appropriate steroids, the current approaches to their detection in equine sport and future trends that may affect equine dope testing.

  20. Crypt Organoid Culture as an in Vitro Model in Drug Metabolism and Cytotoxicity Studies.

    Science.gov (United States)

    Lu, Wenqi; Rettenmeier, Eva; Paszek, Miles; Yueh, Mei-Fei; Tukey, Robert H; Trottier, Jocelyn; Barbier, Olivier; Chen, Shujuan

    2017-07-01

    The gastrointestinal tract is enriched with xenobiotic processing proteins that play important roles in xenobiotic bioactivation, metabolism, and detoxification. The application of genetically modified mouse models has been instrumental in characterizing the function of xenobiotic processing genes (XPG) and their proteins in drug metabolism. Here, we report the utilization of three-dimensional crypt organoid cultures from these animal models to study intestinal drug metabolism and toxicity. With the successful culturing of crypt organoids, we profiled the abundance of Phase I and Phase II XPG expression, drug transporter gene expression, and xenobiotic nuclear receptor (XNR) gene expression. Functions of XNRs were examined by treating crypt cells with XNR prototypical agonists. Real-time quantitative polymerase chain reaction demonstrated that the representative downstream target genes were induced. These findings were validated from cultures developed from XNR-null mice. In crypt cultures isolated from Pxr -/- mice, pregnenolone 16 α -carbonitrile failed to induce Cyp3a11 gene expression; similarly, WY14643 failed to induce Cyp4a10 in the Pparα -/- crypts. Crypt cultures from control ( Ugt1 F/F ) and intestinal epithelial cell (IEC) specific Ugt1 null mice ( Ugt1 ΔIEC ) were treated with camptothecin-11, an anticancer prodrug with severe intestinal toxicity that originates from insufficient UGT1A1-dependent glucuronidation of its active metabolite SN-38. In the absence of Ugt1 gene expression, Ugt1 ΔIEC crypt cultures exhibit very limited production of SN-38 glucuronide, concordant with increased apoptosis in comparison with Ugt1 F/F crypt cultures. This study suggests crypt organoid cultures as an effective in vitro model for studying intestinal drug metabolism and toxicity. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  1. Schisandra chinensis regulates drug metabolizing enzymes and drug transporters via activation of Nrf2-mediated signaling pathway

    Directory of Open Access Journals (Sweden)

    He JL

    2014-12-01

    Full Text Available Jin-Lian He,1 Zhi-Wei Zhou,2,3 Juan-Juan Yin,2 Chang-Qiang He,1 Shu-Feng Zhou,2,3 Yang Yu1 1College of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China; 2Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA; 3Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center and Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, Guizhou, People’s Republic of China Abstract: Drug metabolizing enzymes (DMEs and drug transporters are regulated via epigenetic, transcriptional, posttranscriptional, and translational and posttranslational modifications. Phase I and II DMEs and drug transporters play an important role in the disposition and detoxification of a large number of endogenous and exogenous compounds. The nuclear factor (erythroid-derived 2-like 2 (Nrf2 is a critical regulator of a variety of important cytoprotective genes that are involved in disposition and detoxification of xenobiotics. Schisandra chinensis (SC is a commonly used traditional Chinese herbal medicine that has been primarily used to protect the liver because of its potent antioxidative and anti-inflammatory activities. SC can modulate some DMEs and drug transporters, but the underlying mechanisms are unclear. In this study, we aimed to explore the role of Nrf2 in the regulatory effect of SC extract (SCE on selected DMEs and drug transporters in human hepatocellular liver carcinoma cell line (HepG2 cells. The results showed that SCE, schisandrin A, and schisandrin B significantly increased the expression of NAD(PH: Nicotinamide Adenine Dinucleotide Phosphate-oxidase or:quinone oxidoreductase 1, heme oxygenase-1, glutamate–cysteine ligase, and glutathione S-transferase A4 at both transcriptional and posttranscriptional levels. Incubation of HepG2 cells with SCE resulted in a significant

  2. The protease inhibitors ritonavir and saquinavir influence lipid metabolism: a pig model for the rapid evaluation of new drugs

    DEFF Research Database (Denmark)

    Petersen, E.; Mu, Huiling; Porsgaard, Trine

    2010-01-01

    Background: Studies of the effects of antiretroviral drugs on lipid metabolism are limited by the availability of suitable models. We have thus developed an animal model utilising Gottingen mini-pigs. The normal lipid metabolism of mini-pigs closely reflects that of humans and they are expected...... levels, suggesting a prolonged effect of the antiretroviral drug treatment lasting beyond the 4 week post-treatment observation period. Conclusions: The Gottingen mini-pig model is a promising animal model for rapid screening of the metabolic effects induced by antiretroviral drugs....

  3. In vitro-in vivo correlation for intrinsic clearance for drugs metabolized by human aldehyde oxidase.

    Science.gov (United States)

    Zientek, Michael; Jiang, Ying; Youdim, Kuresh; Obach, R Scott

    2010-08-01

    The ability to predict in vivo clearance from in vitro intrinsic clearance for compounds metabolized by aldehyde oxidase has not been demonstrated. To date, there is no established scaling method for predicting aldehyde oxidase-mediated clearance using in vitro or animal data. This challenge is exacerbated by the fact that rats and dogs, two of the laboratory animal species commonly used to develop in vitro-in vivo correlations of clearance, differ from humans with regard to expression of aldehyde oxidase. The objective of this investigation was to develop an in vitro-in vivo correlation of intrinsic clearance for aldehyde oxidase, using 11 drugs known to be metabolized by this enzyme. The set consisted of methotrexate, XK-469, (+/-)-4-(4-cyanoanilino)-5,6-dihydro-7-hydroxy-7H-cyclopenta[d]pyrimidine (RS-8359), zaleplon, 6-deoxypenciclovir, zoniporide, O(6)-benzylguanine, N-[(2'-dimethylamino)ethyl]acridine-4-carboxamide (DACA), carbazeran, PF-4217903, and PF-945863. These compounds were assayed using two in vitro systems (pooled human liver cytosol and liver S-9 fractions) to calculate scaled unbound intrinsic clearance, and they were then compared with calculated in vivo unbound intrinsic clearance. The investigation provided a relative scale that can be used for in vitro-in vivo correlation of aldehyde oxidase clearance and suggests limits as to when a potential new drug candidate that is metabolized by this enzyme will possess acceptable human clearance, or when structural modification is required to reduce aldehyde oxidase catalyzed metabolism.

  4. Effects of first-pass metabolism on metabolite mean residence time determination after oral administration of parent drug.

    Science.gov (United States)

    Chan, K K; Gibaldi, M

    1990-01-01

    Metabolite kinetics after oral drug administration can be determined, without separate metabolite administration, using the concepts of mean residence time (MRT). The MRT of parent drug and metabolite after oral administration of the parent drug, MRTp,p(oral) and MRTm,p(oral), can be calculated directly from the drug and metabolite profiles. The difference between MRTm,p(oral) and MRTp,p(oral), termed Delta MRT, yields an estimate of MRT of metabolite when the metabolite is given as an iv bolus, MRTm,m(iv). The calculation is simple for drugs that are known to undergo, negligible first-pass metabolism. Correction can also be made when extent of first-pass metabolism is known. Ambiguity is encountered, however, when the degree of first-pass metabolism is unknown. When the delta MRT is negative, then first-pass metabolism must be considered. A positive value of delta MRT, on the other hand, is not a definitive indication of the absence of first-pass metabolism. It may occur in the presence or absence of first-pass metabolism. Ignoring the possibility of first-pass metabolism when a positive value of delta MRT occurs may lead to an incorrect estimate of MRTm,m(iv). The estimation error is relatively small, however, when MRTm,m(iv) much greater than MRTp,p(iv), even when first-pass metabolism is extensive. This situation may apply to the administration of a prodrug.

  5. Gene expression variability in human hepatic drug metabolizing enzymes and transporters.

    Directory of Open Access Journals (Sweden)

    Lun Yang

    Full Text Available Interindividual variability in the expression of drug-metabolizing enzymes and transporters (DMETs in human liver may contribute to interindividual differences in drug efficacy and adverse reactions. Published studies that analyzed variability in the expression of DMET genes were limited by sample sizes and the number of genes profiled. We systematically analyzed the expression of 374 DMETs from a microarray data set consisting of gene expression profiles derived from 427 human liver samples. The standard deviation of interindividual expression for DMET genes was much higher than that for non-DMET genes. The 20 DMET genes with the largest variability in the expression provided examples of the interindividual variation. Gene expression data were also analyzed using network analysis methods, which delineates the similarities of biological functionalities and regulation mechanisms for these highly variable DMET genes. Expression variability of human hepatic DMET genes may affect drug-gene interactions and disease susceptibility, with concomitant clinical implications.

  6. Association of metabolic syndrome with atypical antipsychotic drug (olanzapine) short term versus long term use

    International Nuclear Information System (INIS)

    Ikram, H.; Ahmed, T.M.; Hayat, A.; Ullah, Q.I.; Nawaz, A.

    2017-01-01

    Objective: To determine the association of metabolic syndrome with atypical antipsychotic drug (olanzapine) short term versus long term use. Study Design: Case control study. Place and Duration of Study: Chemical pathology department Army Medical College Rawalpindi, from Nov 2014 to Oct 2015. Material and Methods: The study was carried out on 240 subjects, 120 cases and 120 controls. For the purpose of the study cases were divided into four groups A, B, C and D according to the duration of drug use. Group A patients included those who the last the drug olanzapine for the last three months. Group B patients included those who were using the drug olanzapine for the last six months. Group C and D included those who were using the drug for last 1 year and more than one year (2-5 years) respectively. By employing non probability convenience sampling technique the data was collected from patients having the diagnosis of psychosis as per DSM IV modified criteria through a proforma and fasting blood samples were drawn. These samples were tested for fasting serum lipid profile and fasting plasma glucose. The data obtained were analyzed using SPSS version 21. For quantitative data Mean and SD were calculated. For qualitative data frequency and percentages were calculated. Qualitative data was compared using chi square test whereas quantitative data was compared using independent sample t-test. Results: There was statistically no significant difference in fasting plasma glucose between group A and B and their controls whereas in group C and D these levels were significantly high as compared to controls. Triglyceride levels were significantly higher and HDL cholesterol levels were significantly lower in all four groups as compared to controls. Comparison of qualitative data which included waist circumference and blood pressure showed statistically no significant rise for group A whereas waist circumference showed insignificant rise and blood pressure showed statistically

  7. [Involvement of microRNA in the induction of drug-metabolizing enzymes].

    Science.gov (United States)

    Shizu, Ryota; Numazawa, Satoshi; Yoshida, Takemi

    2012-01-01

    MicroRNAs (miRNAs) are small noncoding RNAs of about 20 nucleotides in length and participate in the post-transcriptional regulation of gene expression. Accumulating evidence indicates that miRNA binds to 3'-UTR of its target mRNAs and thereby destabilizes the transcripts or suppresses the translation. It is expected that miRNAs could have diverse functions and therefore play a role in the gene expression caused by the drug treatment, which have yet to be determined. Demonstration of the participation of specific miRNA in the drug-mediated gene expression would make it a biomarker for the toxicological assessment and help an understanding of molecular machinery of the drug-drug interaction. Under these backgrounds, we investigated the change of miRNAs in the liver of mice treated with phenobarbital, a typical inducer for drug-metabolizing enzymes, and demonstrate the participation of miRNAs in the phenobarbital-regulated gene expression. We investigated the relationship between phenobarbital-mediated changes in miRNA and mRNA by using Agilent miRNA microarray and DNA microarray, followed by real time RT-PCR. From these experiments, it was suggested that the phenobarbital-induced changes in cyp2c29 and mrp3 are regulated by miR-30a and miR-29b, respectively. In addition, we obtained evidence that indicates a phenobarbital-mediated decrease in miR-122, a highly abundant liver-specific miRNA, leads to the activation of the transcription factor CAR and thereby induces drug-metabolizing enzymes.

  8. Putative drug and vaccine target protein identification using comparative genomic analysis of KEGG annotated metabolic pathways of Mycoplasma hyopneumoniae.

    Science.gov (United States)

    Damte, Dereje; Suh, Joo-Won; Lee, Seung-Jin; Yohannes, Sileshi Belew; Hossain, Md Akil; Park, Seung-Chun

    2013-07-01

    In the present study, a computational comparative and subtractive genomic/proteomic analysis aimed at the identification of putative therapeutic target and vaccine candidate proteins from Kyoto Encyclopedia of Genes and Genomes (KEGG) annotated metabolic pathways of Mycoplasma hyopneumoniae was performed for drug design and vaccine production pipelines against M.hyopneumoniae. The employed comparative genomic and metabolic pathway analysis with a predefined computational systemic workflow extracted a total of 41 annotated metabolic pathways from KEGG among which five were unique to M. hyopneumoniae. A total of 234 proteins were identified to be involved in these metabolic pathways. Although 125 non homologous and predicted essential proteins were found from the total that could serve as potential drug targets and vaccine candidates, additional prioritizing parameters characterize 21 proteins as vaccine candidate while druggability of each of the identified proteins evaluated by the DrugBank database prioritized 42 proteins suitable for drug targets. Copyright © 2013 Elsevier Inc. All rights reserved.

  9. Age related changes in fractional elimination pathways for drugs: assessing the impact of variable ontogeny on metabolic drug-drug interactions.

    Science.gov (United States)

    Salem, Farzaneh; Johnson, Trevor N; Barter, Zoe E; Leeder, J Steven; Rostami-Hodjegan, Amin

    2013-08-01

    The magnitude of any metabolic drug-drug interactions (DDIs) depends on fractional importance of inhibited pathway which may not necessarily be the same in young children when compared to adults. The ontogeny pattern of cytochrome P450 (CYP) enzymes (CYPs 1A2, 2B6, 2C8, 2C9, 2C18/19, 2D6, 2E1, 3A4) and renal function were analyzed systematically. Bootstrap methodology was used to account for variability, and to define the age range over which statistical differences existed between each pair of specific pathways. A number of DDIs were simulated (Simcyp Pediatric v12) for virtual compounds to highlight effects of age on fractional elimination and consequent magnitude of DDI. For a theoretical drug metabolized 50% by each of CYP2D6 and CYP3A4 pathways at birth, co-administration of ketoconazole (3 mg/kg) resulted in a 1.65-fold difference between inhibited versus uninhibited AUC compared to 2.4-fold in 1 year olds and 3.2-fold in adults. Conversely, neonates could be more sensitive to DDI than adults in certain scenarios. Thus, extrapolation from adult data may not be applicable across all pediatric age groups. The use of pediatric physiologically based pharmacokinetic (p-PBPK) models may offer an interim solution to uncovering potential periods of vulnerability to DDI where there are no existing clinical data derived from children. © The Author(s) 2013.

  10. Effects of Radiation and Dietary Iron on Expression of Genes and Proteins Involved in Drug Metabolism

    Science.gov (United States)

    Faust, K. M.; Wotring, V. E.

    2014-01-01

    Liver function, especially the rate of metabolic enzyme activities, determines the concentration of circulating drugs and the duration of their efficacy. Most pharmaceuticals are metabolized by the liver, and clinically-used medication doses are given with normal liver function in mind. A drug overdose can result in the case of a liver that is damaged and removing pharmaceuticals from the circulation at a rate slower than normal. Alternatively, if liver function is elevated and removing drugs from the system more quickly than usual, it would be as if too little drug had been given for effective treatment. Because of the importance of the liver in drug metabolism, we want to understand any effects of spaceflight on the enzymes of the liver. Dietary factors and exposure to radiation are aspects of spaceflight that are potential oxidative stressors and both can be modeled in ground experiments. In this experiment, we examined the effects of high dietary iron and low dose gamma radiation (individually and combined) on the gene expression of enzymes involved in drug metabolism, redox homeostasis, and DNA repair. METHODS All procedures were approved by the JSC Animal Care and Use Committee. Male Sprague-Dawley rats were divided into 4 groups (n=8); control, high Fe diet (650 mg iron/kg), radiation (fractionated 3 Gy exposure from a Cs- 137 source) and combined high Fe diet + radiation exposure. Animals were euthanized 24h after the last treatment of radiation; livers were removed immediately and flash -frozen in liquid nitrogen. Expression of genes thought to be involved in redox homeostasis, drug metabolism and DNA damage repair was measured by RT-qPCR. Where possible, protein expression of the same genes was measured by western blotting. All data are expressed as % change in expression normalized to reference gene expression; comparisons were then made of each treatment group to the sham exposed/ normal diet control group. Data was considered significant at pprotein

  11. Microsomal detoxication enzyme responses of the marine snail, Thais haemastoma, to laboratory oil exposure

    Energy Technology Data Exchange (ETDEWEB)

    Livingstone, D.R.; Stickle, W.B.; Kapper, M.; Wang, S.

    1986-06-01

    The cytochrome P-450 monooxygenase or mixed function oxidase (MFO) system is a widely distributed enzyme system involved in the detoxication of foreign organic compounds (xenobiotics) taken up by organisms. Increases in the activities of the MFO system, occur with exposure of the organism to organic xenobiotics and such responses in the field have been proposed as a means of identifying biological impact by organic pollution. The carnivorous marine gastropod Thais haemastoma, or southern oyster drill, rapidly accumulated polynuclear aromatic and other hydrocarbons from the environment, through both the food source and the water-column. In laboratory experiments T. haemastoma were exposed to the water soluble fraction (WSF) of South Louisiana crude oil and the responses of the MFO system examined. Preliminary characterization of the snail MFO system was carried out using methodology developed from studies on the common mussel Mytilus edulis. Microsomal benz(a)pyrene hydroxylase (BPH), NADH- and NADPH- dependent cytochrome c reductase (NAD(P)H-CYTCRED) and NADH-dependent ferricyanide reductase (NADH-FERRIRED) activities were measured but it was not possible to determine cytochrome P-450 or b/sub 5/.

  12. Perception of sleep and dreams in alcohol-dependent patients during detoxication and abstinence.

    Science.gov (United States)

    Steinig, Jana; Foraita, Ronja; Happe, Svenja; Heinze, Martin

    2011-01-01

    This study aims to investigate sleep quality and the subjective dream experience in alcohol-dependent patients during withdrawal and abstinence compared with healthy controls. Thirty-seven patients with alcohol dependency and 35 healthy control subjects were asked to fill in several questionnaires and to give information about their subjective sleep and dream experiences. Twelve patients participated in a follow-up interview 4 weeks later. Sleep quality is impaired in alcohol-dependent patients during detoxication, and the subjective dream experience is more negatively toned compared with healthy controls. Both sleep quality and dream experience improves slightly after 4 weeks of abstinence. Patients with alcohol dependency during withdrawal and abstinence dream significantly more often about alcohol. However, none of the abstinent alcohol-dependent patients dreamed about alcohol during withdrawal. This study shows that the subjective sleep and dream quality is strongly impaired in patients with alcohol dependency. Differences in the dream experience between alcohol-dependent patients and healthy controls are in accordance with the continuity hypotheses of dreaming. The hypothesis of dreaming about alcohol as a compensatory effect, however, could not be confirmed.

  13. Carboxymefloquine, the major metabolite of the antimalarial drug mefloquine, induces drug-metabolizing enzyme and transporter expression by activation of pregnane X receptor.

    Science.gov (United States)

    Piedade, Rita; Traub, Stefanie; Bitter, Andreas; Nüssler, Andreas K; Gil, José P; Schwab, Matthias; Burk, Oliver

    2015-01-01

    Malaria patients are frequently coinfected with HIV and mycobacteria causing tuberculosis, which increases the use of coadministered drugs and thereby enhances the risk of pharmacokinetic drug-drug interactions. Activation of the pregnane X receptor (PXR) by xenobiotics, which include many drugs, induces drug metabolism and transport, thereby resulting in possible attenuation or loss of the therapeutic responses to the drugs being coadministered. While several artemisinin-type antimalarial drugs have been shown to activate PXR, data on nonartemisinin-type antimalarials are still missing. Therefore, this study aimed to elucidate the potential of nonartemisinin antimalarial drugs and drug metabolites to activate PXR. We screened 16 clinically used antimalarial drugs and six major drug metabolites for binding to PXR using the two-hybrid PXR ligand binding domain assembly assay; this identified carboxymefloquine, the major and pharmacologically inactive metabolite of the antimalarial drug mefloquine, as a potential PXR ligand. Two-hybrid PXR-coactivator and -corepressor interaction assays and PXR-dependent promoter reporter gene assays confirmed carboxymefloquine to be a novel PXR agonist which specifically activated the human receptor. In the PXR-expressing intestinal LS174T cells and in primary human hepatocytes, carboxymefloquine induced the expression of drug-metabolizing enzymes and transporters on the mRNA and protein levels. The crucial role of PXR for the carboxymefloquine-dependent induction of gene expression was confirmed by small interfering RNA (siRNA)-mediated knockdown of the receptor. Thus, the clinical use of mefloquine may result in pharmacokinetic drug-drug interactions by means of its metabolite carboxymefloquine. Whether these in vitro findings are of in vivo relevance has to be addressed in future clinical drug-drug interaction studies. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  14. Mechanisms underlying food-drug interactions: inhibition of intestinal metabolism and transport.

    Science.gov (United States)

    Won, Christina S; Oberlies, Nicholas H; Paine, Mary F

    2012-11-01

    Food-drug interaction studies are critical to evaluate appropriate dosing, timing, and formulation of new drug candidates. These interactions often reflect prandial-associated changes in the extent and/or rate of systemic drug exposure. Physiologic and physicochemical mechanisms underlying food effects on drug disposition are well-characterized. However, biochemical mechanisms involving drug metabolizing enzymes and transport proteins remain underexplored. Several plant-derived beverages have been shown to modulate enzymes and transporters in the intestine, leading to altered pharmacokinetic (PK) and potentially negative pharmacodynamic (PD) outcomes. Commonly consumed fruit juices, teas, and alcoholic drinks contain phytochemicals that inhibit intestinal cytochrome P450 and phase II conjugation enzymes, as well as uptake and efflux transport proteins. Whereas myriad phytochemicals have been shown to inhibit these processes in vitro, translation to the clinic has been deemed insignificant or undetermined. An overlooked prerequisite for elucidating food effects on drug PK is thorough knowledge of causative bioactive ingredients. Substantial variability in bioactive ingredient composition and activity of a given dietary substance poses a challenge in conducting robust food-drug interaction studies. This confounding factor can be addressed by identifying and characterizing specific components, which could be used as marker compounds to improve clinical trial design and quantitatively predict food effects. Interpretation and integration of data from in vitro, in vivo, and in silico studies require collaborative expertise from multiple disciplines, from botany to clinical pharmacology (i.e., plant to patient). Development of more systematic methods and guidelines is needed to address the general lack of information on examining drug-dietary substance interactions prospectively. Copyright © 2012 Elsevier Inc. All rights reserved.

  15. The Ussing Chamber Assay to Study Drug Metabolism and Transport in the Human Intestine.

    Science.gov (United States)

    Kisser, Beatrice; Mangelsen, Eva; Wingolf, Caroline; Partecke, Lars Ivo; Heidecke, Claus-Dieter; Tannergren, Christer; Oswald, Stefan; Keiser, Markus

    2017-06-22

    The Ussing chamber is an old but still powerful technique originally designed to study the vectorial transport of ions through frog skin. This technique is also used to investigate the transport of chemical agents through the intestinal barrier as well as drug metabolism in enterocytes, both of which are key determinants for the bioavailability of orally administered drugs. More contemporary model systems, such as Caco-2 cell monolayers or stably transfected cells, are more limited in their use compared to the Ussing chamber because of differences in expression rates of transporter proteins and/or metabolizing enzymes. While there are limitations to the Ussing chamber assay, the use of human intestinal tissue remains the best laboratory test for characterizing the transport and metabolism of compounds following oral administration. Detailed in this unit is a step-by-step protocol for preparing human intestinal tissue, for designing Ussing chamber experiments, and for analyzing and interpreting the findings. © 2017 by John Wiley & Sons, Inc. Copyright © 2017 John Wiley & Sons, Inc.

  16. Primary Hepatocytes Cultured on a Fiber-Embedded PDMS Chip to Study Drug Metabolism

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    Yaowen Liu

    2017-06-01

    Full Text Available In vitro drug screening using reliable and predictable liver models remains a challenge. The identification of an ideal biological substrate is essential to maintain hepatocyte functions during in vitro culture. Here, we developed a fiber-embedded polydimethylsiloxane (PDMS chip to culture hepatocytes. Hepatocyte spheroids formed in this device were subjected to different flow rates, of which a flow rate of 50 μL/min provided the optimal microenvironment for spheroid formation, maintained significantly higher rates of albumin and urea synthesis, yielded higher CYP3A1 (cytochrome P450 3A1 and CYP2C11 (cytochrome P450 2C11 enzyme activities for metabolism, and demonstrated higher expression levels of liver-specific genes. In vitro metabolism tests on tolbutamide and testosterone by hepatocytes indicated predicted clearance rates of 1.98 ± 0.43 and 40.80 ± 10.13 mL/min/kg, respectively, which showed a good in vitro–in vivo correspondence. These results indicate that this system provides a strategy for the construction of functional engineered liver tissue that can be used to study drug metabolism.

  17. Interaction of ibuprofen and probenecid with drug metabolizing enzyme phenotyping procedures using caffeine as the probe drug

    Science.gov (United States)

    Vrtic, Fatima; Haefeli, Walter E; Drewe, Jürgen; Krähenbühl, Stephan; Wenk, Markus

    2003-01-01

    Aim To examine the suspected inhibitory potential of the over-the-counter (OTC) drug ibuprofen on N-acetyltransferase 2 (NAT2) in vitro and in vivo and the possible implications for phenotyping procedures using caffeine as probe drug. Methods We first studied the inhibitory effect of ibuprofen on NAT2 in vitro, using human liver cytosol and sulfamethazine as substrate. In vivo 15 fast and 15 slow acetylating healthy volunteers were treated with a single dose of ibuprofen (800 mg) orally and phenotyped for NAT2, CYP1A2, and xanthine oxidase (XO) with caffeine as probe drug before and during drug treatment. Because of unexpected in vivo results with ibuprofen this study was repeated in 20 healthy volunteers with probenecid, a model substrate of renal organic anion transport (OAT). For phenotyping tests a urine sample was collected 6 h after caffeine (200 mg) intake. The caffeine metabolites acetyl-6-formylamino-3-methyluracil (AFMU), 1-methylxanthine (1MX), 1-methyluric acid (1MU), and 1,7-dimethyluric acid (17MU) were quantified by HPLC, and the corresponding metabolic ratios for CYP1A2, NAT2, and XO were then calculated. Genotyping for NAT2 was performed with standard PCR-RFLP methods. Results In vitro, with human liver cytosol an inhibition by ibuprofen of the acetylation of sulfamethazine with Ki values between 2.2 and 3.1 mm was observed. Surprisingly, in vivo a significant (P probenecid, a model substrate of the renal OAT system. Again, a prominent elevation of the AFMU/1MX ratio from 0.97 ± 0.21 to 1.53 ± 0.35 was found (P < 0.002; 95% CI on the difference 0.237, 0.876), but also the XO ratio 1MU/1MX was significantly (P < 0.0001) increased from 1.34 ± 0.09 to 2.24 ± 0.14 (95% CI on difference 0.735, 1.059) due to a reduction of 1MX excretion. Conclusions Substrates of OAT interact with renal excretion of caffeine metabolites and may falsify NAT2 and XO phenotyping results. Other phenotyping procedures, which are based on urinary metabolic ratios, should

  18. In vitro metabolism and drug-drug interaction potential of UTL-5g, a novel chemo- and radioprotective agent.

    Science.gov (United States)

    Wu, Jianmei; Shaw, Jiajiu; Dubaisi, Sarah; Valeriote, Frederick; Li, Jing

    2014-12-01

    N-(2,4-dichlorophenyl)-5-methyl-1,2-oxazole-3-carboxamide (UTL-5g), a potential chemo- and radioprotective agent, acts as a prodrug requiring bioactivation to the active metabolite 5-methylisoxazole-3-carboxylic acid (ISOX). UTL-5g hydrolysis to ISOX and 2,4-dichloroaniline (DCA) has been identified in porcine and rabbit liver esterases. The purpose of this study was to provide insights on the metabolism and drug interaction potential of UTL-5g in humans. The kinetics of UTL-5g hydrolysis was determined in human liver microsomes (HLM) and recombinant human carboxylesterases (hCE1b and hCE2). The potential of UTL-5g and its metabolites for competitive inhibition and time-dependent inhibition of microsomal cytochrome P450 (P450) was examined in HLM. UTL-5g hydrolysis to ISOX and DCA in HLM were NADPH-independent, with a maximum rate of reaction (Vmax) of 11.1 nmol/min per mg and substrate affinity (Km) of 41.6 µM. Both hCE1b and hCE2 effectively catalyzed UTL-5g hydrolysis, but hCE2 exhibited ∼30-fold higher catalytic efficiency (Vmax/Km) than hCE1b. UTL-5g and DCA competitively inhibited microsomal CYP1A2, CYP2B6, and CYP2C19 (IC50 values 5g. Factors influencing carboxylesterase activities may have a significant impact on the pharmacological and therapeutic effects of UTL-5g. UTL-5g has the potential to inhibit P450-mediated metabolism through competitive inhibition or time-dependent inhibition. Caution is particularly needed for potential drug interactions involving competitive inhibition or time-dependent inhibition of CYP1A2 in the future clinical development of UTL-5g. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

  19. Prediction of metabolic drug clearance in humans: in vitro-in vivo extrapolation vs allometric scaling.

    Science.gov (United States)

    Shiran, M R; Proctor, N J; Howgate, E M; Rowland-Yeo, K; Tucker, G T; Rostami-Hodjegan, A

    2006-07-01

    Previously in vitro-in vivo extrapolation (IVIVE) with the Simcyp Clearance and Interaction Simulator has been used to predict the clearance of 15 clinically used drugs in humans. The criteria for the selection of the drugs were that they are used as probes for the activity of specific cytochromes P450 (CYPs) or have a single CYP isoform as the major or sole contributor to their metabolism and that they do not exhibit non-linear kinetics in vivo. Where data were available for the clearance of the drugs in at least three animal species, the predictions from IVIVE have now been compared with those based on allometric scaling (AS). Adequate data were available for estimating oral clearance (CLp.o.) in 9 cases (alprazolam, sildenafil, caffeine, clozapine, cyclosporine, dextromethorphan, midazolam, omeprazole and tolbutamide) and intravenous clearance in 6 cases (CLi.v.) (cyclosporine, diclofenac, midazolam, omeprazole, theophylline and tolterodine). AS predictions were based on five different methods: (1) simple allometry (clearance versus body weight); (2) correction for maximum life-span potential (CL x MLP); (3) correction for brain weight (CL x BrW); (4) the use of body surface area; and (5) the rule of exponents. A prediction accuracy was indicated by mean-fold error and the Pearson product moment correlation coefficient. Predictions were considered successful if the mean-fold error was error range: 1.02-4.00). All five AS methods were accurate in 13, 11, 10, 10 and 14 cases, respectively. However, in some cases the error of AS exceeded fivefold. On the basis of the current results, IVIVE is more reliable than AS in predicting human clearance values for drugs mainly metabolized by CYP450 enzymes. This suggests that the place of AS methods in pre-clinical drug development warrants further scrutiny.

  20. Electrochemical oxidation by square-wave potential pulses in the imitation of oxidative drug metabolism.

    Science.gov (United States)

    Nouri-Nigjeh, Eslam; Permentier, Hjalmar P; Bischoff, Rainer; Bruins, Andries P

    2011-07-15

    Electrochemistry combined with mass spectrometry (EC-MS) is an emerging analytical technique in the imitation of oxidative drug metabolism at the early stages of new drug development. Here, we present the benefits of electrochemical oxidation by square-wave potential pulses for the oxidation of lidocaine, a test drug compound, on a platinum electrode. Lidocaine was oxidized at constant potential and by square-wave potential pulses with different cycle times, and the reaction products were analyzed by liquid chromatography-mass spectrometry [LC-MS(/MS)]. Application of constant potentials of up to +5.0 V resulted in relatively low yields of N-dealkylation and 4-hydroxylation products, while oxidation by square-wave potential pulses generated up to 50 times more of the 4-hydroxylation product at cycle times between 0.2 and 12 s (estimated yield of 10%). The highest yield of the N-dealkylation product was obtained at cycle times shorter than 0.2 s. Tuning of the cycle time is thus an important parameter to modulate the selectivity of electrochemical oxidation reactions. The N-oxidation product was only obtained by electrochemical oxidation under air atmosphere due to reaction with electrogenerated hydrogen peroxide. Square-wave potential pulses may also be applicable to modulate the selectivity of electrochemical reactions with other drug compounds in order to generate oxidation products with greater selectivity and higher yield based on the optimization of cycle times and potentials. This considerably widens the scope of direct electrochemistry-based oxidation reactions for the imitation of in vivo oxidative drug metabolism.

  1. Recent Advances in Understanding and Mitigating Adipogenic and Metabolic Effects of Antipsychotic Drugs

    Science.gov (United States)

    Gohlke, Julia M.; Dhurandhar, Emily J.; Correll, Christoph U.; Morrato, Elaine H.; Newcomer, John W.; Remington, Gary; Nasrallah, Henry A.; Crystal, Stephen; Nicol, Ginger; Allison, David B.

    2012-01-01

    Although offering many benefits for several psychiatric disorders, antipsychotic drugs (APDs) as a class have a major liability in their tendency to promote adiposity, obesity, and metabolic dysregulation in an already metabolically vulnerable population. The past decade has witnessed substantial research aimed at investigating the mechanisms of these adverse effects and mitigating them. On July 11 and 12, 2011, with support from 2 NIH institutes, leading experts convened to discuss current research findings and to consider future research strategies. Five areas where significant advances are being made emerged from the conference: (1) methodological issues in the study of APD effects; (2) unique characteristics and needs of pediatric patients; (3) genetic components underlying susceptibility to APD-induced metabolic effects; (4) APD effects on weight gain and adiposity in relation to their acute effects on glucose regulation and diabetes risk; and (5) the utility of behavioral, dietary, and pharmacological interventions in mitigating APD-induced metabolic side effects. This paper summarizes the major conclusions and important supporting data from the meeting. PMID:22754543

  2. Albendazole metabolism in patients with neurocysticercosis: antipyrine as a multifunctional marker drug of cytochrome P450

    Directory of Open Access Journals (Sweden)

    M.P. Marques

    2002-02-01

    Full Text Available The present study investigates the isoform(s of cytochrome P450 (CYP involved in the metabolism of albendazole sulfoxide (ASOX to albendazole sulfone (ASON in patients with neurocysticercosis using antipyrine as a multifunctional marker drug. The study was conducted on 11 patients with neurocysticercosis treated with a multiple dose regimen of albendazole for 8 days (5 mg/kg every 8 h. On the 5th day of albendazole treatment, 500 mg antipyrine was administered po. Blood and urine samples were collected up to 72 h after antipyrine administration. Plasma concentrations of (+-ASOX, (--ASOX and ASON were determined by HPLC using a chiral phase column and detection by fluorescence. The apparent clearance (CL/f of ASON and of the (+ and (--ASOX enantiomers were calculated and compared to total antipyrine clearance (CL T and the clearance for the production of the three major antipyrine metabolites (CLm. A correlation (P<=0.05 was obtained only between the CL T of antipyrine and the CL/f of ASON (r = 0.67. The existence of a correlation suggests the involvement of CYP isoforms common to the metabolism of antipyrine and of ASOX to ASON. Since the CL T of antipyrine is a general measure of CYP enzymes but with a slight to moderate weight toward CYP1A2, we suggest the involvement of this enzyme in ASOX to ASON metabolism in man. The study supports the establishment of a specific marker drug of CYP1A2 in the study of the in vivo metabolism of ASOX to ASON.

  3. ROLE OF NON-DRUG THERAPIES OF METABOLIC SYNDROME: CHALLENGES AND PROSPECTS

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    S. N. Strelkova

    2016-01-01

    Full Text Available Abdominal obesity (and the closely related metabolic syndrome is one of the most common diseases in the world. The urgency of the problem of the progression of abdominal obesity is not only in its high prevalence, but also in the formation of a high risk of developing cardiovascular disease and diabetes type 2. The main reasons for the rapid development of obesity are considered high-calorie food (which includes not only the quantity but also the quality of edible products, sedentary lifestyle and genetic predisposition. Until now there are underway great controversies about the procedures of fast and trouble-free weight loss. There are many studies on the treatment of various components of metabolic syndrome. Despite a number of different pharmaceutical drugs developed for the treatment of abdominal obesity, non-drug therapies come first as well as the organization of the right way of life, which is difficult and sometimes impossible task for the clinician. One of the main reasons is the lack of time in doctor during outpatient consultations. To resolve this issue the role of "School of Health" is considered in order to effectively reduce the body weight of patients with metabolic syndrome and maintaining long-term results. It is expected that the implementation of the "School of Health" in the complex treatment of patients with metabolic syndrome will more broadly inform patients about their disease, improve the motivational and cognitive components of plants, and increase compliance to carry out the doctor's prescription. A review of the prevalence and root causes of abdominal obesity is presented, as well as analysis of the effectiveness of existing “Schools of Health” in the clinical practice for the treatment of various chronic diseases.

  4. Changes in drug transport and metabolism and their clinical implications in non-alcoholic fatty liver disease.

    Science.gov (United States)

    Dietrich, Christoph G; Rau, Monika; Jahn, Daniel; Geier, Andreas

    2017-06-01

    The incidence of non-alcoholic fatty liver disease (NAFLD) is rising, especially in Western countries. Drug treatment in patients with NAFLD is common since it is linked to other conditions like diabetes, obesity, and cardiovascular disease. Consequently, changes in drug metabolism may have serious clinical implications. Areas covered: A literature search for studies in animal models or patients with obesity, fatty liver, non-alcoholic steatohepatitis (NASH) or NASH cirrhosis published before November 2016 was performed. After discussing epidemiology and animal models for NAFLD, we summarized both basic as well as clinical studies investigating changes in drug transport and metabolism in NAFLD. Important drug groups were assessed separately with emphasis on clinical implications for drug treatment in patients with NAFLD. Expert opinion: Given the frequency of NAFLD even today, a high degree of drug treatment in NAFLD patients appears safe and well-tolerated despite considerable changes in hepatic uptake, distribution, metabolism and transport of drugs in these patients. NASH causes changes in biliary excretion, systemic concentrations, and renal handling of drugs leading to alterations in drug efficacy or toxicity under specific circumstances. Future clinical drug studies should focus on this special patient population in order to avoid serious adverse events in NAFLD patients.

  5. Electrocatalytic oxidation of hydrogen peroxide on a platinum electrode in the imitation of oxidative drug metabolism of lidocaine

    NARCIS (Netherlands)

    Nouri-Nigjeh, Eslam; Bruins, Andries P.; Bischoff, Rainer; Permentier, Hjalmar P.

    2012-01-01

    Electrochemistry in combination with mass spectrometry has shown promise as a versatile technique not only in the analytical assessment of oxidative drug metabolism, but also for small-scale synthesis of drug metabolites. However, electrochemistry is generally limited to reactions initiated by

  6. The biochemistry of drug metabolism--an introduction: part 4. reactions of conjugation and their enzymes.

    Science.gov (United States)

    Testa, Bernard; Krämer, Stefanie D

    2008-11-01

    This review continues a general presentation of the metabolism of drugs and other xenobiotics begun in three recent issues of Chemistry & Biodiversity. The present Part is dedicated to reactions of conjugation, namely methylation, sulfonation, and phosphorylation, glucuronidation and other glycosidations, acetylation and other acylations, the formation and fate of coenzyme A conjugates, glutathione conjugation, and the reaction of amines with carbonyl compounds. It presents the many transferases involved, their nomenclature, relevant biochemical properties, catalytic mechanisms, and the reactions they catalyze. Nonenzymatic reactions, mainly of glutathione conjugation, also receive due attention. A number of medicinally, environmentally, and toxicologically relevant examples are presented and discussed.

  7. Detoxical aspects of nutritional therapy using natural enterosorbents on the basis of pectins

    Directory of Open Access Journals (Sweden)

    Elena E. Tekutskaya

    2013-09-01

    Full Text Available The rate of anthropogenic pollution and reduction of the environmental quality progress quicker than adaptive possibilities of an organism. This causes pre-pathological and pathological changes. So there is a necessity of preventive measures organization to eliminate toxic load and accelerated eliminating of xenobiotics from an organism. The discoveries of the recent 15 years had been revealed the possibility to change complexons (which are used for detoxication to dietary fibers, pectin as well. Meanwhile pectin substances are not widely used in clinical practice, and their efficiency comparing with small concentrations of cumulating poisons had not been studied yet. During the development of the detoxification nutritional therapy at patients with different pathology of the digestive system organs (with the revealed heavy metals and organochlorine pesticides there had been organized tests of pectin efficiency (citrus and apple for reducing the contamination with these xenobiotics. After the course of pectin treatment there had been fixed not only the reduce of toxic heavy metals, but essential microelements as well, which is connected with nonselective complexing capability of pectin substances. The probe tests also showed that course of citrus pectin treatment favored total excretion of organochlorine pesticides at 11.0% of patients, at other patients pesticide level reduced up to minimal rate (revealed by gas chromatographic method 0.0001 mg/dm³. There is a significant difference of values before and after pectin treatment. At the same time at patients who had not taken enterosorbent (compare group the level of organochlorine pesticides after repeated tests stayed on the level close to the basic. There had been discussed mechanism of excretion of organochlorine pesticides and heavy metals with the help of pectins.

  8. Effects of dibutyl phthalate on lipid metabolism and drug metabolising enzyme system in rats

    International Nuclear Information System (INIS)

    Arakaki, Mitsuo; Ariyoshi, Toshihiko.

    1976-01-01

    Effects of dibutyl phthalate (DBP) on the liver constituents and the drug metabolizing enzyme system were investigated in rats. 1. In the experiments at a single oral dose of DBP (630 or 1260 mg/kg), the glycogen content was decreased only at the high dose, but no effects were observed on the contents of glycogen, triglyceride, microsomal protein and cytochromes, and on the activities of drug metabolizing enzymes. 2. In the repeated oral dose of DBP (630 or 1260 mg/kg/day) for 5 days, the ratio of liver weight to body weight was increased in both female and male rats, whereas the increases of cytochrome P-450 content and aniline hydroxylase activity were noted only in male rats. However, the contents of liver triglyceride, phospholipids, and cholesterol were unchanged. On the other hand, serum cholesterol content which showed the tendency to be decreased at the low dose was significantly decreased at the high dose. 3. In the incorporation of 1- 14 C-acetate into liver and serum lipids after repeated oral dose of DBP (630 mg/kg/day) for 5 days in male rats, the incorporation into triglyceride showed tendency to be increased, whereas the incorporation into cholesterol and cholesterol ester remained unchanged in vivo and in vitro. (auth.)

  9. STAT3-Mediated Metabolic Reprograming in Cellular Transformation and Implications for Drug Resistance

    Science.gov (United States)

    Poli, Valeria; Camporeale, Annalisa

    2015-01-01

    Signal transducer and activator of transcription (STAT)3 mediates the signaling downstream of cytokine and growth factor receptors, regulating the expression of target genes. It is constitutively phosphorylated on tyrosine (Y-P) in many tumors, where its transcriptional activity can induce a metabolic switch toward aerobic glycolysis and down-regulate mitochondrial activity, a prominent metabolic feature of most cancer cells, correlating with reduced production of ROS, delayed senescence, and protection from apoptosis. STAT3 can, however, also localize to mitochondria, where its serine-phosphorylated (S-P) form preserves mitochondrial oxidative phosphorylation and controls the opening of the mitochondrial permeability transition pore, also promoting survival and resistance to apoptosis in response to specific signals/oncogenes such as RAS. Thus, downstream of different signals, both nuclear, Y-P STAT3, and mitochondrial, S-P STAT3, can act by promoting cell survival and reducing ROS production. Here, we discuss these properties in the light of potential connections between STAT3-driven alterations of mitochondrial metabolism and the development of drug resistance in cancer patients. PMID:26106584

  10. Twenty-six years of HIV science: an overview of anti-HIV drugs metabolism

    Directory of Open Access Journals (Sweden)

    Carolina Horta Andrade

    2011-06-01

    Full Text Available From the identification of HIV as the agent causing AIDS, to the development of effective antiretroviral drugs, the scientific achievements in HIV research over the past twenty-six years have been formidable. Currently, there are twenty-five anti-HIV compounds which have been formally approved for clinical use in the treatment of AIDS. These compounds fall into six categories: nucleoside reverse transcriptase inhibitors (NRTIs, nucleotide reverse transcriptase inhibitors (NtRTIs, non-nucleoside reverse transcriptase inhibitors (NNRTIs, protease inhibitors (PIs, cell entry inhibitors or fusion inhibitors (FIs, co-receptor inhibitors (CRIs, and integrase inhibitors (INIs. Metabolism by the host organism is one of the most important determinants of the pharmacokinetic profile of a drug. Formation of active or toxic metabolites will also have an impact on the pharmacological and toxicological outcomes. Therefore, it is widely recognized that metabolism studies of a new chemical entity need to be addressed early in the drug discovery process. This paper describes an overview of the metabolism of currently available anti-HIV drugs.Da identificação do HIV como o agente causador da AIDS, ao desenvolvimento de fármacos antirretrovirais eficazes, os avanços científicos na pesquisa sobre o HIV nos últimos vinte e seis anos foram marcantes. Atualmente, existem vinte e cinco fármacos anti-HIV formalmente aprovados pelo FDA para utilização clínica no tratamento da AIDS. Estes compostos são divididos em seis classes: inibidores nucleosídeos de transcriptase reversa (INTR, inibidores nucleotídeos de transcriptase reversa (INtTR, inibidores não-nucleosídeos de transcriptase reversa (INNTR, inibidores de protease (IP, inibidores da entrada celular ou inibidores de fusão (IF, inibidores de co-receptores (ICR e inibidores de integrase (INI. O metabolismo consiste em um dos maiores determinantes do perfil farmacocinético de um fármaco. A forma

  11. Sex- and age-dependent gene expression in human liver: An implication for drug-metabolizing enzymes.

    Science.gov (United States)

    Uno, Yasuhiro; Takata, Ryo; Kito, Go; Yamazaki, Hiroshi; Nakagawa, Kazuko; Nakamura, Yusuke; Kamataki, Tetsuya; Katagiri, Toyomasa

    2017-02-01

    Sex and age differences in hepatic expression of drug-metabolizing enzyme genes could cause variations in drug metabolism, but has not been fully elucidated, especially in Asian population. In this study, the global expression of human hepatic genes was analyzed by microarrays in 40 Japanese subjects (27 males and 13 females). Thirty-five sex-biased genes were identified (P age-biased genes in two age groups, age-biased genes were related to transcription regulation and cell death. Quantitative polymerase chain reaction confirmed the female-biased expression of drug-metabolizing enzyme genes BChE, CYP4X1, and SULT1E1 (≥1.5-fold, P drug-metabolizing enzyme genes indicated that expression of CYP2A6 and CYP3A4 in females in the ≥70 age group was less than in the age group (≥1.5-fold, P drug metabolism, with respect to sex and age. Copyright © 2016 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

  12. Stable isotope- and mass spectrometry-based metabolomics as tools in drug metabolism: a study expanding tempol pharmacology.

    Science.gov (United States)

    Li, Fei; Pang, Xiaoyan; Krausz, Kristopher W; Jiang, Changtao; Chen, Chi; Cook, John A; Krishna, Murali C; Mitchell, James B; Gonzalez, Frank J; Patterson, Andrew D

    2013-03-01

    The application of mass spectrometry-based metabolomics in the field of drug metabolism has yielded important insights not only into the metabolic routes of drugs but has provided unbiased, global perspectives of the endogenous metabolome that can be useful for identifying biomarkers associated with mechanism of action, efficacy, and toxicity. In this report, a stable isotope- and mass spectrometry-based metabolomics approach that captures both drug metabolism and changes in the endogenous metabolome in a single experiment is described. Here the antioxidant drug tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) was chosen because its mechanism of action is not completely understood and its metabolic fate has not been studied extensively. Furthermore, its small size (MW = 172.2) and chemical composition (C(9)H(18)NO(2)) make it challenging to distinguish from endogenous metabolites. In this study, mice were dosed with tempol or deuterated tempol (C(9)D(17)HNO(2)) and their urine was profiled using ultraperformance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Principal component analysis of the urinary metabolomics data generated a Y-shaped scatter plot containing drug metabolites (protonated and deuterated) that were clearly distinct from the endogenous metabolites. Ten tempol drug metabolites, including eight novel metabolites, were identified. Phase II metabolism was the major metabolic pathway of tempol in vivo, including glucuronidation and glucosidation. Urinary endogenous metabolites significantly elevated by tempol treatment included 2,8-dihydroxyquinoline (8.0-fold, P tempol treatment including pantothenic acid (1.3-fold, P < 0.05) and isobutrylcarnitine (5.3-fold, P < 0.01). This study underscores the power of a stable isotope- and mass spectrometry-based metabolomics in expanding the view of drug pharmacology.

  13. Effect of Various Diets on the Expression of Phase-I Drug Metabolizing Enzymes in Livers of Mice

    Science.gov (United States)

    Guo, Ying; Cui, Julia Yue; Lu, Hong; Klaassen, Curtis D.

    2017-01-01

    Previous studies have shown that diets can alter the metabolism of drugs; however, it is difficult to compare the effects of multiple diets on drug metabolism among different experimental settings. Phase-I related genes play a major role in the biotransformation of pro-drugs and drugs.In the current study, effects of nine diets on the mRNA expression of phase-I drug-metabolizing enzymes in livers of mice were simultaneously investigated. Compared to the AIN-93M purified diet (control), 73 of the 132 critical phase-I drug metabolizing genes were differentially regulated by at least one diet. Diet restriction produced the most number of changed genes (51), followed by the atherogenic diet (27), high-fat diet (25), standard rodent chow (21), western diet (20), high-fructose diet (5), EFA deficient diet (3), and low n-3 FA diet (1). The mRNAs of the Fmo family changed most, followed by Cyp2b and 4a subfamilies, as well as Por (From 1121 to 21-fold increase of theses mRNAs). There were 59 genes not altered by any of these diets.The present results may improve the interpretation of studies with mice and aid in determining effective and safe doses for individuals with different nutritional diets. PMID:25733028

  14. Astrocyte Senescence and Metabolic Changes in Response to HIV Antiretroviral Therapy Drugs

    Directory of Open Access Journals (Sweden)

    Justin Cohen

    2017-08-01

    Full Text Available With the advent of highly active antiretroviral therapy (HAART survival rates among patients infected by HIV have increased. However, even though survival has increased HIV-associated neurocognitive disorders (HAND still persist, suggesting that HAART-drugs may play a role in the neurocognitive impairment observed in HIV-infected patients. Given previous data demonstrating that astrocyte senescence plays a role in neurocognitive disorders such as Alzheimer’s disease (AD, we examined the role of HAART on markers of senescence in primary cultures of human astrocytes (HAs. Our results indicate HAART treatment induces cell cycle arrest, senescence-associated beta-galactosidase, and the cell cycle inhibitor p21. Highly active antiretroviral therapy treatment is also associated with the induction of reactive oxygen species and upregulation of mitochondrial oxygen consumption. These changes in mitochondria correlate with increased glycolysis in HAART drug treated astrocytes. Taken together these results indicate that HAART drugs induce the senescence program in HAs, which is associated with oxidative and metabolic changes that could play a role in the development of HAND.

  15. Modulation of trichloroethylene in vitro metabolism by different drugs in human.

    Science.gov (United States)

    Cheikh Rouhou, Mouna; Haddad, Sami

    2014-08-01

    Toxicological interactions with drugs have the potential to modulate the toxicity of trichloroethylene (TCE). Our objective is to identify metabolic interactions between TCE and 14 widely used drugs in human suspended hepatocytes and characterize the strongest using microsomal assays. Changes in concentrations of TCE and its metabolites were measured by headspace GC-MS. Results with hepatocytes show that amoxicillin, cimetidine, ibuprofen, mefenamic acid and ranitidine caused no significant interactions. Naproxen and salicylic acid showed to increase both TCE metabolites levels, whereas acetaminophen, carbamazepine and erythromycin rather decreased them. Finally, diclofenac, gliclazide, sulphasalazine and valproic acid had an impact on the levels of only one metabolite. Among the 14 tested drugs, 5 presented the most potent interactions and were selected for confirmation with microsomes, namely naproxen, salicylic acid, acetaminophen, carbamazepine and valproic acid. Characterization in human microsomes confirmed interaction with naproxen by competitively inhibiting trichloroethanol (TCOH) glucuronidation (Ki=2.329 mM). Inhibition of TCOH formation was also confirmed for carbamazepine (partial non-competitive with Ki=70 μM). Interactions with human microsomes were not observed with salicylic acid and acetaminophen, similar to prior results in rat material. For valproic acid, interactions with microsomes were observed in rat but not in human. Inhibition patterns were shown to be similar in human and rat hepatocytes, but some differences in mechanisms were noted in microsomal material between species. Next research efforts will focus on determining the adequacy between in vitro observations and the in vivo situation. Copyright © 2014 Elsevier Ltd. All rights reserved.

  16. ecoAO: A Simple System for the Study of Human Aldehyde Oxidases Role in Drug Metabolism

    OpenAIRE

    Paragas, Erickson M.; Humphreys, Sara C.; Min, Joshua; Joswig-Jones, Carolyn A.; Leimk?hler, Silke; Jones, Jeffrey P.

    2017-01-01

    Although aldehyde oxidase (AO) is an important hepatic drug-metabolizing enzyme, it remains understudied and is consequently often overlooked in preclinical studies, an oversight that has resulted in the failure of multiple clinical trials. AO?s preclusion to investigation stems from the following: (1) difficulties synthesizing metabolic standards due to the chemospecificity and regiospecificity of the enzyme and (2) significant inherent variability across existing in vitro systems including ...

  17. Role of cytochrome P450-mediated metabolism and involvement of reactive metabolite formations on antiepileptic drug-induced liver injuries.

    Science.gov (United States)

    Sasaki, Eita; Yokoi, Tsuyoshi

    2018-01-01

    Several drugs have been withdrawn from the market or restricted to avoid unexpected adverse outcomes. Drug-induced liver injury (DILI) is a serious issue for drug development. Among DILIs, idiosyncratic DILIs have been a serious problem in drug development and clinical uses. Idiosyncratic DILI is most often unrelated to pharmacological effects or the dosing amount of a drug. The number of drugs that cause idiosyncratic DILI continue to grow in part because no practical preclinical tests have emerged that can identify drug candidates with the potential for developing idiosyncratic DILIs. Nevertheless, the implications of drug metabolism-related factors and immune-related factors on idiosyncratic DILIs has not been fully clarified because this toxicity can not be reproduced in animals. Therefore, accumulated evidence for the mechanisms of the idiosyncratic toxicity has been limited to only in vitro studies. This review describes current knowledge of the effects of cytochrome P450 (CYP)-mediated metabolism and its detoxification abilities based on studies of idiosyncratic DILI animal models developed recently. This review also focused on antiepileptic drugs, phenytoin (diphenyl hydantoin, DPH) and carbamazepine (CBZ), which have rarely caused severe adverse reactions, such as fulminant hepatitis, and have been recognized as sources of idiosyncratic DILI. The studies of animal models of idiosyncratic DILIs have produced new knowledge of chronic administration, CYP inductions/inhibitions, glutathione contents, and immune-related factors for the initiation of idiosyncratic DILIs. Considering changes in the drug metabolic profile and detoxification abilities, idiosyncratic DILIs caused by antiepileptic drugs will lead to understanding the mechanisms of these DILIs.

  18. Effects of drugs in subtoxic concentrations on the metabolic fluxes in human hepatoma cell line Hep G2

    International Nuclear Information System (INIS)

    Niklas, Jens; Noor, Fozia; Heinzle, Elmar

    2009-01-01

    Commonly used cytotoxicity assays assess the toxicity of a compound by measuring certain parameters which directly or indirectly correlate to the viability of the cells. However, the effects of a given compound at concentrations considerably below EC 50 values are usually not evaluated. These subtoxic effects are difficult to identify but may eventually cause severe and costly long term problems such as idiosyncratic hepatotoxicity. We determined the toxicity of three hepatotoxic compounds, namely amiodarone, diclofenac and tacrine on the human hepatoma cell line Hep G2 using an online kinetic respiration assay and analysed the effects of subtoxic concentrations of these drugs on the cellular metabolism by using metabolic flux analysis. Several changes in the metabolism could be detected upon exposure to subtoxic concentrations of the test compounds. Upon exposure to diclofenac and tacrine an increase in the TCA-cycle activity was observed which could be a signature of an uncoupling of the oxidative phosphorylation. The results indicate that metabolic flux analysis could serve as an invaluable novel tool for the investigation of the effects of drugs. The described methodology enables tracking the toxicity of compounds dynamically using the respiration assay in a range of concentrations and the metabolic flux analysis permits interesting insights into the changes in the central metabolism of the cell upon exposure to drugs.

  19. Metabolic profiling using HPLC allows classification of drugs according to their mechanisms of action in HL-1 cardiomyocytes

    International Nuclear Information System (INIS)

    Strigun, Alexander; Wahrheit, Judith; Beckers, Simone; Heinzle, Elmar; Noor, Fozia

    2011-01-01

    Along with hepatotoxicity, cardiotoxic side effects remain one of the major reasons for drug withdrawals and boxed warnings. Prediction methods for cardiotoxicity are insufficient. High content screening comprising of not only electrophysiological characterization but also cellular molecular alterations are expected to improve the cardiotoxicity prediction potential. Metabolomic approaches recently have become an important focus of research in pharmacological testing and prediction. In this study, the culture medium supernatants from HL-1 cardiomyocytes after exposure to drugs from different classes (analgesics, antimetabolites, anthracyclines, antihistamines, channel blockers) were analyzed to determine specific metabolic footprints in response to the tested drugs. Since most drugs influence energy metabolism in cardiac cells, the metabolite 'sub-profile' consisting of glucose, lactate, pyruvate and amino acids was considered. These metabolites were quantified using HPLC in samples after exposure of cells to test compounds of the respective drug groups. The studied drug concentrations were selected from concentration response curves for each drug. The metabolite profiles were randomly split into training/validation and test set; and then analysed using multivariate statistics (principal component analysis and discriminant analysis). Discriminant analysis resulted in clustering of drugs according to their modes of action. After cross validation and cross model validation, the underlying training data were able to predict 50%-80% of conditions to the correct classification group. We show that HPLC based characterisation of known cell culture medium components is sufficient to predict a drug's potential classification according to its mode of action.

  20. Effect of honokiol on the induction of drug-metabolizing enzymes in human hepatocytes

    Directory of Open Access Journals (Sweden)

    Cho YY

    2014-11-01

    Full Text Available Yong-Yeon Cho,1 Hyeon-Uk Jeong,1 Jeong-Han Kim,2 Hye Suk Lee1 1College of Pharmacy, The Catholic University of Korea, Bucheon, Korea; 2Department of Agricultural Biotechnology, Seoul National University, Seoul, Korea Abstract: Honokiol, 2-(4-hydroxy-3-prop-2-enyl-phenyl-4-prop-2-enyl-phenol, an active component of Magnolia officinalis and Magnolia grandiflora, exerts various pharmacological activities such as antitumorigenic, antioxidative, anti-inflammatory, neurotrophic, and antithrombotic effects. To investigate whether honokiol acts as a perpetrator in drug interactions, messenger ribonucleic acid (mRNA levels of phase I and II drug-metabolizing enzymes, including cytochrome P450 (CYP, UDP-glucuronosyltransferase (UGT, and sulfotransferase 2A1 (SULT2A1, were analyzed by real-time reverse transcription polymerase chain reaction following 48-hour honokiol exposure in three independent cryopreserved human hepatocyte cultures. Honokiol treatment at the highest concentration tested (50 µM increased the CYP2B6 mRNA level and CYP2B6-catalyzed bupropion hydroxylase activity more than two-fold in three different hepatocyte cultures, indicating that honokiol induces CYP2B6 at higher concentrations. However, honokiol treatment (0.5–50 µM did not significantly alter the mRNA levels of phase I enzymes (CYP1A2, CYP3A4, CYP2C8, CYP2C9, and CYP2C19 or phase II enzymes (UGT1A1, UGT1A4, UGT1A9, UGT2B7, and SULT2A1 in cryopreserved human hepatocyte cultures. CYP1A2-catalyzed phenacetin O-deethylase and CYP3A4-catalyzed midazolam 1'-hydroxylase activities were not affected by 48-hour honokiol treatment in cryopreserved human hepatocytes. These results indicate that honokiol is a weak CYP2B6 inducer and is unlikely to increase the metabolism of concomitant CYP2B6 substrates and cause pharmacokinetic-based drug interactions in humans. Keywords: honokiol, human hepatocytes, drug interactions, cytochrome P450, UDP-glucuronosyltransferases

  1. Utilization of carbon 13-labelled stable isotopes for studying drug toxicity on cellular metabolism

    International Nuclear Information System (INIS)

    Herve, M.; Wietzerbin, J.; Tran-Dinh, S.

    1994-01-01

    A new approach for studying the effects of two drugs, amphotericine B (AMB), an anti-fungal antibiotic, and 2-deoxy-D-glucose (DG), on the glucose metabolism in brewer yeast cells (Saccharomyces cerevisiae), is presented; AMB interacts with the membrane sterols, inducing formation of pores through which ions and small molecules can pass. DG may enter in the cytosol, where it is phosphoryled by hexokinase into deoxy-D-glucose 6-phosphate (DG6P) which disappears very slowly. DG slows down the glycolysis process and induces the formation of new substances. This paper shows the advantages of utilizing carbon 13-labelled substrates combined to the NMR-13C and NMR-1H techniques. 6 figs., 5 refs

  2. Metformin: a metabolic disruptor and anti-diabetic drug to target human leukemia.

    Science.gov (United States)

    Rosilio, Célia; Ben-Sahra, Issam; Bost, Frédéric; Peyron, Jean-François

    2014-05-01

    There is a global and urgent need for expanding our current therapeutical arsenal against leukemia in order to improve their actual cure rates and fight relapse. Targeting the reprogrammed, altered cancer metabolism is an emerging strategy which should profoundly affect cancer cells in their intimate and irrepressible needs and addictions for nutrients uptake and incorporation into the biomass during malignant proliferation. We present here how metformin, an anti-diabetic drug that has attracted a strong interest for its recently discovered anti-cancer properties, can be envisioned as a new adjuvant approach to treat leukemia. Metformin may have a double-edged sword effect (i) by acting on the organism to decrease hyperglycaemia and hyperinsulinemia in diabetic patients and (ii) at the cellular level, by inhibiting the mTORC1-cancer supporting pathway through AMPK-dependent and independent mechanisms. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  3. Differential effects of dietary flavonoids on drug metabolizing and antioxidant enzymes in female rat

    DEFF Research Database (Denmark)

    Breinholt, V.; Lauridsen, S.T.; Dragsted, L.O.

    1999-01-01

    1. Gavage administration of the natural flavonoids tangeretin, chrysin, apigenin, naringenin, genistein and quercetin for 2 consecutive weeks to the female rat resulted in differential effects on selected phase 1 and 2 enzymes in liver, colon and heart as well as antioxidant enzymes in red brood......, genistein, tangeretin and BNF. 5. The observed effects of chrysin, quercetin and genistein on antioxidant enzymes, concurrently with a protection against oxidative stress, suggest a feedback mechanism on the antioxidant enzymes triggered by the flavonoid antioxidants. 6. Despite the use of high flavonoid...... doses, which by far exceed the human exposure levels, the effect on drug metabolizing and antioxidant enzymes was still very minor. The role of singly administered flavonoids in the protection against cancer and heart disease is thus expected to be limited....

  4. Nerve agent hydrolysis activity designed into a human drug metabolism enzyme.

    Directory of Open Access Journals (Sweden)

    Andrew C Hemmert

    2011-03-01

    Full Text Available Organophosphorus (OP nerve agents are potent suicide inhibitors of the essential neurotransmitter-regulating enzyme acetylcholinesterase. Due to their acute toxicity, there is significant interest in developing effective countermeasures to OP poisoning. Here we impart nerve agent hydrolysis activity into the human drug metabolism enzyme carboxylesterase 1. Using crystal structures of the target enzyme in complex with nerve agent as a guide, a pair of histidine and glutamic acid residues were designed proximal to the enzyme's native catalytic triad. The resultant variant protein demonstrated significantly increased rates of reactivation following exposure to sarin, soman, and cyclosarin. Importantly, the addition of these residues did not alter the high affinity binding of nerve agents to this protein. Thus, using two amino acid substitutions, a novel enzyme was created that efficiently converted a group of hemisubstrates, compounds that can start but not complete a reaction cycle, into bona fide substrates. Such approaches may lead to novel countermeasures for nerve agent poisoning.

  5. Structural basis for the role of mammalian aldehyde oxidases in the metabolism of drugs and xenobiotics.

    Science.gov (United States)

    Romão, Maria João; Coelho, Catarina; Santos-Silva, Teresa; Foti, Alessandro; Terao, Mineko; Garattini, Enrico; Leimkühler, Silke

    2017-04-01

    Aldehyde oxidases (AOXs) are molybdo-flavoenzymes characterized by broad substrate specificity, oxidizing aromatic/aliphatic aldehydes into the corresponding carboxylic acids and hydroxylating various heteroaromatic rings. Mammals are characterized by a complement of species-specific AOX isoenzymes, that varies from one in humans (AOX1) to four in rodents (AOX1, AOX2, AOX3 and AOX4). The physiological function of mammalian AOX isoenzymes is unknown, although human AOX1 is an emerging enzyme in phase-I drug metabolism. Indeed, the number of therapeutic molecules under development which act as AOX substrates is increasing. The recent crystallization and structure determination of human AOX1 as well as mouse AOX3 has brought new insights into the mechanisms underlying substrate/inhibitor binding as well as the catalytic activity of this class of enzymes. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. The schistosome excretory system: a key to regulation of metabolism, drug excretion and host interaction.

    Science.gov (United States)

    Kusel, John R; McVeigh, Paul; Thornhill, Joyce A

    2009-08-01

    There is a gulf between the enormous information content of the various genome projects and the understanding of the life of the parasite in the host. In vitro studies with adult Schistosoma mansoni using several substrates suggest that the excretory system contains both P-glycoproteins and multiresistance proteins. If both these families of protein were active in vivo, they could regulate parasite metabolism and be responsible for the excretion of drugs. During skin penetration, membrane-impermeant molecules of a wide range of molecular weights can be taken into the cercaria and schistosomulum through the nephridiopore, through the surface membrane or through both. We speculate that this uptake process might stimulate novel signalling pathways involved in growth and development.

  7. Natural products, an important resource for discovery of multitarget drugs and functional food for regulation of hepatic glucose metabolism

    Directory of Open Access Journals (Sweden)

    Li J

    2018-01-01

    Full Text Available Jian Li,1,* Haiyang Yu,2,* Sijian Wang,1 Wei Wang,3 Qian Chen,1 Yanmin Ma,2 Yi Zhang,1 Tao Wang1 1Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin, 2Department of Phytochemistry, Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China; 3Internal Medicine, Houston Methodist Hospital, Houston, TX, USA *These authors contributed equally to this work Abstract: Imbalanced hepatic glucose homeostasis is one of the critical pathologic events in the development of metabolic syndromes (MSs. Therefore, regulation of imbalanced hepatic glucose homeostasis is important in drug development for MS treatment. In this review, we discuss the major targets that regulate hepatic glucose homeostasis in human physiologic and pathophysiologic processes, involving hepatic glucose uptake, glycolysis and glycogen synthesis, and summarize their changes in MSs. Recent literature suggests the necessity of multitarget drugs in the management of MS disorder for regulation of imbalanced glucose homeostasis in both experimental models and MS patients. Here, we highlight the potential bioactive compounds from natural products with medicinal or health care values, and focus on polypharmacologic and multitarget natural products with effects on various signaling pathways in hepatic glucose metabolism. This review shows the advantage and feasibility of discovering multicompound–multitarget drugs from natural products, and providing a new perspective of ways on drug and functional food development for MSs. Keywords: hepatic glucose metabolism, natural products, multitarget, metabolic syndromes, drug and functional food development integrative medicine

  8. Evaluation of modafinil as a perpetrator of metabolic drug-drug interactions using a model informed cocktail reaction phenotyping trial protocol.

    Science.gov (United States)

    Rowland, Angela; van Dyk, Madelé; Warncken, David; Mangoni, Arduino A; Sorich, Michael J; Rowland, Andrew

    2018-03-01

    To evaluate the capacity for modafinil to be a perpetrator of metabolic drug-drug interactions by altering cytochrome P450 activity following a single dose and dosing to steady state. A single centre, open label, single sequence cocktail drug interaction trial. On days 0, 2 and 8 participants were administered an oral drug cocktail comprising 100 mg caffeine, 30 mg dextromethorphan, 25 mg losartan, 1 mg midazolam and 20 mg enteric-coated omeprazole. Timed blood samples were collected prior to and for up to 6 h post cocktail dosing. Between days 2 and 8 participants orally self-administered 200 mg modafinil each morning. Following a single 200 mg dose of modafinil mean (± 95% CI) AUC ratios for caffeine, dextromethorphan, losartan, midazolam and omeprazole were 0.95 (± 0.08), 1.01 (± 0.35), 0.97 (± 0.10), 0.98 (± 0.10) and 1.36 (± 0.06), respectively. Following dosing of modafinil to steady state (200 mg for 7 days), AUC ratios for caffeine, dextromethorphan, losartan, midazolam and omeprazole were 0.90 (± 0.16), 0.79 (± 0.09), 0.98 (± 0.11), 0.66 (± 0.12) and 1.90 (± 0.53), respectively. These data support consideration of the risk of clinically relevant metabolic drug-drug interactions perpetrated by modafinil when this drug is co-administered with drugs that are primarily cleared by CYP2C19 (single modafinil dose or steady state modafinil dosing) or CYP3A4 (steady state modafinil dosing only) catalysed metabolic pathways. © 2017 The British Pharmacological Society.

  9. Inhibitory effects of drugs on the metabolic activity of mouse and human aldehyde oxidases and influence on drug-drug interactions.

    Science.gov (United States)

    Takaoka, Naoki; Sanoh, Seigo; Okuda, Katsuhiro; Kotake, Yaichiro; Sugahara, Go; Yanagi, Ami; Ishida, Yuji; Tateno, Chise; Tayama, Yoshitaka; Sugihara, Kazumi; Kitamura, Shigeyuki; Kurosaki, Mami; Terao, Mineko; Garattini, Enrico; Ohta, Shigeru

    2018-04-17

    As aldehyde oxidase (AOX) plays an emerging role in drug metabolism, understanding its significance for drug-drug interactions (DDI) is important. Therefore, we tested 10 compounds for species-specific and substrate-dependent differences in the inhibitory effect of AOX activity using genetically engineered HEK293 cells over-expressing human AOX1, mouse AOX1 or mouse AOX3. The IC 50 values of 10 potential inhibitors of the three AOX enzymes were determined using phthalazine and O 6 -benzylguanine as substrates. 17β-Estradiol, menadione, norharmane and raloxifene exhibited marked differences in inhibitory effects between the human and mouse AOX isoforms when the phthalazine substrate was used. Some of the compounds tested exhibited substrate-dependent differences in their inhibitory effects. Docking simulations with human AOX1 and mouse AOX3 were conducted for six representative inhibitors. The rank order of the minimum binding energy reflected the order of the corresponding IC 50 values. We also evaluated the potential DDI between an AOX substrate (O 6 -benzylguanine) and an inhibitor (hydralazine) using chimeric mice with humanized livers. Pretreatment of hydralazine increased the maximum plasma concentration (C max ) and the area under the plasma concentration-time curve (AUC 0-24 ) of O 6 -benzylguanine compared to single administration. Our in vitro data indicate species-specific and substrate-dependent differences in the inhibitory effects on AOX activity. Our in vivo data demonstrate the existence of a DDI which may be of relevance in the clinical context. Copyright © 2018 Elsevier Inc. All rights reserved.

  10. Review of Warfarin; A Cytochrome P450 Metabolizing Drug, in Clinical Practice

    Directory of Open Access Journals (Sweden)

    Tolou-Ghamari

    2016-04-01

    Full Text Available Context For the prevention and management of thromboembolic complications, warfarin is the most extensively recommended anticoagulant. It is categorized as a drug with a narrow therapeutic window. Therefore, warfarin prescription requires special attention related to therapeutic drug monitoring. Evidence Acquisition By categorizing the clinical implications of warfarin, this manuscript aims to provide a comprehensive (albeit somewhat brief conclusion associated with its pharmacotherapy. The key words relevant to the topic were searched. Consequently, articles relevant to the pharmacotherapeutic management of warfarin were selected and reviewed in their entirety. Results To obtain a reasonable level of stability between the required antithrombotic treatment and the risk of bleeding, an analysis of the literature revealed that the prothrombin time in terms of the international normalized ratio (INR was found for each individual. The best model for stable warfarin dosage prediction was found to be based on multiple linear regression. Genotype-guided procedures were established to: 1, improve the time in the therapeutic range; 2, reduce time to the first therapeutic INR; and 3, reduce the time for the stable doses. Vitamin K epoxide reductase is an enzyme with an important role in vitamin K metabolism, and warfarin is metabolized in hepatocytes via a monooxygenase, cytochrome P450 2C9. In patients carrying 2C9*1/*2 and 2C9*2/*2 or 2C9*1/*3 alleles, the dose is recommended to be reduced by 18% - 40% and 21% - 49%, respectively. Conclusions Race, age, body surface area, chronic kidney disease, CYP2C9*3 level, and VKORC1 variants could affect the dose of warfarin. To administer the proper doses of warfarin, patients and physicians might achieve the best results with the pharmacologist proficient anticoagulation database and recommended continuation program. Owing to its’ unpredictability, caution must be taken when prescribing warfarin. More advanced

  11. Current status of hyphenated mass spectrometry in studies of the metabolism of drugs of abuse, including doping agents.

    Science.gov (United States)

    Meyer, Markus R; Maurer, Hans H

    2012-01-01

    This paper reviews scientific contributions on the identification and/or quantification of metabolites of drugs of abuse in in vitro assays or various body samples using hyphenated mass spectrometry. Gas chromatography-mass spectrometry (GC-MS) as well as liquid chromatography-mass spectrometry (LC-MS) approaches are considered and discussed if they have been reported in the last five years and are relevant to clinical and forensic toxicology or doping control. Workup and artifact formation are discussed, and typical examples of studies of the metabolism of designer drugs, doping agents, herbal drugs, and synthetic cannabinoids are provided. Procedures for quantifying metabolites in body samples for pharmacokinetic studies or in enzyme incubations for enzyme kinetic studies are also reviewed. In conclusion, the reviewed papers showed that both GC-MS and LC-MS still have important roles to play in research into the metabolism of drugs of abuse, including doping agents.

  12. Natural products, an important resource for discovery of multitarget drugs and functional food for regulation of hepatic glucose metabolism.

    Science.gov (United States)

    Li, Jian; Yu, Haiyang; Wang, Sijian; Wang, Wei; Chen, Qian; Ma, Yanmin; Zhang, Yi; Wang, Tao

    2018-01-01

    Imbalanced hepatic glucose homeostasis is one of the critical pathologic events in the development of metabolic syndromes (MSs). Therefore, regulation of imbalanced hepatic glucose homeostasis is important in drug development for MS treatment. In this review, we discuss the major targets that regulate hepatic glucose homeostasis in human physiologic and pathophysiologic processes, involving hepatic glucose uptake, glycolysis and glycogen synthesis, and summarize their changes in MSs. Recent literature suggests the necessity of multitarget drugs in the management of MS disorder for regulation of imbalanced glucose homeostasis in both experimental models and MS patients. Here, we highlight the potential bioactive compounds from natural products with medicinal or health care values, and focus on polypharmacologic and multitarget natural products with effects on various signaling pathways in hepatic glucose metabolism. This review shows the advantage and feasibility of discovering multicompound-multitarget drugs from natural products, and providing a new perspective of ways on drug and functional food development for MSs.

  13. Optical metabolic imaging measures early drug response in an allograft murine breast cancer model (Conference Presentation)

    Science.gov (United States)

    Sharick, Joe T.; Cook, Rebecca S.; Skala, Melissa C.

    2017-02-01

    Previous work has shown that cellular-level Optical Metabolic Imaging (OMI) of organoids derived from human breast cancer cell-line xenografts accurately and rapidly predicts in vivo response to therapy. To validate OMI as a predictive measure of treatment response in an immune-competent model, we used the polyomavirus middle-T (PyVmT) transgenic mouse breast cancer model. The PyVmT model includes intra-tumoral heterogeneity and a complex tumor microenvironment that can influence treatment responses. Three-dimensional organoids generated from primary PyVmT tumor tissue were treated with a chemotherapy (paclitaxel) and a PI3K inhibitor (XL147), each alone or in combination. Cellular subpopulations of response were measured using the OMI Index, a composite endpoint of metabolic response comprised of the optical redox ratio (ratio of the fluorescence intensities of metabolic co-enzymes NAD(P)H to FAD) as well as the fluorescence lifetimes of NAD(P)H and FAD. Combination treatment significantly decreased the OMI Index of PyVmT tumor organoids (p<0.0001) and in vivo tumors (p<0.0001) versus controls. Subpopulation analyses revealed a homogeneous response to combined therapy in both cultured organoids and in vivo tumors, while single agent treatment with XL147 alone or paclitaxel alone elicited heterogeneous responses in organoids. Tumor volume decreased with combination treatment through treatment day 30. These results indicate that OMI of organoids generated from PyVmT tumors can accurately reflect drug response in heterogeneous allografts with both innate and adaptive immunity. Thus, this method is promising for use in humans to predict long-term treatment responses accurately and rapidly, and could aid in clinical treatment planning.

  14. New Aspects of an Old Drug – Diclofenac Targets MYC and Glucose Metabolism in Tumor Cells

    Science.gov (United States)

    Gottfried, Eva; Lang, Sven A.; Renner, Kathrin; Bosserhoff, Anja; Gronwald, Wolfram; Rehli, Michael; Einhell, Sabine; Gedig, Isabel; Singer, Katrin; Seilbeck, Anton; Mackensen, Andreas; Grauer, Oliver; Hau, Peter; Dettmer, Katja; Andreesen, Reinhard; Oefner, Peter J.; Kreutz, Marina

    2013-01-01

    Non-steroidal anti-inflammatory drugs such as diclofenac exhibit potent anticancer effects. Up to now these effects were mainly attributed to its classical role as COX-inhibitor. Here we show novel COX-independent effects of diclofenac. Diclofenac significantly diminished MYC expression and modulated glucose metabolism resulting in impaired melanoma, leukemia, and carcinoma cell line proliferation in vitro and reduced melanoma growth in vivo. In contrast, the non-selective COX inhibitor aspirin and the COX-2 specific inhibitor NS-398 had no effect on MYC expression and glucose metabolism. Diclofenac significantly decreased glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), and monocarboxylate transporter 1 (MCT1) gene expression in line with a decrease in glucose uptake and lactate secretion. A significant intracellular accumulation of lactate by diclofenac preceded the observed effect on gene expression, suggesting a direct inhibitory effect of diclofenac on lactate efflux. While intracellular lactate accumulation impairs cellular proliferation and gene expression, it does not inhibit MYC expression as evidenced by the lack of MYC regulation by the MCT inhibitor α-cyano-4-hydroxycinnamic acid. Finally, in a cell line with a tetracycline-regulated c-MYC gene, diclofenac decreased proliferation both in the presence and absence of c-MYC. Thus, diclofenac targets tumor cell proliferation via two mechanisms, that is inhibition of MYC and lactate transport. Based on these results, diclofenac holds potential as a clinically applicable MYC and glycolysis inhibitor supporting established tumor therapies. PMID:23874405

  15. New aspects of an old drug--diclofenac targets MYC and glucose metabolism in tumor cells.

    Directory of Open Access Journals (Sweden)

    Eva Gottfried

    Full Text Available Non-steroidal anti-inflammatory drugs such as diclofenac exhibit potent anticancer effects. Up to now these effects were mainly attributed to its classical role as COX-inhibitor. Here we show novel COX-independent effects of diclofenac. Diclofenac significantly diminished MYC expression and modulated glucose metabolism resulting in impaired melanoma, leukemia, and carcinoma cell line proliferation in vitro and reduced melanoma growth in vivo. In contrast, the non-selective COX inhibitor aspirin and the COX-2 specific inhibitor NS-398 had no effect on MYC expression and glucose metabolism. Diclofenac significantly decreased glucose transporter 1 (GLUT1, lactate dehydrogenase A (LDHA, and monocarboxylate transporter 1 (MCT1 gene expression in line with a decrease in glucose uptake and lactate secretion. A significant intracellular accumulation of lactate by diclofenac preceded the observed effect on gene expression, suggesting a direct inhibitory effect of diclofenac on lactate efflux. While intracellular lactate accumulation impairs cellular proliferation and gene expression, it does not inhibit MYC expression as evidenced by the lack of MYC regulation by the MCT inhibitor α-cyano-4-hydroxycinnamic acid. Finally, in a cell line with a tetracycline-regulated c-MYC gene, diclofenac decreased proliferation both in the presence and absence of c-MYC. Thus, diclofenac targets tumor cell proliferation via two mechanisms, that is inhibition of MYC and lactate transport. Based on these results, diclofenac holds potential as a clinically applicable MYC and glycolysis inhibitor supporting established tumor therapies.

  16. Reduction in hepatic drug metabolizing CYP3A4 activities caused by P450 oxidoreductase mutations identified in patients with disordered steroid metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Flueck, Christa E.; Mullis, Primus E. [Pediatric Endocrinology, Diabetology and Metabolism, Department of Clinical Research, University of Bern, Tiefenaustrasse 120c, CH 3004 Bern (Switzerland); Pandey, Amit V., E-mail: amit@pandeylab.org [Pediatric Endocrinology, Diabetology and Metabolism, Department of Clinical Research, University of Bern, Tiefenaustrasse 120c, CH 3004 Bern (Switzerland)

    2010-10-08

    Research highlights: {yields} Cytochrome P450 3A4 (CYP3A4), metabolizes 50% of drugs in clinical use and requires NADPH-P450 reductase (POR). {yields} Mutations in human POR cause congenital adrenal hyperplasia from diminished activities of steroid metabolizing P450s. {yields} We are reporting that mutations in POR may reduce CYP3A4 activity. {yields} POR mutants Y181D, A457H, Y459H, V492E and R616X lost 99%, while A287P, C569Y and V608F lost 60-85% CYP3A4 activity. {yields} Reduction of CYP3A4 activity may cause increased risk of drug toxicities/adverse drug reactions in patients with POR mutations. -- Abstract: Cytochrome P450 3A4 (CYP3A4), the major P450 present in human liver metabolizes approximately half the drugs in clinical use and requires electrons supplied from NADPH through NADPH-P450 reductase (POR, CPR). Mutations in human POR cause a rare form of congenital adrenal hyperplasia from diminished activities of steroid metabolizing P450s. In this study we examined the effect of mutations in POR on CYP3A4 activity. We used purified preparations of wild type and mutant human POR and in vitro reconstitution with purified CYP3A4 to perform kinetic studies. We are reporting that mutations in POR identified in patients with disordered steroidogenesis/Antley-Bixler syndrome (ABS) may reduce CYP3A4 activity, potentially affecting drug metabolism in individuals carrying mutant POR alleles. POR mutants Y181D, A457H, Y459H, V492E and R616X had more than 99% loss of CYP3A4 activity, while POR mutations A287P, C569Y and V608F lost 60-85% activity. Loss of CYP3A4 activity may result in increased risk of drug toxicities and adverse drug reactions in patients with POR mutations.

  17. Reduction in hepatic drug metabolizing CYP3A4 activities caused by P450 oxidoreductase mutations identified in patients with disordered steroid metabolism

    International Nuclear Information System (INIS)

    Flueck, Christa E.; Mullis, Primus E.; Pandey, Amit V.

    2010-01-01

    Research highlights: → Cytochrome P450 3A4 (CYP3A4), metabolizes 50% of drugs in clinical use and requires NADPH-P450 reductase (POR). → Mutations in human POR cause congenital adrenal hyperplasia from diminished activities of steroid metabolizing P450s. → We are reporting that mutations in POR may reduce CYP3A4 activity. → POR mutants Y181D, A457H, Y459H, V492E and R616X lost 99%, while A287P, C569Y and V608F lost 60-85% CYP3A4 activity. → Reduction of CYP3A4 activity may cause increased risk of drug toxicities/adverse drug reactions in patients with POR mutations. -- Abstract: Cytochrome P450 3A4 (CYP3A4), the major P450 present in human liver metabolizes approximately half the drugs in clinical use and requires electrons supplied from NADPH through NADPH-P450 reductase (POR, CPR). Mutations in human POR cause a rare form of congenital adrenal hyperplasia from diminished activities of steroid metabolizing P450s. In this study we examined the effect of mutations in POR on CYP3A4 activity. We used purified preparations of wild type and mutant human POR and in vitro reconstitution with purified CYP3A4 to perform kinetic studies. We are reporting that mutations in POR identified in patients with disordered steroidogenesis/Antley-Bixler syndrome (ABS) may reduce CYP3A4 activity, potentially affecting drug metabolism in individuals carrying mutant POR alleles. POR mutants Y181D, A457H, Y459H, V492E and R616X had more than 99% loss of CYP3A4 activity, while POR mutations A287P, C569Y and V608F lost 60-85% activity. Loss of CYP3A4 activity may result in increased risk of drug toxicities and adverse drug reactions in patients with POR mutations.

  18. Pharmacotherapeutic targeting of the endocannabinoid signaling system: drugs for obesity and the metabolic syndrome.

    Science.gov (United States)

    Vemuri, V Kiran; Janero, David R; Makriyannis, Alexandros

    2008-03-18

    Endogenous signaling lipids ("endocannabinoids") functionally related to Delta(9)-tetrahydrocannabinol, the psychoactive ingredient of marijuana (Cannabis), are important biomediators and metabolic regulators critical to mammalian (patho)physiology. The growing family of endocannabinoids, along with endocannabinoid biosynthetic and inactivating enzymes, transporters, and at least two membrane-bound, G-protein coupled receptors, comprise collectively the mammalian endocannabinoid signaling system. The ubiquitous and diverse regulatory actions of the endocannabinoid system in health and disease have supported the regulatory approval of natural products and synthetic agents as drugs that alter endocannabinoid-system activity. More recent data support the concept that the endocananbinoid system may be modulated for therapeutic gain at discrete pharmacological targets with safety and efficacy. Potential medications based on the endocannabinoid system have thus become a central focus of contemporary translational research for varied indications with important unmet medical needs. One such indication, obesity, is a global pandemic whose etiology has a pathogenic component of endocannabinoid-system hyperactivity and for which current pharmacological treatment is severely limited. Application of high-affinity, selective CB1 cannabinoid receptor ligands to attenuate endocannabinoid signaling represents a state-of-the-art approach for improving obesity pharmacotherapy. To this intent, several selective CB1 receptor antagonists with varied chemical structures are currently in advanced preclinical or clinical trials, and one (rimonabant) has been approved as a weight-management drug in some markets. Emerging preclinical data suggest that CB1 receptor neutral antagonists may represent breakthrough medications superior to antagonists/inverse agonists such as rimonabant for therapeutic attenuation of CB1 receptor transmission. Since obesity is a predisposing condition for the

  19. SREBP activation by antipsychotic- and antidepressant-drugs in cultured human liver cells: relevance for metabolic side-effects?

    Science.gov (United States)

    Raeder, Maria B; Fernø, Johan; Vik-Mo, Audun O; Steen, Vidar M

    2006-09-01

    Drug-induced weight gain is a major problem in the treatment of psychiatric disorders, especially with some antipsychotic- and antidepressant drugs. We have recently demonstrated that antipsychotic- and antidepressant drugs activate the SREBP (sterol regulatory element-binding proteins) transcription factors in human- and rat glial cells, with subsequent up-regulation of downstream genes involved in cholesterol- and fatty acid biosynthesis. Since stimulation of cellular lipogenesis in the liver could be of relevance for the metabolic side effects of these drugs, we have now investigated the effects of antidepressants, antipsychotic- and mood-stabilizing drugs on cell cultures of human liver cells. For several of the drugs being strongly associated with weight gain (clozapine, imipramine, and amitriptyline), we observed a very pronounced activation of SREBP. Ziprasidone and buproprion, however, which are not associated with weight gain, did hardly stimulate the SREBP system. For haloperidol, olanzapine and mirtazapine, the correspondence between metabolic side effects and SREBP stimulation in liver cells was less obvious. The mood-stabilizers did not increase SREBP activation. The results indicate a relationship between drug-induced activation of SREBP in cultured human liver cells and weight gain side-effects of antidepressant and antipsychotic drugs.

  20. Metabolic Syndrome in Drug-naïve Patients with Depressive Disorders.

    Science.gov (United States)

    Grover, Sandeep; Nebhinani, Naresh; Chakrabarti, Subho; Avasthi, Ajit; Kulhara, Parmanand

    2013-04-01

    The prevalence of metabolic syndrome (MS) is found to be higher in patients with depression than in the general population. As there is lack of data from India, this study aimed to assess the prevalence of MS in patients with depression who had never been treated with antidepressants for their depressive disorder and compare the same with a matched group of healthy controls. Forty-three drug-naïve patients with depressive disorders and 43 age- and gender-matched healthy controls were assessed for the prevalence of MS as per the consensus definition. The prevalence of MS in patients with depression was 37.2% and was significantly higher than that seen in the healthy controls (16.3%). Increased waist circumference was the most common abnormality in both the study groups. Compared to healthy controls, a significantly higher proportion of patients with depression had abnormal waist circumference, systolic blood pressure, or high blood pressure. Besides 16 patients with depressive disorders having MS, another 53.5% of patients fulfilled one or two criteria of MS. None of the sociodemographic variables was associated with development of MS in patients with depression. Slightly more than one-third of depressed patients who are drug-naïve have MS and this prevalence rate is significantly higher than in healthy controls.

  1. Korean, Japanese, and Chinese populations featured similar genes encoding drug-metabolizing enzymes and transporters: a DMET Plus microarray assessment.

    Science.gov (United States)

    Yi, SoJeong; An, Hyungmi; Lee, Howard; Lee, Sangin; Ieiri, Ichiro; Lee, Youngjo; Cho, Joo-Youn; Hirota, Takeshi; Fukae, Masato; Yoshida, Kenji; Nagatsuka, Shinichiro; Kimura, Miyuki; Irie, Shin; Sugiyama, Yuichi; Shin, Dong Wan; Lim, Kyoung Soo; Chung, Jae-Yong; Yu, Kyung-Sang; Jang, In-Jin

    2014-10-01

    Interethnic differences in genetic polymorphism in genes encoding drug-metabolizing enzymes and transporters are one of the major factors that cause ethnic differences in drug response. This study aimed to investigate genetic polymorphisms in genes involved in drug metabolism, transport, and excretion among Korean, Japanese, and Chinese populations, the three major East Asian ethnic groups. The frequencies of 1936 variants representing 225 genes encoding drug-metabolizing enzymes and transporters were determined from 786 healthy participants (448 Korean, 208 Japanese, and 130 Chinese) using the Affymetrix Drug-Metabolizing Enzymes and Transporters Plus microarray. To compare allele or genotype frequencies in the high-dimensional data among the three East Asian ethnic groups, multiple testing, principal component analysis (PCA), and regularized multinomial logit model through least absolute shrinkage and selection operator were used. On microarray analysis, 1071 of 1936 variants (>50% of markers) were found to be monomorphic. In a large number of genetic variants, the fixation index and Pearson's correlation coefficient of minor allele frequencies were less than 0.034 and greater than 0.95, respectively, among the three ethnic groups. PCA identified 47 genetic variants with multiple testing, but was unable to discriminate ethnic groups by the first three components. Multinomial least absolute shrinkage and selection operator analysis identified 269 genetic variants that showed different frequencies among the three ethnic groups. However, none of those variants distinguished between the three ethnic groups during subsequent PCA. Korean, Japanese, and Chinese populations are not pharmacogenetically distant from one another, at least with regard to drug disposition, metabolism, and elimination.

  2. Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction

    NARCIS (Netherlands)

    Martignoni, Marcella; Groothuis, Geny M. M.; de Kanter, Ruben

    2006-01-01

    Animal models are commonly used in the preclinical development of new drugs to predict the metabolic behaviour of new compounds in humans. It is, however, important to realise that humans differ from animals with regards to isoform composition, expression and catalytic activities of

  3. The metabolic fate of the Anti-HIV active drug carrier succinylated human serum albumin after intravenous administration in rats

    NARCIS (Netherlands)

    Swart, P J; Kuipers, M E; Smit, C; Beljaars, L; Ter Wiel, J; Meijer, D K

    The pharmacokinetics and metabolic fate of the intrinsically active (anti-HIV) drug carrier succinylated human serum albumin (Suc-HSA) was studied in rats. Suc-HSA was prepared by derivatizing HSA with 1,4-[C-14]-succinic anhydride, a modification by which all available epsilonNH2-groups in HSA were

  4. Protein metabolism in the rat cerebral cortex in vivo and in vitro as affected by the acquisition enhancing drug piracetam

    NARCIS (Netherlands)

    Nickolson, V.J.; Wolthuis, O.L.

    1976-01-01

    The effect of Piracetam on rat cerebral protein metabolism in vivo and in vitro was studied. It was found that the drug stimulates the uptake of labelled leucine by cerebral cortex slices, has no effect on the incorporation of leucine into cerebral protein, neither in slices nor in vivo, but

  5. The METEOR study of diabetes and other metabolic disorders in patients with schizophrenia treated with antipsychotic drugs. I. Methodology.

    Science.gov (United States)

    De Hert, Marc; Mauri, Mauro; Shaw, Ken; Wetterling, Tilman; Doble, Adam; Giudicelli, Agnès; Falissard, Bruno

    2010-12-01

    Patients with schizophrenia present a two- to three-fold higher prevalence of diabetes, of metabolic syndrome and of cardiovascular morbidity. The reason for this increased prevalence may involve intrinsic vulnerability, lifestyle factors and iatrogenic effects of antipsychotic drugs. The objective of this multinational, cross-sectional, pharmacoepidemiological study was to determine the prevalence of diabetes, lipid disorders, obesity, hypertension and the metabolic syndrome in patients with schizophrenia treated with antipsychotic drugs. Particular attention was taken to acquire data on a wide a range as possible of demographic, clinical and lifestyle variables that may influence the risk of metabolic disorders, which were taken into account in the calculation of prevalence data by propensity scoring. The study included 2270 subjects from 16 European countries, predominantly from Central and Eastern Europe. The proportion of subjects presenting the pathologies of interest was relatively high, ranging from 28% for glycaemic disorders to 70% for lipid disorders. Copyright © 2010 John Wiley & Sons, Ltd.

  6. Xenobiotic-metabolizing enzymes in plants and their role in uptake and biotransformation of veterinary drugs in the environment.

    Science.gov (United States)

    Bártíková, Hana; Skálová, Lenka; Stuchlíková, Lucie; Vokřál, Ivan; Vaněk, Tomáš; Podlipná, Radka

    2015-08-01

    Many various xenobiotics permanently enter plants and represent potential danger for their organism. For that reason, plants have evolved extremely sophisticated detoxification systems including a battery of xenobiotic-metabolizing enzymes. Some of them are similar to those in humans and animals, but there are several plant-specific ones. This review briefly introduces xenobiotic-metabolizing enzymes in plants and summarizes present information about their action toward veterinary drugs. Veterinary drugs are used worldwide to treat diseases and protect animal health. However, veterinary drugs are also unwantedly introduced into environment mostly via animal excrements, they persist in the environment for a long time and may impact on the non-target organisms. Plants are able to uptake, transform the veterinary drugs to non- or less-toxic compounds and store them in the vacuoles and cell walls. This ability may protect not only plant themselves but also other organisms, predominantly invertebrates and wild herbivores. The aim of this review is to emphasize the importance of plants in detoxification of veterinary drugs in the environment. The results of studies, which dealt with transport and biotransformation of veterinary drugs in plants, are summarized and evaluated. In conclusion, the risks and consequences of veterinary drugs in the environment and the possibilities of phytoremediation technologies are considered and future perspectives are outlined.

  7. Effects of Uremic Toxins on Transport and Metabolism of Different Biopharmaceutics Drug Disposition Classification System (BDDCS) Xenobiotics

    Science.gov (United States)

    Reyes, Maribel; Benet, Leslie Z.

    2013-01-01

    Chronic kidney disease (CKD) is recognized to cause pharmacokinetic changes in renally excreted drugs; however, pharmacokinetic changes are also reported for drugs that are non-renally eliminated. Few studies have investigated how uremic toxins may affect drug transporters and metabolizing enzymes and how these may result in pharmacokinetic/metabolic changes in CKD. Here, we investigated the effects of uremic toxins and human uremic serum on the transport of the prototypical transporter substrate [3H]-estrone sulfate and three BDDCS drugs, propranolol, losartan, and eprosartan. We observed a significant decrease in [3H]-estrone sulfate, losartan, and eprosartan uptake with some uremic toxins in both transfected cells and rat hepatocytes. The uptake of losartan was decreased in rat and human hepatocytes (28%, and 48% respectively) in the presence of hemodialysis (HD) serum. Time-course studies of losartan showed a 27%, 65% and 68% increase in AUC in the presence of HD serum, rifampin, and sulfaphenazole respectively. Intracellular losartan AUC decreased significantly in the treatment groups and the metabolite AUC decreased by 41% and 26% in rifampin and sulfaphenazole treated group. The intracellular AUC of eprosartan increased 190% in the presence of HD serum. These studies indicate that the uremic toxins contained in HD serum play an important role in drug disposition through drug transporters, and that there would be differential effects depending on the BDDCS classification of the drug. PMID:21618544

  8. CNS metabolism in high-risk drug abuse : Insights gained from 1H-, 31P-MRS and PET.

    Science.gov (United States)

    Bodea, S

    2017-07-10

    High-risk drug consumption is a matter of great concern for public health actors in industrialised countries. The latest trends show a market tendency towards diversification and increasing demand for high-purity synthetic drugs. While most consumers seek medical help after cannabis use, it is high-risk drugs like cocaine, heroin and amphetamines that account for most of the 1000 drug-related deaths that occur in Germany every year. This article presents the most prominent in vivo cerebral metabolic information in cocaine, heroin and methamphetamine users provided by MRI spectroscopy and PET imaging. We reviewed the literature reporting neuroimaging studies of in vivo metabolic data for methamphetamine, cocaine and heroin consumption published up to March 2017. The search was conducted using PubMed and a combination of the following key words: methamphetamine, cocaine, heroin, MR spectroscopy, PET. MRI and PET are indispensable tools in gauging brain metabolic response to illegal drug abuse. Future breakthroughs in this field will most likely come from the investigation of novel neurotransmitter systems in PET and imaging phosphorus and carbon metabolites in MRI.

  9. A Human Hepatocyte-Bearing Mouse: An Animal Model to Predict Drug Metabolism and Effectiveness in Humans

    Directory of Open Access Journals (Sweden)

    Katsutoshi Yoshizato

    2009-01-01

    Full Text Available Preclinical studies to predict the efficacy and safety of drugs have conventionally been conducted almost exclusively in mice and rats as rodents, despite the differences in drug metabolism between humans and rodents. Furthermore, human (ℎ viruses such as hepatitis viruses do not infect the rodent liver. A mouse bearing a liver in which the hepatocytes have been largely repopulated with ℎ-hepatocytes would overcome some of these disadvantages. We have established a practical, efficient, and large-scale production system for such mice. Accumulated evidence has demonstrated that these hepatocyte-humanized mice are a useful and reliable animal model, exhibiting ℎ-type responses in a series of in vivo drug processing (adsorption, distribution, metabolism, excretion experiments and in the infection and propagation of hepatic viruses. In this review, we present the current status of studies on chimeric mice and describe their usefulness in the study of peroxisome proliferator-activated receptors.

  10. CHANGING METABOLIC FUNCTIONS IN EXPERIMENTAL ANIMALS AFTER INTRODUCTION OF THE XENOBIOTIC, IMMUNOTROPIC DRUG AND PROBIOTIC

    Directory of Open Access Journals (Sweden)

    Zvyagintseva O.V.

    2015-05-01

    Full Text Available The aim of the study was to evaluate in vivo changes in metabolic and barrier function of the resistance factors (activity of enzymes of neutrophils, the efficiency of phagocytosis, some biochemical parameters (concentration of ceruloplasmin and haptoglobin and proliferate activity in vitro cells after introduction of copper sulfate, probiotics and immunostimulant "Fungidol" the experimental animals. Material and methods. The in vivo experiments were performed on 6-month-old male rats of Wistar line. Identified the following groups: group 1 - control animals, which were intraperitoneally injected with saline (n = 5; group 2 - animals that were administered saline per os and 48 hours a solution of copper sulphate intraperitoneally (n = 5; group 3 - animals, which were injected with immunotropic drug "Fungidol" per os and 48 hours a solution of copper sulphate intraperitoneally (n = 5; group 4 animals, which were injected with a solution of probiotics per os and 48 hours a solution of copper sulphate intraperitoneally (n = 5. As a probiotic used capsules firm Yogurt that contains active Lactobacillus acidophilus, Lactobacillus rhamnosus, Streptococcus thermophillus, Lactobacillus bulgaricus. The concentration of haptoglobin and ceruloplasmin were determined spectrophotometrically. Oxygen-dependent metabolism of neutrophils was investigated by microscopy according to their ability to absorb nitroblue tetrazolium (NBT-test and restore it to deformazione in the form of granules blue color under the influence of superoxide anion, which is formed in the NADP-oxidase reaction, initiating the process of stimulation of phagocytosis (NBT-test. To determine the barrier function of phagocytic cells by light microscopy to evaluate the activity of phagocytosis of neutrophilic granulocytes with subsequent determination of phagocytic index, phagocytic number and the index of completeness of phagocytosis. As a microbial agent used is a suspension culture of

  11. Quantitative analysis of drug effects at the whole-body level: a case study for glucose metabolism in malaria patients.

    Science.gov (United States)

    Snoep, Jacky L; Green, Kathleen; Eicher, Johann; Palm, Daniel C; Penkler, Gerald; du Toit, Francois; Walters, Nicolas; Burger, Robert; Westerhoff, Hans V; van Niekerk, David D

    2015-12-01

    We propose a hierarchical modelling approach to construct models for disease states at the whole-body level. Such models can simulate effects of drug-induced inhibition of reaction steps on the whole-body physiology. We illustrate the approach for glucose metabolism in malaria patients, by merging two detailed kinetic models for glucose metabolism in the parasite Plasmodium falciparum and the human red blood cell with a coarse-grained model for whole-body glucose metabolism. In addition we use a genome-scale metabolic model for the parasite to predict amino acid production profiles by the malaria parasite that can be used as a complex biomarker. © 2015 Authors; published by Portland Press Limited.

  12. Vagal Nerve Stimulation in the Treatment of Drug-Resistant Epileptic Encephalopathies in Inborn Errors of Metabolism

    Directory of Open Access Journals (Sweden)

    Daniele Grioni MD

    2015-10-01

    Full Text Available Patients affected by inborn errors of metabolism can develop catastrophic epilepsies ineligible for resective surgery. Few reports concerning vagal nerve stimulation in patients with epileptic encephalopathy in the context of metabolic diseases have been published in the literature. Drug-resistant epilepsies in metabolic disease could be a specific target for vagal nerve stimulation, although the efficacy of this technique in these patients still needs to be proved. The authors report our experience in treating refractory epilepsy with vagal nerve stimulation in 2 patients affected by inborn errors of metabolism. The first patient is a 23-year-old patient affected by glutaric aciduria type II, the other one is a 16-month-old child with nonketotic hyperglycinemia. Vagal nerve stimulation reduced seizures up to 50% in the first case and up to 90% in the second one.

  13. Antinociceptive effects, metabolism and disposition of ketamine in ponies under target-controlled drug infusion

    International Nuclear Information System (INIS)

    Knobloch, M.; Portier, C.J.; Levionnois, O.L.; Theurillat, R.; Thormann, W.; Spadavecchia, C.; Mevissen, M.

    2006-01-01

    Ketamine is widely used as an anesthetic in a variety of drug combinations in human and veterinary medicine. Recently, it gained new interest for use in long-term pain therapy administered in sub-anesthetic doses in humans and animals. The purpose of this study was to develop a physiologically based pharmacokinetic (PBPk) model for ketamine in ponies and to investigate the effect of low-dose ketamine infusion on the amplitude and the duration of the nociceptive withdrawal reflex (NWR). A target-controlled infusion (TCI) of ketamine with a target plasma level of 1 μg/ml S-ketamine over 120 min under isoflurane anesthesia was performed in Shetland ponies. A quantitative electromyographic assessment of the NWR was done before, during and after the TCI. Plasma levels of R-/S-ketamine and R-/S-norketamine were determined by enantioselective capillary electrophoresis. These data and two additional data sets from bolus studies were used to build a PBPk model for ketamine in ponies. The peak-to-peak amplitude and the duration of the NWR decreased significantly during TCI and returned slowly toward baseline values after the end of TCI. The PBPk model provides reliable prediction of plasma and tissue levels of R- and S-ketamine and R- and S-norketamine. Furthermore, biotransformation of ketamine takes place in the liver and in the lung via first-pass metabolism. Plasma concentrations of S-norketamine were higher compared to R-norketamine during TCI at all time points. Analysis of the data suggested identical biotransformation rates from the parent compounds to the principle metabolites (R- and S-norketamine) but different downstream metabolism to further metabolites. The PBPk model can provide predictions of R- and S-ketamine and norketamine concentrations in other clinical settings (e.g. horses)

  14. Increased circulating full-length betatrophin levels in drug-naïve metabolic syndrome.

    Science.gov (United States)

    Liu, Dan; Li, Sheyu; He, He; Yu, Chuan; Li, Xiaodan; Liang, Libo; Chen, Yi; Li, Jianwei; Li, Jianshu; Sun, Xin; Tian, Haoming; An, Zhenmei

    2017-03-14

    Betatrophin is a newly identified circulating adipokine playing a role in the regulation of glucose homeostasis and lipid metabolism. But its role in metabolic syndrome (MetS) remains unknown. Therefore, we aimed to compare the circulating betatrophin concentrations between patients with MetS and healthy controls. We recruited 47 patients with MetS and 47 age and sex matched healthy controls. Anthropometric and biochemical measurements were performed, and serum betatrophin levels were detected by ELISA. Full-length betatrophin levels in patients with MetS were significantly higher than those in controls (694.84 ± 365.51 pg/ml versus 356.64 ± 287.92 pg/ml; P <0.001). While no significant difference of total betatrophin levels was found between the two groups (1.20 ± 0.79 ng/ml versus 1.31 ± 1.08 ng/ml; P = 0.524). Full-length betatrophin level was positively correlated with fasting plasma glucose (FPG) (r = 0.357, P = 0.014) and 2-hour plasma glucose (2hPG) (r = 0.38, P <0.01). Binary logistic regression models indicated that subjects in the tertile of the highest full-length betatrophin level experienced higher odds of having MetS (OR, 8.6; 95% CI 2.8-26.8; P <0.001). Our study showed that full-length betatrophin concentrations were increased in drug-naïve MetS patients.

  15. Metabolic side-effects of the novel second-generation antipsychotic drugs asenapine and iloperidone: a comparison with olanzapine.

    Directory of Open Access Journals (Sweden)

    Heidi N Boyda

    Full Text Available The second generation antipsychotic (SGA drugs are widely used in psychiatry due to their clinical efficacy and low incidence of neurological side-effects. However, many drugs in this class cause deleterious metabolic side-effects. Animal models accurately predict metabolic side-effects for SGAs with known clinical metabolic liability. We therefore used preclinical models to evaluate the metabolic side-effects of glucose intolerance and insulin resistance with the novel SGAs asenapine and iloperidone for the first time. Olanzapine was used as a comparator.Adults female rats were treated with asenapine (0.01, 0.05, 0.1, 0.5, 1.0 mg/kg, iloperidone (0.03, 0.5, 1.0, 5.0, 10.0 mg/kg or olanzapine (0.1, 0.5, 1.5, 5.0, 10.0 mg/kg and subjected to the glucose tolerance test (GTT. Separate groups of rats were treated with asenapine (0.1 and 1.0 mg/kg, iloperidone (1.0 and 10 mg/kg or olanzapine (1.5 and 15 mg/kg and tested for insulin resistance with the hyperinsulinemic-euglycemic clamp (HIEC.Asenapine showed no metabolic effects at any dose in either test. Iloperidone caused large and significant glucose intolerance with the three highest doses in the GTT, and insulin resistance with both doses in the HIEC. Olanzapine caused significant glucose intolerance with the three highest doses in the GTT, and insulin resistance with the higher dose in the HIEC.In preclinical models, asenapine shows negligible metabolic liability. By contrast, iloperidone exhibits substantial metabolic liability, comparable to olanzapine. These results emphasize the need for appropriate metabolic testing in patients treated with novel SGAs where current clinical data do not exist.

  16. Effects of Curcuma xanthorrhiza Extracts and Their Constituents on Phase II Drug-metabolizing Enzymes Activity

    Science.gov (United States)

    Salleh, Nurul Afifah Mohd; Ismail, Sabariah; Ab Halim, Mohd Rohaimi

    2016-01-01

    Background: Curcuma xanthorrhiza is a native Indonesian plant and traditionally utilized for a range of illness including liver damage, hypertension, diabetes, and cancer. Objective: The study determined the effects of C. xanthorrhiza extracts (ethanol and aqueous) and their constituents (curcumene and xanthorrhizol) on UDP-glucuronosyltransferase (UGT) and glutathione transferase (GST) activities. Materials and Methods: The inhibition studies were evaluated both in rat liver microsomes and in human recombinant UGT1A1 and UGT2B7 enzymes. p-nitrophenol and beetle luciferin were used as the probe substrates for UGT assay while 1-chloro-2,4-dinitrobenzene as the probe for GST assay. The concentrations of extracts studied ranged from 0.1 to 1000 μg/mL while for constituents ranged from 0.01 to 500 μM. Results: In rat liver microsomes, UGT activity was inhibited by the ethanol extract (IC50 =279.74 ± 16.33 μg/mL). Both UGT1A1 and UGT2B7 were inhibited by the ethanol and aqueous extracts with IC50 values ranging between 9.59–22.76 μg/mL and 110.71–526.65 μg/Ml, respectively. Rat liver GST and human GST Pi-1 were inhibited by ethanol and aqueous extracts, respectively (IC50 =255.00 ± 13.06 μg/mL and 580.80 ± 18.56 μg/mL). Xanthorrhizol was the better inhibitor of UGT1A1 (IC50 11.30 ± 0.27 μM) as compared to UGT2B7 while curcumene did not show any inhibition. For GST, both constituents did not show any inhibition. Conclusion: These findings suggest that C. xanthorrhiza have the potential to cause herb-drug interaction with drugs that are primarily metabolized by UGT and GST enzymes. SUMMARY Findings from this study would suggest which of Curcuma xanthorrhiza extracts and constituents that would have potential interactions with drugs which are highly metabolized by UGT and GST enzymes. Further clinical studies can then be designed if needed to evaluate the in vivo pharmacokinetic relevance of these interactions Abbreviations Used: BSA: Bovine serum albumin

  17. Hydrophilic Interaction Liquid Chromatography/Mass Spectrometry: An Attractive and Prospective Method for the Quantitative Bioanalysis in Drug Metabolism.

    Science.gov (United States)

    Li, Zheng; Han, Jie; Sun, Shi-an; Chen, Kai; Tang, Dao-quan

    2016-01-01

    During the development, dosage optimization and safety evaluation of a drug, rapid and precise monitoring of administered drug and/or its metabolites in biological samples including blood, plasma, serum, tissues and saliva are vital. As drug biotransformation produces more hydrophilic metabolites for the enhancement of drug elimination, which is often a challenge for traditional reversed-phase liquid chromatography (RPLC) separation. Because hydrophilic interaction liquid chromatography (HILIC) is capable of retaining polar compounds and readily compatible with mass spectrometry (MS), HILIC has been used as a complementary separation technique to RPLC for analysis of polar metabolites, especially polar drugs and their metabolites. This review covers core aspects of HILIC-MS/MS method and overall profile of its application in analysis of drug and/or its metabolites. The emphasis of this paper has been placed on the applications of HILIC-MS/MS method in quantitative bioanalysis of drugs alone or along with their metabolites in drug metabolism studies in recent years. As a fundamental and critical step of bioanalytical method, conventional sample preparation techniques of biological matrices for the HILIC-MS/MS analysis of drugs and/or their metabolites are also briefly featured.

  18. A Physiologically Based Pharmacokinetic Model for Pregnant Women to Predict the Pharmacokinetics of Drugs Metabolized Via Several Enzymatic Pathways.

    Science.gov (United States)

    Dallmann, André; Ince, Ibrahim; Coboeken, Katrin; Eissing, Thomas; Hempel, Georg

    2017-09-18

    Physiologically based pharmacokinetic modeling is considered a valuable tool for predicting pharmacokinetic changes in pregnancy to subsequently guide in-vivo pharmacokinetic trials in pregnant women. The objective of this study was to extend and verify a previously developed physiologically based pharmacokinetic model for pregnant women for the prediction of pharmacokinetics of drugs metabolized via several cytochrome P450 enzymes. Quantitative information on gestation-specific changes in enzyme activity available in the literature was incorporated in a pregnancy physiologically based pharmacokinetic model and the pharmacokinetics of eight drugs metabolized via one or multiple cytochrome P450 enzymes was predicted. The tested drugs were caffeine, midazolam, nifedipine, metoprolol, ondansetron, granisetron, diazepam, and metronidazole. Pharmacokinetic predictions were evaluated by comparison with in-vivo pharmacokinetic data obtained from the literature. The pregnancy physiologically based pharmacokinetic model successfully predicted the pharmacokinetics of all tested drugs. The observed pregnancy-induced pharmacokinetic changes were qualitatively and quantitatively reasonably well predicted for all drugs. Ninety-seven percent of the mean plasma concentrations predicted in pregnant women fell within a twofold error range and 63% within a 1.25-fold error range. For all drugs, the predicted area under the concentration-time curve was within a 1.25-fold error range. The presented pregnancy physiologically based pharmacokinetic model can quantitatively predict the pharmacokinetics of drugs that are metabolized via one or multiple cytochrome P450 enzymes by integrating prior knowledge of the pregnancy-related effect on these enzymes. This pregnancy physiologically based pharmacokinetic model may thus be used to identify potential exposure changes in pregnant women a priori and to eventually support informed decision making when clinical trials are designed in this

  19. CYP2C9 genotype vs. metabolic phenotype for individual drug dosing--a correlation analysis using flurbiprofen as probe drug.

    Directory of Open Access Journals (Sweden)

    Silvia Vogl

    Full Text Available Currently, genotyping of patients for polymorphic enzymes responsible for metabolic elimination is considered a possibility to adjust drug dose levels. For a patient to profit from this procedure, the interindividual differences in drug metabolism within one genotype should be smaller than those between different genotypes. We studied a large cohort of healthy young adults (283 subjects, correlating their CYP2C9 genotype to a simple phenotyping metric, using flurbiprofen as probe drug. Genotyping was conducted for CYP2C9*1, *2, *3. The urinary metabolic ratio MR (concentration of CYP2C9-dependent metabolite divided by concentration of flurbiprofen determined two hours after flurbiprofen (8.75 mg administration served as phenotyping metric. Linear statistical models correlating genotype and phenotype provided highly significant allele-specific MR estimates of 0.596 for the wild type allele CYP2C9*1, 0.405 for CYP2C9*2 (68 % of wild type, and 0.113 for CYP2C9*3 (19 % of wild type. If these estimates were used for flurbiprofen dose adjustment, taking 100 % for genotype *1/*1, an average reduction to 84 %, 60 %, 68 %, 43 %, and 19 % would result for genotype *1/*2, *1/*3, *2/*2, *2/*3, and *3/*3, respectively. Due to the large individual variation within genotypes with coefficients of variation ≥ 20 % and supposing the normal distribution, one in three individuals would be out of the average optimum dose by more than 20 %, one in 20 would be 40 % off. Whether this problem also applies to other CYPs and other drugs has to be investigated case by case. Our data for the given example, however, puts the benefit of individual drug dosing to question, if it is exclusively based on genotype.

  20. Metabolism

    Science.gov (United States)

    ... functions: Anabolism (uh-NAB-uh-liz-um), or constructive metabolism, is all about building and storing. It ... in infants and young children. Hypothyroidism slows body processes and causes fatigue (tiredness), slow heart rate, excessive ...

  1. Metabolism

    Science.gov (United States)

    ... a particular food provides to the body. A chocolate bar has more calories than an apple, so ... acid phenylalanine, needed for normal growth and protein production). Inborn errors of metabolism can sometimes lead to ...

  2. Regulation of drug metabolism and toxicity by multiple factors of genetics, epigenetics, lncRNAs, gut microbiota, and diseases: a meeting report of the 21st International Symposium on Microsomes and Drug Oxidations (MDO

    Directory of Open Access Journals (Sweden)

    Ai-Ming Yu

    2017-03-01

    Full Text Available Variations in drug metabolism may alter drug efficacy and cause toxicity; better understanding of the mechanisms and risks shall help to practice precision medicine. At the 21st International Symposium on Microsomes and Drug Oxidations held in Davis, California, USA, in October 2–6, 2016, a number of speakers reported some new findings and ongoing studies on the regulation mechanisms behind variable drug metabolism and toxicity, and discussed potential implications to personalized medications. A considerably insightful overview was provided on genetic and epigenetic regulation of gene expression involved in drug absorption, distribution, metabolism, and excretion (ADME and drug response. Altered drug metabolism and disposition as well as molecular mechanisms among diseased and special populations were presented. In addition, the roles of gut microbiota in drug metabolism and toxicology as well as long non-coding RNAs in liver functions and diseases were discussed. These findings may offer new insights into improved understanding of ADME regulatory mechanisms and advance drug metabolism research.

  3. Novel Drug Targets for Food-Borne Pathogen Campylobacter jejuni: An Integrated Subtractive Genomics and Comparative Metabolic Pathway Study.

    Science.gov (United States)

    Mehla, Kusum; Ramana, Jayashree

    2015-07-01

    Campylobacters are a major global health burden and a cause of food-borne diarrheal illness and economic loss worldwide. In developing countries, Campylobacter infections are frequent in children under age two and may be associated with mortality. In developed countries, they are a common cause of bacterial diarrhea in early adulthood. In the United States, antibiotic resistance against Campylobacter is notably increased from 13% in 1997 to nearly 25% in 2011. Novel drug targets are urgently needed but remain a daunting task to accomplish. We suggest that omics-guided drug discovery is timely and worth considering in this context. The present study employed an integrated subtractive genomics and comparative metabolic pathway analysis approach. We identified 16 unique pathways from Campylobacter when compared against H. sapiens with 326 non-redundant proteins; 115 of these were found to be essential in the Database of Essential Genes. Sixty-six proteins among these were non-homologous to the human proteome. Six membrane proteins, of which four are transporters, have been proposed as potential vaccine candidates. Screening of 66 essential non-homologous proteins against DrugBank resulted in identification of 34 proteins with drug-ability potential, many of which play critical roles in bacterial growth and survival. Out of these, eight proteins had approved drug targets available in DrugBank, the majority serving crucial roles in cell wall synthesis and energy metabolism and therefore having the potential to be utilized as drug targets. We conclude by underscoring that screening against these proteins with inhibitors may aid in future discovery of novel therapeutics against campylobacteriosis in ways that will be pathogen specific, and thus have minimal toxic effect on host. Omics-guided drug discovery and bioinformatics analyses offer the broad potential for veritable advances in global health relevant novel therapeutics.

  4. Importância do metabolismo no planejamento de fármacos The importance of metabolism in drug design

    Directory of Open Access Journals (Sweden)

    Dárcio Gomes Pereira

    2007-02-01

    Full Text Available It is widely recognized that pharmacokinetic optimization needs to be addressed early in drug discovery to reduce the high failure rate in bringing drugs to market. Poor absorption, too short duration of action due to high elimination rate, or the presence of active metabolites are examples of properties that can potentially lead to unsuccessful clinical programmes. Here I describe a brief overview of advantages and molecular strategies for improving metabolic and pharmacokinetic properties applied to the discovery of fluconazol, beta-blockers, ritonavir and ezetimibe and to the development of the prodrugs enalapril and bambuterol.

  5. Dose-response effects of lycopene on selected drug-metabolizing and antioxidant enzymes in the rat

    DEFF Research Database (Denmark)

    Breinholt, V.; Lauridsen, S. T.; Daneshvar, B.

    2000-01-01

    enzymes involved in the protection against oxidative stress and cancer. The fact that these enzymatic activities are induced at all of these very low plasma levels, could be taken to suggest that modulation of antioxidant and drug-metabolizing enzymes map indeed be relevant to humans, which in general......The administration of lycopene to female rats at doses ranging from 0.001 to 0.1 g/kg b.w, per day for 2 weeks was found to alter the drug-metabolizing capacity and antioxidant status of the exposed animals. An investigation of four cytochrome P450-dependent enzymes revealed that benzyloxyresorufin...... is barely within the lower range of the mean human plasma concentration of lycopene, which ranges from 70-1790 nM. Oxidative stress induced by the heterocyclic amine, 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP), and investigated by analyzing for malondialdehyde in plasma, was not found...

  6. Core Proteomic Analysis of Unique Metabolic Pathways of Salmonella enterica for the Identification of Potential Drug Targets.

    Science.gov (United States)

    Uddin, Reaz; Sufian, Muhammad

    2016-01-01

    Infections caused by Salmonella enterica, a Gram-negative facultative anaerobic bacteria belonging to the family of Enterobacteriaceae, are major threats to the health of humans and animals. The recent availability of complete genome data of pathogenic strains of the S. enterica gives new avenues for the identification of drug targets and drug candidates. We have used the genomic and metabolic pathway data to identify pathways and proteins essential to the pathogen and absent from the host. We took the whole proteome sequence data of 42 strains of S. enterica and Homo sapiens along with KEGG-annotated metabolic pathway data, clustered proteins sequences using CD-HIT, identified essential genes using DEG database and discarded S. enterica homologs of human proteins in unique metabolic pathways (UMPs) and characterized hypothetical proteins with SVM-prot and InterProScan. Through this core proteomic analysis we have identified enzymes essential to the pathogen. The identification of 73 enzymes common in 42 strains of S. enterica is the real strength of the current study. We proposed all 73 unexplored enzymes as potential drug targets against the infections caused by the S. enterica. The study is comprehensive around S. enterica and simultaneously considered every possible pathogenic strain of S. enterica. This comprehensiveness turned the current study significant since, to the best of our knowledge it is the first subtractive core proteomic analysis of the unique metabolic pathways applied to any pathogen for the identification of drug targets. We applied extensive computational methods to shortlist few potential drug targets considering the druggability criteria e.g. Non-homologous to the human host, essential to the pathogen and playing significant role in essential metabolic pathways of the pathogen (i.e. S. enterica). In the current study, the subtractive proteomics through a novel approach was applied i.e. by considering only proteins of the unique metabolic

  7. 78 FR 22270 - Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety...

    Science.gov (United States)

    2013-04-15

    ..., indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes... Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes (RECORD) trial, for new drug...

  8. 75 FR 32189 - Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety...

    Science.gov (United States)

    2010-06-07

    ..., GlaxoSmithKline, a drug approved for blood glucose control in adults with type 2 diabetes mellitus. Data... Outcome and Regulation of Glycemia in Diabetes (RECORD) Trial, observational data, health claims data, and...

  9. Functional interrogation of Plasmodium genus metabolism identifies species- and stage-specific differences in nutrient essentiality and drug targeting.

    Directory of Open Access Journals (Sweden)

    Alyaa M Abdel-Haleem

    2018-01-01

    Full Text Available Several antimalarial drugs exist, but differences between life cycle stages among malaria species pose challenges for developing more effective therapies. To understand the diversity among stages and species, we reconstructed genome-scale metabolic models (GeMMs of metabolism for five life cycle stages and five species of Plasmodium spanning the blood, transmission, and mosquito stages. The stage-specific models of Plasmodium falciparum uncovered stage-dependent changes in central carbon metabolism and predicted potential targets that could affect several life cycle stages. The species-specific models further highlight differences between experimental animal models and the human-infecting species. Comparisons between human- and rodent-infecting species revealed differences in thiamine (vitamin B1, choline, and pantothenate (vitamin B5 metabolism. Thus, we show that genome-scale analysis of multiple stages and species of Plasmodium can prioritize potential drug targets that could be both anti-malarials and transmission blocking agents, in addition to guiding translation from non-human experimental disease models.

  10. Cancer therapy leading to state of cancer metabolism depression for efficient operation of small dosage cytotoxic drugs

    Directory of Open Access Journals (Sweden)

    Ponizovskiy MR

    2015-04-01

    Full Text Available “Prolonged medical starvation” as the method of cancer therapy was borrowed from folk healers Omelchenko A and Breuss R. Author was convinced in efficiency of this method of cancer treatment via examination of cured patients and on own experience. The mechanism of this method of cancer therapy operates via Warburg effect targeting that promotes efficient cancer treatment with small cytotoxic drugs. Just it was described the mechanism of Warburg effect as well as mechanism transmutation of mitochondrial function in cancer metabolism which are exhibited in connection with operation of described method cancer therapy. There were described the biochemical and biophysical mechanisms of formations resistance to some cytotoxic drugs and recurrence cancer disease after disease remission which occur sometimes as result of treatment with great dosage of cytotoxic drugs. Also it was described the benefits of use the method “Prolonged medical starvation” with decreased dosage of cytotoxic drugs for cancer treatment. The significance of this work that it was substantiated the mechanism operation of combination “Prolonged medical starvation” with small dosages cytotoxic drugs of cancer treatment, which mechanism leads to prevention recurrence cancer disease and resistance to anticancer drugs in comparison with intensive anticancer chemotherapy with great dosages of cytotoxic drugs in cancer therapy. Also the offered concepts of cancer therapy mechanism gave possibility to explain mechanisms of some results of experiments eliminating the doubts of the authors these experiments.

  11. In silico drug metabolism and pharmacokinetic profiles of natural products from medicinal plants in the Congo basin.

    Science.gov (United States)

    Ntie-Kang, Fidele; Lifongo, Lydia L; Mbah, James A; Owono Owono, Luc C; Megnassan, Eugene; Mbaze, Luc Meva'a; Judson, Philip N; Sippl, Wolfgang; Efange, Simon M N

    2013-01-01

    Drug metabolism and pharmacokinetics (DMPK) assessment has come to occupy a place of interest during the early stages of drug discovery today. The use of computer modelling to predict the DMPK and toxicity properties of a natural product library derived from medicinal plants from Central Africa (named ConMedNP). Material from some of the plant sources are currently employed in African Traditional Medicine. Computer-based methods are slowly gaining ground in this area and are often used as preliminary criteria for the elimination of compounds likely to present uninteresting pharmacokinetic profiles and unacceptable levels of toxicity from the list of potential drug candidates, hence cutting down the cost of discovery of a drug. In the present study, we present an in silico assessment of the DMPK and toxicity profile of a natural product library containing ~3,200 compounds, derived from 379 species of medicinal plants from 10 countries in the Congo Basin forests and savannas, which have been published in the literature. In this analysis, we have used 46 computed physico-chemical properties or molecular descriptors to predict the absorption, distribution, metabolism and elimination and toxicity (ADMET) of the compounds. This survey demonstrated that about 45% of the compounds within the ConMedNP compound library are compliant, having properties which fall within the range of ADME properties of 95% of currently known drugs, while about 69% of the compounds have ≤ 2 violations. Moreover, about 73% of the compounds within the corresponding "drug-like" subset showed compliance. In addition to the verified levels of "drug-likeness", diversity and the wide range of measured biological activities, the compounds from medicinal plants in Central Africa show interesting DMPK profiles and hence could represent an important starting point for hit/lead discovery.

  12. Fast detoxication of 2-chloro ethyl ethyl sulfide by p-type Ag2O semiconductor nanoparticle-loaded Al2O3-based supports

    International Nuclear Information System (INIS)

    Ma, Meng-Wei; Kuo, Dong-Hau

    2016-01-01

    Highlights: • Detoxication of CWA surrogate of 2-chloro ethyl ethyl sulfide is investigated. • A small amount of Ag 2 O on Al 2 O 3 -base support is sufficient to degrade 2-CEES. • Detoxication conversion >82% in 15 min is achieved for >2.5% Ag 2 O/Na 2 SiO 3 /Al 2 O 3 . • Na 2 SiO 3 modified Al 2 O 3 to have the valley-like line pattern for depositing Ag 2 O. • 2-CEES oxidation is initiated from the dominant electronic holes in p-type Ag 2 O. - Abstract: p-type Ag 2 O semiconductor nanoparticle-loaded Al 2 O 3 or Na 2 SiO 3 /Al 2 O 3 powders used for detoxicating the surrogate of sulfur mustard of 2-chloro ethyl ethyl sulfide (C 2 H 5 SCH 2 CH 2 Cl, 2-CEES) were investigated. Different amounts of Ag 2 O and Na 2 SiO 3 on catalyst supports were evaluated. Gas chromatography with a pulsed flame photometric detector (GC–PFPD) and gas chromatography coupled with a mass spectroscopy (GC–MS) were used to monitor and identify the catalytic reactions, together with reaction products analysis. The GC analyses showed that the decontamination of 2-CEES in isopropanol solvent for 15 min was above 82% efficiency for the 0.5% Na 2 SiO 3 /Al 2 O 3 support deposited with a Ag 2 O content above 2.5%. 2-(ethylthio)ethanol and 2-(ethylthio)ethanoic acid were identified as the major products after catalytic reactions. The electronic holes dominating in p-type Ag 2 O is proposed to provide the key component and to initiate the catalytic reactions. The electronic hole-based detoxication mechanism is proposed.

  13. Exploration of Unimolecular Gas-Phase Detoxication Pathways of Sarin and Soman: A Computational Study from the Perspective of Reaction Energetics and Kinetics.

    Science.gov (United States)

    Ash, Tamalika; Debnath, Tanay; Banu, Tahamida; Das, Abhijit Kumar

    2016-09-19

    A mechanistic investigation has been carried out to explore all possible gas phase unimolecular isomerization as well as decomposition pathways of toxic organophosphorus compounds (OPCs), namely, sarin (GB) and soman (GD), which are better known as nerve agents. We have identified a total of 13 detoxication pathways for sarin, where the α-H, β-H, and γ-H take part in the H-transfer process. However, for soman, due to the presence of ω-H, three additional detoxication pathways are obtained, where the ω-H is involved in the H-transfer process. Among all the pathways, the D3 decomposition pathway, where the phosphorus oxoacid derivative and alkene are generated via the formation of a six-membered ring in the transition state, is identified as the most feasible pathway from the perspective of both activation barrier and reaction enthalpy values. Moreover, we have studied the feasibility of the isomerization and decomposition pathways by performing the reaction kinetics in the temperature range of 300 K-1000 K using the one-dimensional Rice-Ramsperger-Kassel-Marcus (RRKM) master equation. From the RRKM calculation also, D3 pathway is confirmed as the most feasible pathway for both OPCs. The rate constant values associated with the D3 pathway within the temperature range of 600 K-700 K imply that the degradation of the OPCs is possible within this temperature range via the D3 pathway, which is in good agreement with the earlier reported experimental result. It is also observed that at higher temperature range (∼900 K), the increased rate constant values of other detoxication pathways indicate that along with D3, all other pathways become more or less equally feasible. Therefore, the entire work provides a widespread idea about the kinetic as well as thermodynamic feasibility of the explored detoxication pathways of the titled OPCs.

  14. Biofabrication of a three-dimensional liver micro-organ as an in vitro drug metabolism model

    International Nuclear Information System (INIS)

    Chang, Robert; Sun Wei; Emami, Kamal; Wu Honglu

    2010-01-01

    In their normal in vivo matrix milieu, tissues assume complex well-organized three-dimensional architectures. Therefore, the primary aim in the tissue engineering design process is to fabricate an optimal analog of the in vivo scenario. This challenge can be addressed by applying emerging layered biofabrication approaches in which the precise configuration and composition of cells and bioactive matrix components can recapitulate the well-defined three-dimensional biomimetic microenvironments that promote cell-cell and cell-matrix interactions. Furthermore, the advent of and refinements in microfabricated systems can present physical and chemical cues to cells in a controllable and reproducible fashion unmatched with conventional cultures, resulting in the precise construction of engineered biomimetic microenvironments on the cellular length scale in geometries that are readily parallelized for high throughput in vitro models. As such, the convergence of layered solid freeform fabrication (SFF) technologies along with microfabrication techniques enables the creation of a three-dimensional micro-organ device to serve as an in vitro platform for cell culture, drug screening or to elicit further biological insights, particularly for NASA's interest in a flight-suitable high-fidelity microscale platform to study drug metabolism in space and planetary environments. The proposed model in this paper involves the combinatorial setup of an automated syringe-based, layered direct cell writing bioprinting process with micro-patterning techniques to fabricate a microscale in vitro device housing a chamber of bioprinted three-dimensional liver cell-encapsulated hydrogel-based tissue constructs in defined design patterns that biomimic the cell's natural microenvironment for enhanced biological functionality. In order to assess the structural formability and biological feasibility of such a micro-organ, reproducibly fabricated tissue constructs were biologically characterized for

  15. Effects of resveratrol on drug? and carcinogen?metabolizing enzymes, implications for cancer prevention

    OpenAIRE

    Guthrie, Ariane R.; Chow, H?H. Sherry; Martinez, Jessica A.

    2017-01-01

    Abstract Resveratrol is a polyphenol found in grape skins and peanuts that has demonstrated many health benefits including protection against aging, cardiovascular and metabolic disease, neurological decline, and cancer. The anticancer properties of resveratrol have been attributed to a variety of mechanisms, including its general inhibition of phase I metabolism and induction of phase II metabolism. The effects of resveratrol on these enzymes, however, are still unclear, as in?vitro evidence...

  16. Allosteric regulation of metabolism in cancer: endogenous mechanisms and considerations for drug design.

    Science.gov (United States)

    Macpherson, Jamie A; Anastasiou, Dimitrios

    2017-12-01

    Alterations in metabolic processes have been linked to various diseases, including cancer. Although gene expression can dictate long-term metabolic adaptation, many metabolic changes found in cancer are associated with altered allosteric properties of the underlying enzymes. Small molecule-protein interactions and intracellular signalling converge to orchestrate these allosteric mechanisms, which, emerging evidence suggests, constitute a promising therapeutic avenue. In this review we focus on glucose and energy metabolism to illustrate the role of allostery in cancer physiology and we discuss approaches to streamline the process of targeting aberrant allosteric pathways with small molecules. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Genome-scale reconstruction of the Streptococcus pyogenes M49 metabolic network reveals growth requirements and indicates potential drug targets.

    Science.gov (United States)

    Levering, Jennifer; Fiedler, Tomas; Sieg, Antje; van Grinsven, Koen W A; Hering, Silvio; Veith, Nadine; Olivier, Brett G; Klett, Lara; Hugenholtz, Jeroen; Teusink, Bas; Kreikemeyer, Bernd; Kummer, Ursula

    2016-08-20

    Genome-scale metabolic models comprise stoichiometric relations between metabolites, as well as associations between genes and metabolic reactions and facilitate the analysis of metabolism. We computationally reconstructed the metabolic network of the lactic acid bacterium Streptococcus pyogenes M49. Initially, we based the reconstruction on genome annotations and already existing and curated metabolic networks of Bacillus subtilis, Escherichia coli, Lactobacillus plantarum and Lactococcus lactis. This initial draft was manually curated with the final reconstruction accounting for 480 genes associated with 576 reactions and 558 metabolites. In order to constrain the model further, we performed growth experiments of wild type and arcA deletion strains of S. pyogenes M49 in a chemically defined medium and calculated nutrient uptake and production fluxes. We additionally performed amino acid auxotrophy experiments to test the consistency of the model. The established genome-scale model can be used to understand the growth requirements of the human pathogen S. pyogenes and define optimal and suboptimal conditions, but also to describe differences and similarities between S. pyogenes and related lactic acid bacteria such as L. lactis in order to find strategies to reduce the growth of the pathogen and propose drug targets. Copyright © 2016 Elsevier B.V. All rights reserved.

  18. Impact of Gut Microbiota-Mediated Bile Acid Metabolism on the Solubilization Capacity of Bile Salt Micelles and Drug Solubility.

    Science.gov (United States)

    Enright, Elaine F; Joyce, Susan A; Gahan, Cormac G M; Griffin, Brendan T

    2017-04-03

    In recent years, the gut microbiome has gained increasing appreciation as a determinant of the health status of the human host. Bile salts that are secreted into the intestine may be biotransformed by enzymes produced by the gut bacteria. To date, bile acid research at the host-microbe interface has primarily been directed toward effects on host metabolism. The aim of this work was to investigate the effect of changes in gut microbial bile acid metabolism on the solubilization capacity of bile salt micelles and consequently intraluminal drug solubility. First, the impact of bile acid metabolism, mediated in vivo by the microbial enzymes bile salt hydrolase (BSH) and 7α-dehydroxylase, on drug solubility was assessed by comparing the solubilization capacity of (a) conjugated vs deconjugated and (b) primary vs secondary bile salts. A series of poorly water-soluble drugs (PWSDs) were selected as model solutes on the basis of an increased tendency to associate with bile micelles. Subsequently, PWSD solubility and dissolution was evaluated in conventional biorelevant simulated intestinal fluid containing host-derived bile acids, as well as in media modified to contain microbial bile acid metabolites. The findings suggest that deconjugation of the bile acid steroidal core, as dictated by BSH activity, influences micellar solubilization capacity for some PWSDs; however, these differences appear to be relatively minor. In contrast, the extent of bile acid hydroxylation, regulated by microbial 7α-dehydroxylase, was found to significantly affect the solubilization capacity of bile salt micelles for all nine drugs studied (p solubility and dissolution. Observed differences in biorelevant media appeared to be both drug- and amphiphile (bile salt/lecithin) concentration-dependent. Our studies herein indicate that bile acid modifications occurring at the host-microbe interface could lead to alterations in the capacity of intestinal bile salt micelles to solubilize drugs

  19. Structural and functional study of YER067W, a new protein involved in yeast metabolism control and drug resistance.

    Directory of Open Access Journals (Sweden)

    Tatiana Domitrovic

    2010-06-01

    Full Text Available The genome of Saccharomyces cerevisiae is arguably the best studied eukaryotic genome, and yet, it contains approximately 1000 genes that are still relatively uncharacterized. As the majority of these ORFs have no homologs with characterized sequence or protein structure, traditional sequence-based approaches cannot be applied to deduce their biological function. Here, we characterize YER067W, a conserved gene of unknown function that is strongly induced in response to many stress conditions and repressed in drug resistant yeast strains. Gene expression patterns of YER067W and its paralog YIL057C suggest an involvement in energy metabolism. We show that yeast lacking YER067W display altered levels of reserve carbohydrates and a growth deficiency in media that requires aerobic metabolism. Impaired mitochondrial function and overall reduction of ergosterol content in the YER067W deleted strain explained the observed 2- and 4-fold increase in resistance to the drugs fluconazole and amphotericin B, respectively. Cell fractionation and immunofluorescence microscopy revealed that Yer067w is associated with cellular membranes despite the absence of a transmembrane domain in the protein. Finally, the 1.7 A resolution crystal structure of Yer067w shows an alpha-beta fold with low similarity to known structures and a putative functional site.YER067W's involvement with aerobic energetic metabolism suggests the assignment of the gene name RGI1, standing for respiratory growth induced 1. Altogether, the results shed light on a previously uncharacterized protein family and provide basis for further studies of its apparent role in energy metabolism control and drug resistance.

  20. Pharmacokinetic evaluation of UK-49,858, a metabolically stable triazole antifungal drug, in animals and humans.

    Science.gov (United States)

    Humphrey, M J; Jevons, S; Tarbit, M H

    1985-11-01

    The pharmacokinetic profile of UK-49,858 (fluconazole), a novel triazole antifungal agent which is being developed for oral and intravenous use, was determined in mice, rats, dogs, and humans. Comparative data following oral and intravenous administration showed that bioavailability was essentially complete in all four species. Peak concentrations in plasma of drug normalized to a 1-mg/kg dose level following oral administration, were relatively high: 0.7, 0.6, 1.1, and 1.4 micrograms/ml in mice, rats, dogs, and humans, respectively. The volumes of distribution ranged between 1.1 liter/kg in mice and 0.7 liter/kg in humans, which are approximate to the values for total body water. Whole body autoradiography studies in mice following intravenous administration of [14C]UK-49,858 demonstrated that the drug was evenly distributed throughout the tissues, including the central nervous system and the gastrointestinal tract. Plasma protein binding was low (11 to 12%) in all species. Marked species differences were observed in elimination half-lives, with mean values of 4.8, 4.0, 14, and 22 h in mice, rats, dogs, and humans, respectively. The major route of elimination of the drug was renal clearance, with about 70% of the dose being excreted unchanged in the urine in each species. Studies with [14C]UK-49,858 on metabolism and excretion (intravenous and oral) in mice and dogs showed that about 90% of the dose was recovered as unchanged drug in urine and feces, confirming the metabolic stability of the drug. This pharmacokinetic profile is markedly different from that of imidazole antifungal drugs and undoubtedly contributes to the excellent efficacy of UK-49,858 in vivo.

  1. Health and human rights concerns of drug users in detention in Guangxi Province, China.

    Directory of Open Access Journals (Sweden)

    J Elizabeth Cohen

    2008-12-01

    Full Text Available BACKGROUND: Although confinement in drug detoxification ("detox" and re-education through labor (RTL centers is the most common form of treatment for drug dependence in China, little has been published about the experience of drug users in such settings. We conducted an assessment of the impact of detention on drug users' access to HIV prevention and treatment services and consequent threats to fundamental human rights protections. METHODS AND FINDINGS: Chinese government HIV and anti-narcotics legislation and policy documents were reviewed, and in-depth and key informant interviews were conducted with 19 injection drug users (IDUs and 20 government and nongovernmental organization officials in Nanning and Baise, Guangxi Province. Significant contradictions were found in HIV and antinarcotics policies, exemplified by the simultaneous expansion of community-based methadone maintenance therapy and the increasing number of drug users detained in detox and RTL center facilities. IDU study participants reported, on average, having used drugs for 14 y (range 8-23 y and had been confined to detox four times (range one to eight times and to RTL centers once (range zero to three times. IDUs expressed an intense fear of being recognized by the police and being detained, regardless of current drug use. Key informants and IDUs reported that routine HIV testing, without consent and without disclosure of the result, was the standard policy of detox and RTL center facilities, and that HIV-infected detainees were not routinely provided medical or drug dependency treatment, including antiretroviral therapy. IDUs received little or no information or means of HIV prevention, but reported numerous risk behaviors for HIV transmission while detained. CONCLUSIONS: Legal and policy review, and interviews with recently detained IDUs and key informants in Guangxi Province, China, found evidence of anti-narcotics policies and practices that appear to violate human rights

  2. Antibiotic-Induced Changes to the Host Metabolic Environment Inhibit Drug Efficacy and Alter Immune Function

    DEFF Research Database (Denmark)

    Yang, Jason H.; Bhargava, Prerna; McCloskey, Douglas

    2017-01-01

    Bactericidal antibiotics alter microbial metabolism as part of their lethality and can damage mitochondria in mammalian cells. In addition, antibiotic susceptibility is sensitive to extracellular metabolites, but it remains unknown whether metabolites present at an infection site can affect eithe...... the immunomodulatory potential of antibiotics and reveal the local metabolic microenvironment to be an important determinant of infection resolution....

  3. The Metabolic Inhibition Model Which Predicts the Intestinal Absorbability and Metabolizability of Drug: Theory and Experiment

    Directory of Open Access Journals (Sweden)

    Mizuma Takashi

    1998-01-01

    Full Text Available The intestinal absorption of analgesic peptides (leucine enkephalin and kyotorphin and modified peptides in rat were studied. Although these peptides were not absorbed, the absorbability (absorption clearance of these peptides were increased in the presence of peptidase inhibitors. In order to kinetically analyze these phenomena, we proposed the metabolic inhibition model, which incorporated the metabolic clearance (metabolizability with the absorption clearance. Metabolic activity was determined with intestinal homogenates. The higher the metabolic clearance was, the lower was the absorption clearance. The relationships between the absorption clearance and the metabolic clearance of the experimental data as well as of the theoretical values were hyperbolic. This model predicted the maximum absorption clearances of cellobiose-coupled leucine enkephalin (0.654 &mgr;l/min/cm and kyotorphin (0.247 &mgr;l/min/cm. Details of the experimental methods are described.

  4. ecoAO: A Simple System for the Study of Human Aldehyde Oxidases Role in Drug Metabolism.

    Science.gov (United States)

    Paragas, Erickson M; Humphreys, Sara C; Min, Joshua; Joswig-Jones, Carolyn A; Leimkühler, Silke; Jones, Jeffrey P

    2017-08-31

    Although aldehyde oxidase (AO) is an important hepatic drug-metabolizing enzyme, it remains understudied and is consequently often overlooked in preclinical studies, an oversight that has resulted in the failure of multiple clinical trials. AO's preclusion to investigation stems from the following: (1) difficulties synthesizing metabolic standards due to the chemospecificity and regiospecificity of the enzyme and (2) significant inherent variability across existing in vitro systems including liver cytosol, S9 fractions, and primary hepatocytes, which lack specificity and generate discordant expression and activity profiles. Here, we describe a practical bacterial biotransformation system, ecoAO, addressing both issues simultaneously. ecoAO is a cell paste of MoCo-producing Escherichia coli strain TP1017 expressing human AO. It exhibits specific activity toward known substrates, zoniporide, 4- trans -( N , N -dimethylamino)cinnamaldehyde, O 6 -benzylguanine, and zaleplon; it also has utility as a biocatalyst, yielding milligram quantities of synthetically challenging metabolite standards such as 2-oxo-zoniporide. Moreover, ecoAO enables routine determination of k cat and V / K , which are essential parameters for accurate in vivo clearance predictions. Furthermore, ecoAO has potential as a preclinical in vitro screening tool for AO activity, as demonstrated by its metabolism of 3-aminoquinoline, a previously uncharacterized substrate. ecoAO promises to provide easy access to metabolites with the potential to improve pharmacokinetic clearance predictions and guide drug development.

  5. Andrographis paniculata Extract and Andrographolide Modulate the Hepatic Drug Metabolism System and Plasma Tolbutamide Concentrations in Rats

    Directory of Open Access Journals (Sweden)

    Haw-Wen Chen

    2013-01-01

    Full Text Available Andrographolide is the most abundant terpenoid of A. paniculata which is used in the treatment of diabetes. In this study, we investigated the effects of A. paniculata extract (APE and andrographolide on the expression of drug-metabolizing enzymes in rat liver and determined whether modulation of these enzymes changed the pharmacokinetics of tolbutamide. Rats were intragastrically dosed with 2 g/kg/day APE or 50 mg/kg/day andrographolide for 5 days before a dose of 20 mg/kg tolbutamide was given. APE and andrographolide reduced the AUC0–12 h of tolbutamide by 37% and 18%, respectively, compared with that in controls. The protein and mRNA levels and enzyme activities of CYP2C6/11, CYP1A1/2, and CYP3A1/2 were increased by APE and andrographolide. To evaluate whether APE or andrographolide affected the hypoglycemic action of tolbutamide, high-fat diet-induced obese mice were used and treated in the same manner as the rats. APE and andrographolide increased CYP2C6/11 expression and decreased plasma tolbutamide levels. In a glucose tolerance test, however, the hypoglycemic effect of tolbutamide was not changed by APE or andrographolide. These results suggest that APE and andrographolide accelerate the metabolism rate of tolbutamide through increased expression and activity of drug-metabolizing enzymes. APE and andrographolide, however, do not impair the hypoglycemic effect of tolbutamide.

  6. Functional interrogation of Plasmodium genus metabolism identifies species- and stage-specific differences in nutrient essentiality and drug targeting

    KAUST Repository

    Abdel-Haleem, Alyaa M.

    2018-01-04

    Several antimalarial drugs exist, but differences between life cycle stages among malaria species pose challenges for developing more effective therapies. To understand the diversity among stages and species, we reconstructed genome-scale models (GEMs) of metabolism for five life cycle stages and five species of Plasmodium spanning the blood, transmission, and mosquito stages. The stage-specific models of Plasmodium falciparum uncovered stage-dependent changes in central carbon metabolism and predicted potential targets that could affect several life cycle stages. The species-specific models further highlight differences between experimental animal models and the human-infecting species. Comparisons between human- and rodent-infecting species revealed differences in thiamine (vitamin B1), choline, and pantothenate (vitamin B5) metabolism. Thus, we show that genome-scale analysis of multiple stages and species of Plasmodium can prioritize potential drug targets that could be both anti-malarials and transmission blocking agents, in addition to guiding translation from non-human experimental disease models.

  7. Application of isolated hepatocytes to studies of drug metabolism in large food animals.

    Science.gov (United States)

    Shull, L R; Kirsch, D G; Lohse, C L; Wisniewski, J A

    1987-03-01

    A definitive hazard assessment of xenobiotics translocated through food animals into edible products such as meat or milk requires a complete analysis of metabolism in food animals. However, large animal metabolism studies present many experimental difficulties. None of several in vitro alternatives such as subcellular fractions has been established as an acceptable predictor of in vivo metabolism. The feasibility of using isolated hepatocytes to predict the metabolism of xenobiotics, both quantitatively and qualitatively, in large ruminant animals (e.g. cattle) is being studied in our laboratory. A procedure was developed for isolating hepatocytes aseptically from the caudate process of the liver which was obtained surgically from 100-125 kg calves. A modified two-step vascular perfusion procedure provides hepatocyte suspensions that are typically greater than or equal to 85% viable and greater than or equal to 1 X 10(7) viable hepatocytes/g of liver (wet wt). Xenobiotic metabolism has been evaluated in suspensions and primary cultures using aldrin epoxidation, ethoxycoumarin O-deethylation, and 7-hydroxycoumarin glucuronidation and sulfation. Metabolic activities are relatively short-lived in suspensions less than or equal to 4 h, but quite stable up to 10 h when cultured on collagen-coated plates in chemically defined medium. Bovine hepatocytes behave similarly in culture to rodent hepatocytes. Although primary culturing of hepatocytes is more difficult than suspensions, primarily due to the asepsis requirements, it is the method of choice for xenobiotic metabolism determinations in isolated hepatocytes of cattle.

  8. An Exceptionally Facile Two-Step Structural Isomerization and Detoxication via a Water-Assisted Double Lossen Rearrangement

    Science.gov (United States)

    Li, Feng; Huang, Chun-Hua; Xie, Lin-Na; Qu, Na; Shao, Jie; Shao, Bo; Zhu, Ben-Zhan

    2016-01-01

    N-hydroxyphthalimide (NHPI), which is best known as an organocatalyst for efficient C-H activation, has been found to be oxidized by quinoid compounds to its corresponding catalytically active nitroxide-radical. Here, we found that NHPI can be isomerized into isatoic anhydride by an unusually facile two-step method using tetrachloro-1,4-benzoquinone (TCBQ, p-chloranil), accompanied by a two-step hydrolytic dechlorination of highly toxic TCBQ into the much less toxic dihydroxylation product, 2,5-dichloro-3,6-dihydroxy-1,4-benzoquinone (chloranilic acid). Interestingly, through the complementary application of oxygen-18 isotope-labeling, HPLC combined with electrospray ionization quadrupole time-of-flight and high resolution Fourier transform ion cyclotron resonance mass spectrometric studies, we determined that water was the source and origin of oxygen for isatoic anhydride. Based on these data, we proposed that nucleophilic attack with a subsequent water-assisted Lossen rearrangement coupled with rapid intramolecular addition and cyclization in two consecutive steps was responsible for this unusual structural isomerization of NHPI and concurrent hydroxylation/detoxication of TCBQ. This is the first report of an exceptionally facile double-isomerization of NHPI via an unprecedented water-assisted double-Lossen rearrangement under normal physiological conditions. Our findings may have broad implications for future research on hydroxamic acids and polyhalogenated quinoid carcinogens, two important classes of compounds of major chemical and biological interest. PMID:28008985

  9. Combining Potent Statin Therapy with Other Drugs to Optimize Simultaneous Cardiovascular and Metabolic Benefits while Minimizing Adverse Events.

    Science.gov (United States)

    Koh, Kwang Kon; Sakuma, Ichiro; Shimada, Kazunori; Hayashi, Toshio; Quon, Michael J

    2017-07-01

    Hypercholesterolemia and hypertension are among the most important risk factors for cardiovascular (CV) disease. They are also important contributors to metabolic diseases including diabetes that further increase CV risk. Updated guidelines emphasize targeted reduction of overall CV risks but do not explicitly incorporate potential adverse metabolic outcomes that also influence CV health. Hypercholesterolemia and hypertension have synergistic deleterious effects on interrelated insulin resistance and endothelial dysfunction. Dysregulation of the renin-angiotensin system is an important pathophysiological mechanism linking insulin resistance and endothelial dysfunction to atherogenesis. Statins are the reference standard treatment to prevent CV disease in patients with hypercholesterolemia. Statins work best for secondary CV prevention. Unfortunately, most statin therapies dose-dependently cause insulin resistance, increase new onset diabetes risk and exacerbate existing type 2 diabetes mellitus. Pravastatin is often too weak to achieve target low-density lipoprotein cholesterol levels despite having beneficial metabolic actions. Renin-angiotensin system inhibitors improve both endothelial dysfunction and insulin resistance in addition to controlling blood pressure. In this regard, combined statin-based and renin-angiotensin system (RAS) inhibitor therapies demonstrate additive/synergistic beneficial effects on endothelial dysfunction, insulin resistance, and other metabolic parameters in addition to lowering both cholesterol levels and blood pressure. This combined therapy simultaneously reduces CV events when compared to either drug type used as monotherapy. This is mediated by both separate and interrelated mechanisms. Therefore, statin-based therapy combined with RAS inhibitors is important for developing optimal management strategies in patients with hypertension, hypercholesterolemia, diabetes, metabolic syndrome, or obesity. This combined therapy can help

  10. Reduction and Scavenging of Chemically Reactive Drug Metabolites by NAD(P)H:Quinone Oxidoreductase 1 and NRH:Quinone Oxidoreductase 2 and Variability in Hepatic Concentrations

    NARCIS (Netherlands)

    den Braver-Sewradj, Shalenie P; den Braver, Michiel W; Toorneman, Robin M; van Leeuwen, Stephanie; Zhang, Yongjie; Dekker, Stefan J; Vermeulen, Nico P E; Commandeur, Jan N M; Vos, J Chris

    2018-01-01

    Detoxicating enzymes NAD(P)H:quinone oxidoreductase 1 (NQO1) and NRH:quinone oxidoreductase 2 (NQO2) catalyze the two-electron reduction of quinone-like compounds. The protective role of the polymorphic NQO1 and NQO2 enzymes is especially of interest in the liver as the major site of drug

  11. Hepatocytes--the choice to investigate drug metabolism and toxicity in man: in vitro variability as a reflection of in vivo.

    Science.gov (United States)

    Gómez-Lechón, María José; Castell, José Vicente; Donato, María Teresa

    2007-05-20

    The pharmaceutical industry is committed to marketing safer drugs with fewer side effects, predictable pharmacokinetic properties and quantifiable drug-drug interactions. Drug metabolism is a major determinant of drug clearance and interindividual pharmacokinetic differences, and an indirect determinant of the clinical efficacy and toxicity of drugs. Progressive advances in the knowledge of metabolic routes and enzymes responsible for drug biotransformation have contributed to understanding the great metabolic variations existing in human beings. Phenotypic as well genotypic differences in the expression of the enzymes involved in drug metabolism are the main causes of this variability. However, only a minor part of phenotypic variability in man is attributable to gene polymorphisms, thus making the definition of a normal liver complex. At present, the use of human in vitro hepatic models at early preclinical stages means that the process of selecting drug candidates is becoming much more rational. Cultured human hepatocytes are considered to be the closest model to human liver. However, the fact that hepatocytes are located in a microenvironment that differs from that of the cell in the liver raises the question: to what extent does drug metabolism variability observed in vitro actually reflect that of the liver in vivo? By comparing the metabolism of a model compound both in vitro and in vivo in the same individual, a good correlation between the in vitro and in vivo relative abundance of oxidized metabolites and the hydrolysis of the compound was observed. Thus, it is reasonable to consider that the variability observed in human hepatocytes reflects the existing phenotypic heterogeneity of the P450 expression in human liver.

  12. Paradigm shift - Metabolic transformation of docosahexaenoic and eicosapentaenoic acids to bioactives exemplify the promise of fatty acid drug discovery.

    Science.gov (United States)

    Halade, Ganesh V; Black, Laurence M; Verma, Mahendra Kumar

    2018-02-28

    Fatty acid drug discovery (FADD) is defined as the identification of novel, specialized bioactive mediators that are derived from fatty acids and have precise pharmacological/therapeutic potential. A number of reports indicate that dietary intake of omega-3 fatty acids and limited intake of omega-6 promotes overall health benefits. In 1929, Burr and Burr indicated the significant role of essential fatty acids for survival and functional health of many organs. In reference to specific dietary benefits of differential omega-3 fatty acids, docosahexaenoic and eicosapentaenoic acids (DHA and EPA) are transformed to monohydroxy, dihydroxy, trihydroxy, and other complex mediators during infection, injury, and exercise to resolve inflammation. The presented FADD approach describes the metabolic transformation of DHA and EPA in response to injury, infection, and exercise to govern uncontrolled inflammation. Metabolic transformation of DHA and EPA into a number of pro-resolving molecules exemplifies a novel, inexpensive approach compared to traditional, expensive drug discovery. DHA and EPA have been recommended for prevention of cardiovascular disease since 1970. Therefore, the FADD approach is relevant to cardiovascular disease and resolution of inflammation in many injury models. Future research demands identification of novel action targets, receptors for biomolecules, mechanism(s), and drug-interactions with resolvins in order to maintain homeostasis. Copyright © 2018 Elsevier Inc. All rights reserved.

  13. EFFECTS OF METABOLIC DRUG ELTACINE ON CLINICAL, FUNCTIONAL AND BIOCHEMICAL INDICES IN PATIENTS WITH CHRONIC HEART FAILURE

    Directory of Open Access Journals (Sweden)

    R. M. Zaslavskaya

    2015-12-01

    Full Text Available Aim. To study clinical efficacy of a new domestic metabolic drug Eltacine in patients with chronic heart failure (CHF.Material and methods. 134 patients with CHF of I-III functional classes were randomized in two parallel groups of patients receiving Eltacine or placebo additionally to standard therapy. Common clinical and laboratory investigations were used as well as 6-minute-walking test and Echocardiography. Besides Holter monitoring with determination of heart rate variability, peroxidal oxidation of lipids (POL and cell anti-oxidant protection were implemented.Results. Eltacine increased in tolerance to physical burden, improved cardiac haemodynamics, parameters of POL and cell anti-oxidant protection, improved the patient quality of life.Conclusion. The efficacy and safety of Eltacine as metabolic and antioxidant therapy was shown in patients with CHF.

  14. EFFECTS OF METABOLIC DRUG ELTACINE ON CLINICAL, FUNCTIONAL AND BIOCHEMICAL INDICES IN PATIENTS WITH CHRONIC HEART FAILURE

    Directory of Open Access Journals (Sweden)

    R. M. Zaslavskaya

    2007-01-01

    Full Text Available Aim. To study clinical efficacy of a new domestic metabolic drug Eltacine in patients with chronic heart failure (CHF.Material and methods. 134 patients with CHF of I-III functional classes were randomized in two parallel groups of patients receiving Eltacine or placebo additionally to standard therapy. Common clinical and laboratory investigations were used as well as 6-minute-walking test and Echocardiography. Besides Holter monitoring with determination of heart rate variability, peroxidal oxidation of lipids (POL and cell anti-oxidant protection were implemented.Results. Eltacine increased in tolerance to physical burden, improved cardiac haemodynamics, parameters of POL and cell anti-oxidant protection, improved the patient quality of life.Conclusion. The efficacy and safety of Eltacine as metabolic and antioxidant therapy was shown in patients with CHF.

  15. Manidipine: an antihypertensive drug with positive effects on metabolic parameters and adrenergic tone in patients with diabetes

    Directory of Open Access Journals (Sweden)

    Margarita SaizSatjes

    2018-01-01

    Full Text Available Antihypertensive treatment of patients with diabetes should include those drugs with a positive effect on metabolic parameters. Most patients with diabetes require at least two antihypertensive agents. Combining a dihydropyridine calcium channel blocker with a renin-angiotensin-aldosterone system inhibitor is a rational approach. However, not all dihydropyridines are equal with respect to their effects on metabolic parameters. Thus, manidipine exerts a positive effect on insulin resistance. However, this effect has not been observed with amlodipine. On the other hand, the excessive activation of sympathetic nervous system has been related with an increase of insulin resistance, pulse pressure, and ankle edema rates. Compared with amlodipine, manidipine activates sympathetic nervous system to a lesser extent. As a result, treatment with manidipine represents a good option in hypertensive patients with diabetes.

  16. Atrazine Metabolism and Herbicidal Selectivity

    Science.gov (United States)

    Shimabukuro, R. H.

    1967-01-01

    Metabolism of the herbicide 2-chloro-4-ethylamino-6-isopropylamino-s-triazine (atrazine) was investigated in resistant corn (Zea mays L.) and sorghum (Sorghum vulgare Pers.), intermediately susceptible pea (Pisum sativum L.), and highly susceptible wheat (Triticum vulgare Vill.) and soybean (Glycine max Merril.). This study revealed that 2 possible pathways for atrazine metabolism exist in higher plants. All species studied were able to metabolize atrazine initially by N-dealkylation of either of the 2 substituted alkylamine groups. Corn and wheat, which contain benzoxazinone, also metabolized atrazine initially by hydrolysis in the 2-position of the s-triazine ring to form hydroxyatrazine. Subsequent metabolism by both pathways resulted in the conversion of the parent atrazine to more polar compounds and eventually into methanol-insoluble plant residue. No evidence for s-triazine ring cleavage was obtained. Both pathways for atrazine metabolism appear to detoxify atrazine. The hydroxylation pathway results in a direct conversion of a highly phytotoxic compound to a completely non-phytotoxic derivative. The dealkylation pathway leads to detoxication through one or more partially detoxified, stable intermediates. Therefore, the rate and pathways of atrazine metabolism are important in determining the tolerance of plants to the herbicide. Both quantitative and qualitative differences in atrazine metabolism were detected between resistant, intermediately susceptible, and susceptible species. The ability of plants to metabolize atrazine by N-dealkylation and the influence of this pathway in determining tolerance of plants to atrazine are discussed. Images PMID:16656648

  17. Consumption of poisonous plants (Senecio jacobaea, Symphytum officinale, Pteridium aquilinum, Hypericum perforatum) by rats: chronic toxicity, mineral metabolism, and hepatic drug-metabolizing enzymes.

    Science.gov (United States)

    Garrett, B J; Cheeke, P R; Miranda, C L; Goeger, D E; Buhler, D R

    1982-02-01

    Effect of dietary tancy ragwort (Senecio jacobaea), comfrey (Symphytum officinale), bracken (Pteridium aquilinum) and alfalfa (Medicago sativa) on hepatic drug-metabolizing enzymes in rats were measured. Tansy ragwort and bracken increased (P less than 0.05) the activity of glutathione transferase and epoxide hydrolase. Comfrey and alfalfa increased (P less than 0.05) the activity of aminopyrine N-demethylase. Feeding bracken or St. John's wort (Hypericum perforatum) in conjunction with tansy ragwort did not influence chronic toxicity of tansy ragwort as assessed by rat survival time. Dietary tansy ragwort resulted in increased (P less than 0.05) hepatic copper levels; the other plants did not affect copper levels. The results do not suggest any major interaction in the toxicity of tansy ragwort with bracken or St. John's wort.

  18. Effect of Methamphetamine on Spectral Binding, Ligand Docking and Metabolism of Anti-HIV Drugs with CYP3A4

    Science.gov (United States)

    Ande, Anusha; Wang, Lei; Vaidya, Naveen K.; Li, Weihua; Kumar, Santosh; Kumar, Anil

    2016-01-01

    Cytochrome P450 3A4 (CYP3A4) is the major drug metabolic enzyme, and is involved in the metabolism of antiretroviral drugs, especially protease inhibitors (PIs). This study was undertaken to examine the effect of methamphetamine on the binding and metabolism of PIs with CYP3A4. We showed that methamphetamine exhibits a type I spectral change upon binding to CYP3A4 with δAmax and KD of 0.016±0.001 and 204±18 μM, respectively. Methamphetamine-CYP3A4 docking showed that methamphetamine binds to the heme of CYP3A4 in two modes, both leading to N-demethylation. We then studied the effect of methamphetamine binding on PIs with CYP3A4. Our results showed that methamphetamine alters spectral binding of nelfinavir but not the other type I PIs (lopinavir, atazanavir, tipranavir). The change in spectral binding for nelfinavir was observed at both δAmax (0.004±0.0003 vs. 0.0068±0.0001) and KD (1.42±0.36 vs.2.93±0.08 μM) levels. We further tested effect of methamphetamine on binding of 2 type II PIs; ritonavir and indinavir. Our results showed that methamphetamine alters the ritonavir binding to CYP3A4 by decreasing both the δAmax (0.0038±0.0003 vs. 0.0055±0.0003) and KD (0.043±0.0001 vs. 0.065±0.001 nM), while indinavir showed only reduced KD in presence of methamphetamine (0.086±0.01 vs. 0.174±0.03 nM). Furthermore, LC-MS/MS studies in high CYP3A4 human liver microsomes showed a decrease in the formation of hydroxy ritonavir in the presence of methamphetamine. Finally, CYP3A4 docking with lopinavir and ritonavir in the absence and presence of methamphetamine showed that methamphetamine alters the docking of ritonavir, which is consistent with the results obtained from spectral binding and metabolism studies. Overall, our results demonstrated differential effects of methamphetamine on the binding and metabolism of PIs with CYP3A4. These findings have clinical implication in terms of drug dose adjustment of antiretroviral medication, especially with ritonavir

  19. Development of an in vitro assay for the investigation of metabolism-induced drug hepatotoxicity

    DEFF Research Database (Denmark)

    Otto, Marie; Hansen, Steen Honore'; Dalgaard, L.

    2008-01-01

    the cytotoxicity of diclofenac was increased by S9 enzymes when an NADPH regenerating system was used. The increased toxicity was NADPH dependent. Reactive drug metabolites of diclofenac, formed by NADPH-dependent metabolism, were identified by LC-MS. Furthermore, an increase in toxicity, not related to enzymatic...... activity but to G6P, was observed for diclofenac and minocycline. Tacrine and amodiaquine displayed decreased toxicity with S9-mix, and carbamazepine, phenytoin, bromfenac and troglitazone were nontoxic at all tested concentrations, with or without S9-mix. The results show that this method...

  20. Possible drug-metabolism interactions of medicinal herbs with antiretroviral agents.

    NARCIS (Netherlands)

    Beukel, C.J.P. van den; Koopmans †, P.P.; Ven, A.J.A.M. van der; Smet, P.A.G.M. de; Burger, D.M.

    2006-01-01

    Herbal medicines are widely used by HIV patients. Several herbal medicines have been shown to interact with antiretroviral drugs, which might lead to drug failure. We have aimed to provide an overview of the modulating effects of Western and African herbal medicines on antiretroviral

  1. 76 FR 80948 - Endocrinologic and Metabolic Drugs Advisory Committee; Notice of Meeting

    Science.gov (United States)

    2011-12-27

    ..., Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 31...., as an adjunct to diet and exercise for weight management in patients with a body mass index (BMI) equal to or greater than 30 kilograms (kg) per square meter or a BMI equal to or greater than 27 kg per...

  2. Ex vivo preparations of human tissue for drug metabolism, toxicity and transport

    NARCIS (Netherlands)

    Groothuis, Genoveva

    2012-01-01

    Before new drugs are allowed on the market, their safety and metabolite profile should be extensively tested, as often reactive metabolites are the ultimate toxicant. The exposure of the target cell to the drug and its metabolites is determined by the expression levels of the transporters and the

  3. Development of Metabolic Syndrome in Drug-Naive Adolescents After 12 Months of Second-Generation Antipsychotic Treatment

    DEFF Research Database (Denmark)

    Sjo, Christina Power; Stenstrøm, Anne Dorte; Bojesen, Anders Bo

    2017-01-01

    if obesity or metabolic aberration starts in childhood or adolescence. METHODS: Drug-naive adolescents were recruited after contact with an outpatient Psychosis Team. Changes relative to baseline in body mass index (BMI), waist circumference (WC), blood pressure (BP), fasting blood glucose (FBG...... months the participants' BMI had increased from 0.5 to 1.57 standard deviation (SD) above the 50th percentile for age and gender (p = 0.0001). CONCLUSION: To our knowledge, this is the first study to include all the aspects of MetS in a sample of drug-naive adolescents followed over the first 12 months...... after starting SGA treatment. A significant shift in all parameters (except BP) toward MetS was found, presumably due to SGA use. Therefore, these adolescents will need proper follow-up, consisting of not only monitoring but also preventive measures to diminish these effects of SGA use....

  4. Effects of meal composition and meal timing on the expression of genes involved in hepatic drug metabolism in rats.

    Science.gov (United States)

    de Vries, E M; Oosterman, J E; Eggink, H M; de Goede, P; Sen, S; Foppen, E; Boudzovitch-Surovtseva, O; Boelen, A; Romijn, J A; laFleur, S E; Kalsbeek, A

    2017-01-01

    With chronotherapy, drug administration is synchronized with daily rhythms in drug clearance and pharmacokinetics. Daily rhythms in gene expression are centrally mastered by the suprachiasmatic nucleus of the hypothalamus as well as by tissue clocks containing similar molecular mechanisms in peripheral organs. The central timing system is sensitive to changes in the external environment such as those of the light-dark cycle, meal timing and meal composition. We investigated how changes in diet composition and meal timing would affect the daily hepatic expression rhythms of the nuclear receptors PXR and CAR and of enzymes involved in P450 mediated drug metabolism, as such changes could have consequences for the practice of chronotherapy. Rats were subjected to either a regular chow or a free choice high-fat-high-sugar (fcHFHS) diet. These diets were provided ad libitum, or restricted to either the light phase or the dark phase. In a second experiment, rats had access to chow either ad libitum or in 6 meals equally distributed over 24 hours. Pxr, Alas1 and Por displayed significant day-night rhythms under ad libitum chow fed conditions, which for Pxr was disrupted under fcHFHS diet conditions. Although no daily rhythms were detected in expression of CAR, Cyp2b2 and Cyp3a2, the fcHFHS diet did affect basal expression of these genes. In chow fed rats, dark phase feeding induced a diurnal rhythm in Cyp2b2 expression while light phase feeding induced a diurnal rhythm in Car expression and completely shifted the peak expression of Pxr, Car, Cyp2b2, Alas1 and Por. The 6-meals-a-day feeding only abolished the Pxr rhythm but not the rhythms of the other genes. We conclude that although nuclear receptors and enzymes involved in the regulation of hepatic drug metabolism are sensitive to meal composition, changes in meal timing are mainly effectuated via changes in the molecular clock.

  5. Probenecid interferes with renal oxidative metabolism: A potential pitfall in its use as an inhibitor of drug transport

    Science.gov (United States)

    Masereeuw, Rosalinde; van Pelt, Ard P; van Os, Sandra H G; Willems, Peter H G M; Smits, Paul; Russel, Frans G M

    2000-01-01

    The anionic drug probenecid has been traditionally used as an inhibitor of renal organic anion transport. More recently the drug was found to inhibit organic cation transport as well, and it is used to retain intracellularly loaded fluorophores. In these investigations it is implicitly assumed that probenecid performs its activity through competition for transport. Here we studied the possibility that probenecid provokes its effect through inhibition of cellular oxidative metabolism. Oxygen consumption was measured in isolated rat kidney cortex mitochondria. At concentrations of 1 mM or higher, probenecid increased the resting state (state 4) and decreased the ADP-stimulated respiration (state 3). A complete loss in respiratory control was observed at 10 mM probenecid. After incubating isolated rat kidney proximal tubular cells (PTC) for 30 min with probenecid a concentration-dependent reduction in ATP content was observed, which was significant at concentrations of 1 mM and higher. Using digital image fluorescence microscopy the membrane potential in PTC was measured with bisoxonol. The mitochondrial effects of probenecid were paralleled by a depolarization of the plasma membrane, immediately after drug addition. All events are likely to be a result of membrane disordering due to the lipophilic character of probenecid, and may explain, at least in part, the various inhibitory effects found for the drug. We recommend to be cautious with applying probenecid in cellular research. PMID:10960069

  6. A novel metabolism-based phenotypic drug discovery platform in zebrafish uncovers HDACs 1 and 3 as a potential combined anti-seizure drug target.

    Science.gov (United States)

    Ibhazehiebo, Kingsley; Gavrilovici, Cezar; de la Hoz, Cristiane L; Ma, Shun-Chieh; Rehak, Renata; Kaushik, Gaurav; Meza Santoscoy, Paola L; Scott, Lucas; Nath, Nandan; Kim, Do-Young; Rho, Jong M; Kurrasch, Deborah M

    2018-01-24

    Despite the development of newer anti-seizure medications over the past 50 years, 30-40% of patients with epilepsy remain refractory to treatment. One explanation for this lack of progress is that the current screening process is largely biased towards transmembrane channels and receptors, and ignores intracellular proteins and enzymes that might serve as efficacious molecular targets. Here, we report the development of a novel drug screening platform that harnesses the power of zebrafish genetics and combines it with in vivo bioenergetics screening assays to uncover therapeutic agents that improve mitochondrial health in diseased animals. By screening commercially available chemical libraries of approved drugs, for which the molecular targets and pathways are well characterized, we were able to reverse-identify the proteins targeted by efficacious compounds and confirm the physiological roles that they play by utilizing other pharmacological ligands. Indeed, using an 870-compound screen in kcna1-morpholino epileptic zebrafish larvae, we uncovered vorinostat (Zolinza™; suberanilohydroxamic acid, SAHA) as a potent anti-seizure agent. We further demonstrated that vorinostat decreased average daily seizures by ∼60% in epileptic Kcna1-null mice using video-EEG recordings. Given that vorinostat is a broad histone deacetylase (HDAC) inhibitor, we then delineated a specific subset of HDACs, namely HDACs 1 and 3, as potential drug targets for future screening. In summary, we have developed a novel phenotypic, metabolism-based experimental therapeutics platform that can be used to identify new molecular targets for future drug discovery in epilepsy. © The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain.

  7. Quantitative dynamic nuclear polarization‐NMR on blood plasma for assays of drug metabolism

    DEFF Research Database (Denmark)

    Lerche, Mathilde Hauge; Meier, Sebastian; Jensen, Pernille Rose

    2011-01-01

    ‐NMR determinations were performed without analyte derivatization or sample purification other than plasma protein precipitation. Quantitative DNP‐NMR is an emerging methodology which requires little sample preparation and yields quantitative data with high sensitivity for therapeutic drug monitoring. Copyright......Analytical platforms for the fast detection, identification and quantification of circulating drugs with a narrow therapeutic range are vital in clinical pharmacology. As a result of low drug concentrations, analytical tools need to provide high sensitivity and specificity. Dynamic nuclear...... polarization‐NMR (DNP‐NMR) in the form of the hyperpolarization–dissolution method should afford the sensitivity and spectral resolution for the direct detection and quantification of numerous isotopically labeled circulating drugs and their metabolites in single liquid‐state NMR transients. This study...

  8. DMET™ (Drug-Metabolizing Enzymes and Transporters) microarray analysis of colorectal cancer patients with severe 5-fluorouracil-induced toxicity.

    Science.gov (United States)

    Rumiato, Enrica; Boldrin, Elisa; Amadori, Alberto; Saggioro, Daniela

    2013-08-01

    5-fluorouracil (5-FU) has been widely used since the 1980s, and it remains the backbone of many chemotherapeutic combination regimens. However, its use is often limited by the occurrence of severe toxicity. Although several reports have shown the detrimental effect of some dihydropyrimidine dehydrogenase (DPYD) and thymidylate synthase (TYMS) gene polymorphisms in patients undergoing 5-FU-based treatment, they account for only a minority of toxicities. Looking for new candidate genetic variants associated with 5-FU-induced toxicity, we used the innovative genotyping microarray Affymetrix Drug-Metabolizing Enzymes and Transporters (DMET)™ Plus GeneChip that interrogates 1,936 genetic variants distributed in 231 genes involved in drug metabolism, excretion, and transport. To reduce variability, we analyzed samples from colorectal cancer patients who underwent fairly homogenous treatments (i.e., Machover or Folfox) and experienced G3 or G4 toxicity; control patients were matched for therapy and selected from those who did not disclose toxicity (G0-G1). Pharmacogenetic genotyping showed no significant difference in DPYD and TYMS genetic variants distribution between cases and controls. However, other polymorphisms could account for 5-FU-induced toxicity, with the CHST1 rs9787901 and GSTM3 rs1799735 having the strongest association. Although exploratory, this study suggests that genetic polymorphisms not directly related to 5-FU pharmacokinetics and pharmacodynamics are involved in 5-FU-induced toxicity. Our data also indicates DMET™ microarray as a valid approach to discover new genetic determinants influencing chemotherapy-induced toxicity.

  9. A Metabolic Study on the Biochemical Effects of Chiral Illegal Drugs in Rats Using1H-NMR Spectroscopy.

    Science.gov (United States)

    Fukuhara, Kiyoshi; Ohno, Akiko; Kikura-Hanajiri, Ruri

    2017-01-01

    Considering the pharmacological effects of chiral drugs, enantiopure drugs may differ from their racemic mixture formulation in efficacy, potency, or adverse effects. Levomethorphan (LVM) and Dextromethorphan (DXM) act on the central nervous system and exhibit different pharmacological features. LVM, the l-stereoisomer of methorphan, shows many similarities to opiates such as heroin, morphine and codeine, including the potential for addiction, while the d-stereoisomer, DXM, does not have the same opioid effect. In the present study, NMR-based metabolomics were performed on the urine of rats treated with these stereoisomers, and showed significant differences in metabolic profiles. In urine within 24 h after treatment of these samples, levels of citrate, 2-oxoglutarate, creatine, and dimethylglycine were higher in LVM-treated rats than in DXM-treated rats. While urinary levels of hippurate and creatinine gradually increased over 72 h in DXM-treated rats, these metabolites were decreased in the urine by 48-72 h after treatment with LVM. The levels of these changed metabolites may provide the first evidence for different cellular responses to the metabolism of stereoisomers.

  10. Quantum Mechanics/Molecular Mechanics Modeling of Drug Metabolism: Mexiletine N-Hydroxylation by Cytochrome P450 1A2.

    Science.gov (United States)

    Lonsdale, Richard; Fort, Rachel M; Rydberg, Patrik; Harvey, Jeremy N; Mulholland, Adrian J

    2016-06-20

    The mechanism of cytochrome P450(CYP)-catalyzed hydroxylation of primary amines is currently unclear and is relevant to drug metabolism; previous small model calculations have suggested two possible mechanisms: direct N-oxidation and H-abstraction/rebound. We have modeled the N-hydroxylation of (R)-mexiletine in CYP1A2 with hybrid quantum mechanics/molecular mechanics (QM/MM) methods, providing a more detailed and realistic model. Multiple reaction barriers have been calculated at the QM(B3LYP-D)/MM(CHARMM27) level for the direct N-oxidation and H-abstraction/rebound mechanisms. Our calculated barriers indicate that the direct N-oxidation mechanism is preferred and proceeds via the doublet spin state of Compound I. Molecular dynamics simulations indicate that the presence of an ordered water molecule in the active site assists in the binding of mexiletine in the active site, but this is not a prerequisite for reaction via either mechanism. Several active site residues play a role in the binding of mexiletine in the active site, including Thr124 and Phe226. This work reveals key details of the N-hydroxylation of mexiletine and further demonstrates that mechanistic studies using QM/MM methods are useful for understanding drug metabolism.

  11. Polymorphisms in genes encoding drug metabolizing enzymes and their influence on the outcome of children with neuroblastoma.

    Science.gov (United States)

    Ashton, Lesley J; Murray, Jayne E; Haber, Michelle; Marshall, Glenn M; Ashley, David M; Norris, Murray D

    2007-09-01

    Although several studies have shown that drug metabolizing enzyme gene polymorphisms may influence the impact of therapy in childhood leukemia, no comprehensive investigations have been carried out in children with neuroblastoma. The aim of this study was to identify polymorphisms in the genes encoding phase I and II drug metabolizing enzymes associated with the risk of relapse or death in a cohort of 209 children with neuroblastoma. Real-time PCR allelic discrimination was used to characterize the presence of polymorphisms in DNA from children with neuroblastoma. Three broad gene categories were examined: cytochrome P450, glutathione-S-transferase and N-acetyltransferase. Cumulative event-free survival was computed by the Kaplan-Meier method. The influence of selected factors on event-free survival was tested using the Cox proportional hazards model. As previously reported, amplification of MYCN (hazards ratio=4.25, 95% confidence interval=2.76-6.56, Pchildren who were GSTM1 null were more likely to relapse or die during follow-up after adjusting for MYCN amplification, stage and age at diagnosis (hazard ratio=1.6, 95% confidence interval=1.02-2.9, P=0.04). These observations suggest that the NAT1*11 variant and the GSTM1 wild-type genotype contribute to a more favorable outcome in patients treated for neuroblastoma and are the first to demonstrate a relationship between NAT1 and GSTM1 genotypes in childhood neuroblastoma.

  12. Fast Metabolic Response to Drug Intervention Through Analysis on a Miniaturized, Highly Integrated Molecular Imaging System

    OpenAIRE

    Wang, Jun; Hwang, Kiwook; Braas, Daniel; Dooraghi, Alex; Nathanson, David; Campbell, Dean O.; Gu, Yuchao; Sandberg, Troy; Mischel, Paul; Radu, Caius; Chatziioannou, Arion F.; Phelps, Michael E.; Christofk, Heather; Heath, James R.

    2013-01-01

    We report on a radiopharmaceutical imaging platform designed to capture the kinetics of cellular responses to drugs. Methods: A portable in vitro molecular imaging system comprising a microchip and a β-particle imaging camera permitted routine cell-based radioassays of small numbers of either suspended or adherent cells. We investigated the kinetics of responses of model lymphoma and glioblastoma cancer cell lines to ^(18)F-FDG uptake after drug exposure. Those responses were correlated with ...

  13. A Comparison of Psychotomimetic Drug Effects on Rat Brain Norepinephrine Metabolism

    Science.gov (United States)

    1973-02-19

    Thor. 189: 42-50,1974. V The effects of LSD, psilocybin, mescaline, amphetamine and cold water swimming stress on the metabolism of ’H-norepinephrine...to ef- C.ARR, L. A. AND Mooc , K E.: Norepincphrinv: 50 STOLK ET AL. Vol. 189’ Release from brain by d-amphetamine in vivo. SMITH, C. B.: Effects of d

  14. Novel small molecule drugs inhibit tumor cell metabolism and show potent anti-tumorigenic potential

    DEFF Research Database (Denmark)

    Trojel-Hansen, Christina; Erichsen, Kamille Dumong; Christensen, Mette Knak

    2011-01-01

    oxyphenisatine analogs TOP001 and TOP216 exert their anti-cancer effect by affecting tumor cell metabolism and inducing intracellular amino acid deprivation, leading to a block of cell proliferation. GCN2-mediated phosphorylation of eIF2a as well as mTOR pathway inhibition supports the above notion. In addition...

  15. Novel small molecule drugs inhibit tumor cell metabolism and show potent anti-tumorigenic potential

    DEFF Research Database (Denmark)

    Trojel-Hansen, Christina; Erichsen, Kamille Dumong; Christensen, Mette Knak

    2011-01-01

    oxyphenisatine analogs TOP001 and TOP216 exert their anti-cancer effect by affecting tumor cell metabolism and inducing intracellular amino acid deprivation, leading to a block of cell proliferation. GCN2-mediated phosphorylation of eIF2α as well as mTOR pathway inhibition supports the above notion. In addition...

  16. Regulation of Brain Glucose Metabolic Patterns by Protein Phosphorlyation and Drug Therapy

    Science.gov (United States)

    2007-03-30

    Bipolar GLU cell • ®.-. GLN Figure 3. Diagrammatic representation ofthe metabolic stuttering oflactate between glia and photoreceptors in the retina...film. Films were digitized and the resulting images were analyzed using ImageJ software . Two Dimensional Gel Electrophoresis Rat brain mitochondria were

  17. Expression of two drug-metabolizing cytochrome P450-enzymes in human salivary glands

    DEFF Research Database (Denmark)

    Kragelund, C; Hansen, C; Torpet, L A

    2008-01-01

    OBJECTIVE: The oral cavity is constantly lubricated by saliva and even small amounts of xenobiotics and / or their metabolites in the saliva may affect the oral mucosa. Our aim was therefore to clarify if xenobiotic metabolizing enzymes CYP1A2 and CYP3A4 are expressed in salivary glands. METHODS...

  18. The influence of starvation upon hepatic drug metabolism in rats, mice, and guinea pigs.

    Science.gov (United States)

    Furner, R. L.; Feller, D. D.

    1971-01-01

    Male rats, mice, and guinea pigs were starved for 1, 2, or 3 days, and the metabolism of ethylmorphine, p-nitroanisole, and aniline was studied. Results suggest that the oxidative enzyme systems studied are not interdependent, and the pathways studied appear to be species dependent.

  19. 78 FR 63224 - Endocrinologic and Metabolic Drugs Advisory Committee; Notice of Meeting

    Science.gov (United States)

    2013-10-23

    ... treatment of Mucopolysaccharidosis Type IVA (Morquio A syndrome). Morquio A syndrome is a rare congenital disorder caused by the absence or malfunctioning of an enzyme involved in an important metabolic pathway... scheduled open public hearing session, FDA may conduct a lottery to determine the speakers for the scheduled...

  20. 78 FR 64956 - Endocrinologic and Metabolic Drugs Advisory Committee; Notice of Meeting

    Science.gov (United States)

    2013-10-30

    ... treatment of metabolic disorders associated with lipodystrophy, including diabetes mellitus and/or... than can be reasonably accommodated during the scheduled open public hearing session, FDA may conduct a... 7 days in advance of the meeting. FDA is committed to the orderly conduct of its advisory committee...

  1. FGF21 as a mediator of adaptive responses to stress and metabolic benefits of anti-diabetic drugs.

    Science.gov (United States)

    Kim, Kook Hwan; Lee, Myung-Shik

    2015-07-01

    Most hormones secreted from specific organs of the body in response to diverse stimuli contribute to the homeostasis of the whole organism. Fibroblast growth factor 21 (FGF21), a hormone induced by a variety of environmental or metabolic stimuli, plays a crucial role in the adaptive response to these stressful conditions. In addition to its role as a stress hormone, FGF21 appears to function as a mediator of the therapeutic effects of currently available drugs and those under development for treatment of metabolic diseases. In this review, we highlight molecular mechanisms and the functional importance of FGF21 induction in response to diverse stress conditions such as changes of nutritional status, cold exposure, and exercise. In addition, we describe recent findings regarding the role of FGF21 in the pathogenesis and treatment of diabetes associated with obesity, liver diseases, pancreatitis, muscle atrophy, atherosclerosis, cardiac hypertrophy, and diabetic nephropathy. Finally, we discuss the current understanding of the actions of FGF21 as a crucial regulator mediating beneficial metabolic effects of therapeutic agents such as metformin, glucagon/glucagon-like peptide 1 analogues, thiazolidinedione, sirtuin 1 activators, and lipoic acid. © 2015 Society for Endocrinology.

  2. Effects of lemongrass oil and citral on hepatic drug-metabolizing enzymes, oxidative stress, and acetaminophen toxicity in rats

    Directory of Open Access Journals (Sweden)

    Chien-Chun Li

    2018-01-01

    Full Text Available The essential oil from a lemongrass variety of Cymbopogon flexuosus [lemongrass oil (LO] is used in various food and aroma industry products and exhibits biological activities, such as anticancer and antimicrobial activities. To investigate the effects of 200 LO (200 mg/kg and 400 LO (400 mg/kg and its major component, citral (240 mg/kg, on drug-metabolizing enzymes, oxidative stress, and acetaminophen toxicity in the liver, male Sprague-Dawley rats were fed a pelleted diet and administered LO or citral by gavage for 2 weeks. After 2 weeks of feeding, the effects of LO and citral on the metabolism and toxicity of acetaminophen were determined. The results showed that rats treated with 400 LO or citral had significantly reduced hepatic testosterone 6β-hydroxylation and ethoxyresorufin O-deethylation activities. In addition, NAD(PH:quinone oxidoreductase 1 activity was significantly increased by citral, and Uridine 5′-diphospho (UDP glucurosyltransferase activity was significantly increased by 400 LO in the rat liver. Treatment with 400 LO or citral reduced lipid peroxidation and reactive oxygen species levels in the liver. After acetaminophen treatment, however, LO and citral treatment resulted in little or no change in plasma alanine aminotransferase activity and acetaminophen-protein adducts content in the liver. Our results indicate that LO and citral may change the activities of drug-metabolizing enzymes and reduce oxidative stress in the liver. However, LO and citral may not affect the detoxification of acetaminophen.

  3. Genome-scale reconstruction of the Streptococcus pyogenes M49 metabolic network reveals growth requirements and indicates potential drug targets

    NARCIS (Netherlands)

    Levering, J.; Fiedler, T.; Sieg, A.; van Grinsven, K.W.A.; Hering, S.; Veith, N.; Olivier, B.G.; Klett, L.; Hugenholtz, J.; Teusink, B.; Kreikemeyer, B.; Kummer, U.

    2016-01-01

    Genome-scale metabolic models comprise stoichiometric relations between metabolites, as well as associations between genes and metabolic reactions and facilitate the analysis of metabolism. We computationally reconstructed the metabolic network of the lactic acid bacterium Streptococcus pyogenes

  4. Metabolic acidosis, hypoglycemia, and severe myalgias: an attempt to mask urine drug screen results.

    Science.gov (United States)

    Arcinegas-Rodriguez, Silvana; Gaspers, Mary Glas; Lowe, Merlin Channing

    2011-04-01

    Adolescent use of illicit substances remains a significant problem. In attempts to hide their use of these substances, some are using Internet-recommended methods of masking these drugs on drug screens, potentially exposing the adolescent to severe and possibly dangerous adverse effects. We report a 16-year-old patient who ingested approximately 13 g (twenty-six 500-mg tablets) of niacin during a 48-hour period in an attempt to mask his use of tetrahydrocannabinol on an upcoming drug screen. He subsequently developed severe chest and abdominal pain as well as extreme diffuse myalgias (previously unreported in association with niacin use). In addition, he developed severe hypoglycemia, acidosis, transaminitis, and coagulopathy. He required significant fluid resuscitation and bicarbonate infusion. Over approximately 5 days his symptoms resolved and he ultimately did well. Given increasingly available home drug screens and the abundance of false information readily available to adolescents via the Internet regarding "masking" of drug use, it is likely that cases such as ours will become more prevalent. Pediatric emergency physicians and pediatricians should maintain a high suspicion for use of niacin or other substances to obscure detection of illicit substances when patients present with symptoms similar to those of our patient. Copyright © 2011 by Lippincott Williams & Wilkins

  5. Nutritional modulation of intestinal drug-metabolizing cytochrome P450 by butyrate of different origin in chicken.

    Science.gov (United States)

    Kulcsár, Anna; Mátis, Gábor; Molnár, Andor; Petrilla, Janka; Wágner, László; Fébel, Hedvig; Husvéth, Ferenc; Dublecz, Károly; Neogrády, Zsuzsanna

    2017-08-01

    Intestinal cytochrome P450 (CYP) enzymes play key role in the first pass metabolism of orally ingested xenobiotics, providing a primary metabolic barrier, being of special importance in maintaining animal health and production. This study was aimed to investigate how intestinal drug-metabolizing CYPs can be modulated by nutritional factors in broiler chicken. We investigated the effects of the natural growth promoter (n-)butyrate of different origin (feed supplementation of protected or non-protected forms and/or inducing caecal microbial production by supporting higher level of dietary non-starch polysaccharides [NSP]) on the activity of duodenal CYPs. To observe the connection between intestinal CYP activity and butyrate concentration, the distribution of differently originated butyrate was also assessed by measuring its concentration in various intestinal segments and different vessels of portal and systemic circulation. Butyrate of different origin showed varying distribution properties as being absorbed from different parts of the gastrointestinal tract. Intestinal CYP1A and CYP2H2 activities were increased by dietary butyrate supplementation and by the increased caecal microbial butyrate production, while CYP3A37 activity was minimally influenced by microbial butyrate only. The present study proved that both dietary and microbial butyrate could alter the activity of CYPs in the duodenal epithelium. Our findings suggest that intestinal CYPs could be induced not only by the intestinal luminal butyrate, but also from basolateral side, by the already absorbed butyrate. Such action of butyrate can be of special importance from food safety and pharmacotherapeutic point of view as it may modify the metabolism and intestinal kinetics of simultaneously applied xenobiotics. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Brain Aging and Disorders of the Central Nervous System: Kynurenines and Drug Metabolism.

    Science.gov (United States)

    Török, Nóra; Majláth, Zsófia; Fülöp, Ferenc; Toldi, József; Vécsei, László

    2016-01-01

    The kynurenine pathway includes several neuroactive compounds, including kynurenic acid, picolinic acid, 3-hydroxykynurenine and quinolinic acid. The enzymatic cascade of the kynurenine pathway is tightly connected with the immune system, and may provide a link between the immune system and neurotransmission. Main Areas Covered: Alterations in this cascade are associated with neurodegenerative, neurocognitive, autoimmune and psychiatric disorders, such as Parkinson's disease, Huntington's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, migraine or schizophrenia. This review highlights the alterations in this metabolic pathway in the physiological aging process and in different disorders. A survey is also presented of therapeutic possibilities of influencing this metabolic route, which can be achieved through the use of synthetic kynurenic acid analogues, enzyme inhibitors or even nanotechnology.

  7. Accelerating the semisynthesis of alkaloid-based drugs through metabolic engineering.

    Science.gov (United States)

    Ehrenworth, Amy M; Peralta-Yahya, Pamela

    2017-02-15

    Alkaloid-derived pharmaceuticals are commonly semisynthesized from plant-extracted starting materials, which often limits their availability and final price. Recent advances in synthetic biology have enabled the introduction of complete plant pathways into microbes for the production of plant alkaloids. Microbial production of modified alkaloids has the potential to accelerate the semisynthesis of alkaloid-derived drugs by providing advanced intermediates that are structurally closer to the final pharmaceuticals and could be used as advanced intermediates for the synthesis of novel drugs. Here, we analyze the scientific and engineering challenges that must be overcome to generate microbes to produce modified plant alkaloids that can provide more suitable intermediates to US Food and Drug Administration-approved pharmaceuticals. We highlight modified alkaloids that currently could be produced by leveraging existing alkaloid microbial platforms with minor variations to accelerate the semisynthesis of seven pharmaceuticals on the market.

  8. ROLE OF NON-DRUG THERAPIES OF METABOLIC SYNDROME: CHALLENGES AND PROSPECTS

    OpenAIRE

    S. N. Strelkova; K. V. Ovsyannicov; N. I. Utkina

    2016-01-01

    Abdominal obesity (and the closely related metabolic syndrome) is one of the most common diseases in the world. The urgency of the problem of the progression of abdominal obesity is not only in its high prevalence, but also in the formation of a high risk of developing cardiovascular disease and diabetes type 2. The main reasons for the rapid development of obesity are considered high-calorie food (which includes not only the quantity but also the quality of edible products), sedentary lifest...

  9. The Anti-Oxidant Drug Tempol Promotes Functional Metabolic Changes in the Gut Microbiota

    Science.gov (United States)

    Cai, Jingwei; Zhang, Limin; Jones, Richard A.; Correll, Jared B.; Hatzakis, Emmanuel; Smith, Philip B.; Gonzalez, Frank J.; Patterson, Andrew D.

    2016-01-01

    Recent studies have identified the important role of the gut microbiota in the pathogenesis and progression of obesity and related metabolic disorders. The antioxidant tempol was shown to prevent or reduce weight gain and modulate the gut microbiota community in mice; however, the mechanism by which tempol modulates weight gain/loss with respect to the host and gut microbiota has not been clearly established. Here we show that tempol (0, 1, 10, and 50 mg/kg p.o. for 5 days) decreased cecal bacterial fermentation and increased fecal energy excretion in a dose-dependent manner. Liver 1H NMR-based metabolomics identified a dose-dependent decrease in glycogen and glucose, enhanced glucogenic and ketogenic activity (tyrosine and phenylalanine), and increased activation of the glycolysis pathway. Serum 1H NMR-based metabolomics indicated that tempol promotes enhanced glucose catabolism. Hepatic gene expression was significantly altered as demonstrated by an increase in Pepck and G6pase and a decrease in Hnf4a, ChREBP, Fabp1, and Cd36 mRNAs. No significant change in the liver and serum metabolomic profiles were observed in germ-free mice thus establishing a significant role for the gut microbiota in mediating the beneficial metabolic effects of tempol. These results demonstrate that tempol modulates the gut microbial community and its function resulting in reduced host energy availability and a significant shift in liver metabolism towards a more catabolic state. PMID:26696396

  10. Antioxidant Drug Tempol Promotes Functional Metabolic Changes in the Gut Microbiota.

    Science.gov (United States)

    Cai, Jingwei; Zhang, Limin; Jones, Richard A; Correll, Jared B; Hatzakis, Emmanuel; Smith, Philip B; Gonzalez, Frank J; Patterson, Andrew D

    2016-02-05

    Recent studies have identified the important role of the gut microbiota in the pathogenesis and progression of obesity and related metabolic disorders. The antioxidant tempol was shown to prevent or reduce weight gain and modulate the gut microbiota community in mice; however, the mechanism by which tempol modulates weight gain/loss with respect to the host and gut microbiota has not been clearly established. Here we show that tempol (0, 1, 10, and 50 mg/kg p.o. for 5 days) decreased cecal bacterial fermentation and increased fecal energy excretion in a dose-dependent manner. Liver (1)H NMR-based metabolomics identified a dose-dependent decrease in glycogen and glucose, enhanced glucogenic and ketogenic activity (tyrosine and phenylalanine), and increased activation of the glycolysis pathway. Serum (1)H NMR-based metabolomics indicated that tempol promotes enhanced glucose catabolism. Hepatic gene expression was significantly altered as demonstrated by an increase in Pepck and G6pase and a decrease in Hnf4a, ChREBP, Fabp1, and Cd36 mRNAs. No significant change in the liver and serum metabolomic profiles was observed in germ-free mice, thus establishing a significant role for the gut microbiota in mediating the beneficial metabolic effects of tempol. These results demonstrate that tempol modulates the gut microbial community and its function, resulting in reduced host energy availability and a significant shift in liver metabolism toward a more catabolic state.

  11. Pharmacological, Physiochemical, and Drug-Relevant Biological Properties of Short Chain Fatty Acid Hexosamine Analogues Used in Metabolic Glycoengineering.

    Science.gov (United States)

    Saeui, Christopher T; Liu, Lingshu; Urias, Esteban; Morrissette-McAlmon, Justin; Bhattacharya, Rahul; Yarema, Kevin J

    2018-03-05

    In this study, we catalog structure activity relationships (SAR) of several short chain fatty acid (SCFA)-modified hexosamine analogues used in metabolic glycoengineering (MGE) by comparing in silico and experimental measurements of physiochemical properties important in drug design. We then describe the impact of these compounds on selected biological parameters that influence the pharmacological properties and safety of drug candidates by monitoring P-glycoprotein (Pgp) efflux, inhibition of cytochrome P450 3A4 (CYP3A4), hERG channel inhibition, and cardiomyocyte cytotoxicity. These parameters are influenced by length of the SCFAs (e.g., acetate vs n-butyrate), which are added to MGE analogues to increase the efficiency of cellular uptake, the regioisomeric arrangement of the SCFAs on the core sugar, the structure of the core sugar itself, and by the type of N-acyl modification (e.g., N-acetyl vs N-azido). By cataloging the influence of these SAR on pharmacological properties of MGE analogues, this study outlines design considerations for tuning the pharmacological, physiochemical, and the toxicological parameters of this emerging class of small molecule drug candidates.

  12. Toxicokinetics of drugs of abuse: current knowledge of the isoenzymes involved in the human metabolism of tetrahydrocannabinol, cocaine, heroin, morphine, and codeine.

    Science.gov (United States)

    Maurer, Hans H; Sauer, Christoph; Theobald, Denis S

    2006-06-01

    This review summarizes the major metabolic pathways of the drugs of abuse, tetrahydrocannabinol, cocaine, heroin, morphine, and codeine, in humans including the involvement of isoenzymes. This knowledge may be important for predicting their possible interactions with other xenobiotics, understanding pharmaco-/toxicokinetic and pharmacogenetic variations, toxicological risk assessment, developing suitable toxicological analysis procedures, and finally for understanding certain pitfalls in drug testing. The detection times of these drugs and/or their metabolites in biological samples are summarized and the implications of the presented data on the possible interactions of drugs of abuse with other xenobiotics, ie, inhibition or induction of individual polymorphic and nonpolymorphic isoenzymes, discussed.

  13. Role of cytochromes P450 1A1/2 in detoxication and activation of carcinogenic aristolochic acid I: studies with the hepatic NADPH:cytochrome P450 reductase null (HRN) mouse model.

    Science.gov (United States)

    Levová, Katerina; Moserová, Michaela; Kotrbová, Vera; Sulc, Miroslav; Henderson, Colin J; Wolf, C Roland; Phillips, David H; Frei, Eva; Schmeiser, Heinz H; Mares, Jaroslav; Arlt, Volker M; Stiborová, Marie

    2011-05-01

    Aristolochic acid (AA) causes aristolochic acid nephropathy, Balkan endemic nephropathy, and their urothelial malignancies. To identify enzymes involved in the metabolism of aristolochic acid I (AAI), the major toxic component of AA we used HRN (hepatic cytochrome P450 [Cyp] reductase null) mice, in which NADPH:Cyp oxidoreductase (Por) is deleted in hepatocytes. AAI was demethylated by hepatic Cyps in vitro to 8-hydroxy-aristolochic acid I (AAIa), indicating that less AAI is distributed to extrahepatic organs in wild-type (WT) mice. Indeed, AAI-DNA-adduct levels were significantly higher in organs of HRN mice, having low hepatic AAI demethylation capacity, than in WT mice. Absence of AAI demethylation in HRN mouse liver was confirmed in vitro; hepatic microsomes from WT, but not from HRN mice, oxidized AAI to AAIa. To define the role of hepatic Cyps in AAI demethylation, modulation of AAIa formation by CYP inducers was investigated. We conclude that AAI demethylation is attributable mainly to Cyp1a1/2. The higher AAI-DNA adduct levels in HRN than WT mice were the result of the lack of hepatic AAI demethylation concomitant with a higher activity of cytosolic NAD(P)H:quinone oxidoreductase (Nqo1), which activates AAI. Mouse hepatic Cyp1a1/2 also activated AAI to DNA adducts under hypoxic conditions in vitro, but in renal microsomes, Por and Cyp3a are more important than Cyp1a for AAI-DNA adduct formation. We propose that AAI activation and detoxication in mice are dictated mainly by AAI binding affinity to Cyp1a1/2 or Nqo1, by their turnover, and by the balance between oxidation and reduction of AAI by Cyp1a.

  14. 77 FR 16038 - Endocrinologic and Metabolic Drugs Advisory Committee; Notice of Meeting

    Science.gov (United States)

    2012-03-19

    ... and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 31, rm. 2417, Silver... weight management in patients with a body mass index (BMI) equal to or greater than 30 kilograms (kg) per square meter or a BMI equal to or greater than 27 kg per square meter if accompanied by weight-related...

  15. Genetic analysis of drug metabolizing phase-I enzymes CYP3A4 in ...

    Indian Academy of Sciences (India)

    LIJUN LIU

    5Xi'an Tiangen Precision Medical Institute, Xi'an, Shaanxi 710075, People's Republic of China. Abstract ... nant, and (iv) smoking, drug/alcohol addiction. The purpose .... 96. Table 2. Frequency distribution of CYP3A4 polymorphisms in 96 Tibetan subjects. Nucleotide change. Position. Region. SNP. Allele. Amino acid effect.

  16. Genetic analysis of drug metabolizing phase-I enzymes CYP3A4 in ...

    Indian Academy of Sciences (India)

    LIJUN LIU1

    nant, and (iv) smoking, drug/alcohol addiction. The purpose of exclusion was to minimize some factors that may have influenced genetic variation in the ..... 81560516), Major science and technology research projects of Xizang (Tibet) Autonomous Region (2015XZ01G23), Natural. Science Foundation of Tibet Autonomous ...

  17. Metabolism of ATP-binding cassette drug transporter inhibitors: complicating factor for multidrug resistance.

    NARCIS (Netherlands)

    Cnubben, N.H.; Wortelboer, H.M.; Zanden, J.J. van; Rietjens, I.M.; Bladeren, P.J. van

    2005-01-01

    Membrane transport proteins belonging to the ATP-binding cassette (ABC) family of transport proteins play a central role in the defence of organisms against toxic compounds, including anticancer drugs. However, for compounds that are designed to display a toxic effect, this defence system diminishes

  18. Antipsychotic drugs may worsen metabolic control in type 2 diabetes mellitus

    NARCIS (Netherlands)

    Spoelstra, JA; Stolk, RP; Cohen, D; Klungel, OH; Erkens, JA; Leufkens, HGM; Grobbee, DE

    (B)ackground: Several studies have indicated that type 2 diabetes mellitus is more common among schizophrenic patients than in the general population. In this study, we investigated whether the use of antipsychotic drugs in patients with diabetes leads to worsening of glycemic control. Method: In

  19. 75 FR 64313 - Endocrinologic and Metabolic Drugs Advisory Committee; Notice of Meeting

    Science.gov (United States)

    2010-10-19

    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2010-N-0001... risk factors (e.g. diabetes, dyslipidemia, or hypertension). The BMI is a measure of body weight (mass... be made to the contact person on or before November 22, 2010. Oral presentations from the public will...

  20. 77 FR 73471 - Endocrinologic and Metabolic Drugs Advisory Committee; Notice of Meeting

    Science.gov (United States)

    2012-12-10

    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2012-N-0001... adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. FDA... person on or before December 27, 2012. Oral presentations from the public will be scheduled between...

  1. 77 FR 61609 - Endocrinologic and Metabolic Drugs Advisory Committee; Notice of Meeting

    Science.gov (United States)

    2012-10-10

    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No FDA-2012-N-0001... treatment of Type 1 and Type 2 diabetes mellitus. FDA intends to make background material available to the... submissions may be made to the contact person on or before October 24, 2012. Oral presentations from the...

  2. Thiamin diphosphate-dependent enzymes: from enzymology to metabolic regulation, drug design and disease models.

    Science.gov (United States)

    Bunik, Victoria I; Tylicki, Adam; Lukashev, Nikolay V

    2013-12-01

    Bringing a knowledge of enzymology into research in vivo and in situ is of great importance in understanding systems biology and metabolic regulation. The central metabolic significance of thiamin (vitamin B1 ) and its diphosphorylated derivative (thiamin diphosphate; ThDP), and the fundamental differences in the ThDP-dependent enzymes of metabolic networks in mammals versus plants, fungi and bacteria, or in health versus disease, suggest that these enzymes are promising targets for biotechnological and medical applications. Here, the in vivo action of known regulators of ThDP-dependent enzymes, such as synthetic structural analogs of the enzyme substrates and thiamin, is analyzed in light of the enzymological data accumulated during half a century of research. Mimicking the enzyme-specific catalytic intermediates, the phosphonate analogs of 2-oxo acids selectively inhibit particular ThDP-dependent enzymes. Because of their selectivity, use of these compounds in cellular and animal models of ThDP-dependent enzyme malfunctions improves the validity of the model and its predictive power when compared with the nonselective and enzymatically less characterized oxythiamin and pyrithiamin. In vitro studies of the interaction of thiamin analogs and their biological derivatives with potential in vivo targets are necessary to identify and attenuate the analog selectivity. For both the substrate and thiamin synthetic analogs, in vitro reactivities with potential targets are highly relevant in vivo. However, effective concentrations in vivo are often higher than in vitro studies would suggest. The significance of specific inihibition of the ThDP-dependent enzymes for the development of herbicides, antibiotics, anticancer and neuroprotective strategies is discussed. © 2013 FEBS.

  3. Fondaparinux sodium is not metabolised in mammalian liver fractions and does not inhibit cytochrome P450-mediated metabolism of concomitant drugs.

    Science.gov (United States)

    Lieu, Carolyne; Shi, Juan; Donat, François; Van Horn, Robert; Brian, William; Newton, John; Delbressine, Leon; Vos, Ria

    2002-01-01

    To investigate the in vitro metabolism of the antithrombotic agent fondaparinux sodium in mammalian liver fractions and to evaluate its potential inhibitory effect on human cytochrome P450 (CYP)-mediated metabolism of other drugs. Metabolism was evaluated by incubating radioisotope-labelled fondaparinux sodium with postmitochondrial liver fractions of rat, rabbit, monkey or human origin (three subjects). Human liver microsomal preparations and an NADPH-generating system were incubated with phenacetin, coumarin, tolbutamide, S-mephenytoin, bufuralol, chlorzoxazone or nifedipine. These are selectively metabolised by CYP isoforms: CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4, respectively. Experiments were designed to determine apparent K(i) (inhibitory constant) values for fondaparinux sodium against each CYP isoform, by varying concentrations of fondaparinux sodium and the selective substrate. Each experiment included control reaction mixtures containing an isoform-selective inhibitor. After incubation, the mixtures were analysed by LC-MS/MS or with fluorometric detection. All liver fractions were enzymatically active, as demonstrated by degradation of [(14)C]testosterone. No metabolism of fondaparinux sodium was detectable in postmitochondrial liver fractions. Apparent K(i) values for fondaparinux sodium against the CYP isoforms could not be determined because the oxidative metabolism of the isoform-selective CYP substrates was not significantly inhibited in pooled microsomal reaction mixtures. In the presence of selective CYP inhibitors, metabolism of each substrate was significantly reduced, confirming that inhibition could be observed in these assays. The demonstrated lack of mammalian hepatic metabolism of fondaparinux sodium is consistent with animal and human studies. The absence of inhibition of the human CYP isoforms commonly involved in the metabolism of drugs suggests that clinical treatment with fondaparinux sodium is unlikely to interfere

  4. The comparison of glucose and lipid metabolism parameters in drug-naïve, antipsychotic-treated, and antipsychotic discontinuation patients with schizophrenia

    Directory of Open Access Journals (Sweden)

    Wu X

    2014-07-01

    Full Text Available Xiaoli Wu,1,2 Zeping Huang,3 Hongying Han,2 Zhiyong Zhong,2 Zhaoyu Gan,2 Xiaofeng Guo,1 Feici Diao,2 Zili Han,2 Jingping Zhao1 1Mental Health Institute of the Second Xiangya Hospital, Key Laboratory of Psychiatry and Mental Health of Hunan Province, Central South University, Changsha, Hunan, People’s Republic of China; 2Psychiatry Department, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China; 3Ultrasound Department, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China Background: Although many studies have reported that glucose and lipid metabolism disorders are a significant side effect associated with the use of antipsychotic drugs, the characteristics of glucose and lipid metabolism disorders in patients with schizophrenia who are taking antipsychotic drugs remain poorly understood, and the possible effects that antipsychotic discontinuation may have on glucose and lipid metabolism remain unclear. Methods: The sample consisted of 131 Chinese patients with schizophrenia, including 70 first-episode, drug-naïve patients; 33 patients who had received continuous antipsychotic drug treatment for ≥1 year prior to the beginning of the study; and 28 patients who had discontinued antipsychotic drug treatment for ≥3 months prior to the beginning of study. We compared the glucose and lipid metabolic parameter levels among the three groups of patients with schizophrenia. All assessments were performed upon hospital admission. Results: The characteristics of glucose and lipid metabolism disorders in Chinese patients with schizophrenia who are taking antipsychotic drugs included significant augmentation of the body mass index and waist circumference, significantly higher levels of fasting plasma insulin and insulin resistance, and significantly lower plasma high-density lipoprotein cholesterol levels. Antipsychotic discontinuation

  5. Effects of meal composition and meal timing on the expression of genes involved in hepatic drug metabolism in rats.

    Directory of Open Access Journals (Sweden)

    E M de Vries

    Full Text Available With chronotherapy, drug administration is synchronized with daily rhythms in drug clearance and pharmacokinetics. Daily rhythms in gene expression are centrally mastered by the suprachiasmatic nucleus of the hypothalamus as well as by tissue clocks containing similar molecular mechanisms in peripheral organs. The central timing system is sensitive to changes in the external environment such as those of the light-dark cycle, meal timing and meal composition. We investigated how changes in diet composition and meal timing would affect the daily hepatic expression rhythms of the nuclear receptors PXR and CAR and of enzymes involved in P450 mediated drug metabolism, as such changes could have consequences for the practice of chronotherapy.Rats were subjected to either a regular chow or a free choice high-fat-high-sugar (fcHFHS diet. These diets were provided ad libitum, or restricted to either the light phase or the dark phase. In a second experiment, rats had access to chow either ad libitum or in 6 meals equally distributed over 24 hours.Pxr, Alas1 and Por displayed significant day-night rhythms under ad libitum chow fed conditions, which for Pxr was disrupted under fcHFHS diet conditions. Although no daily rhythms were detected in expression of CAR, Cyp2b2 and Cyp3a2, the fcHFHS diet did affect basal expression of these genes. In chow fed rats, dark phase feeding induced a diurnal rhythm in Cyp2b2 expression while light phase feeding induced a diurnal rhythm in Car expression and completely shifted the peak expression of Pxr, Car, Cyp2b2, Alas1 and Por. The 6-meals-a-day feeding only abolished the Pxr rhythm but not the rhythms of the other genes.We conclude that although nuclear receptors and enzymes involved in the regulation of hepatic drug metabolism are sensitive to meal composition, changes in meal timing are mainly effectuated via changes in the molecular clock.

  6. Toxicokinetics of amphetamines: metabolism and toxicokinetic data of designer drugs, amphetamine, methamphetamine, and their N-alkyl derivatives.

    Science.gov (United States)

    Kraemer, Thomas; Maurer, Hans H

    2002-04-01

    This paper reviews the toxicokinetics of amphetamines. The designer drugs MDA (methylenedioxy-amphetamine, R,S-1-(3;,4;-methylenedioxyphenyl)2-propanamine), MDMA (R,S-methylenedioxymethamphetamine), and MDE (R,S-methylenedioxyethylamphetamine), as well as BDB (benzodioxolylbutanamine; R,S-1-(1;,3;-benzodioxol-5;-yl)-2-butanamine or R,S-1-(3;,4;-methylenedioxyphenyl)-2-butanamine) and MBDB (R,S-N-methyl-benzodioxolylbutanamine), were taken into consideration, as were the following N-alkylated amphetamine derivatives: amphetaminil, benzphetamine, clobenzorex, dimethylamphetamine, ethylamphetamine, famprofazone, fencamine, fenethylline, fenproporex, furfenorex, mefenorex, mesocarb, methamphetamine, prenylamine, and selegiline. English-language publications from 1995 to 2000 were reviewed. Papers describing identification of metabolites or cytochrome P450 isoenzyme-dependent metabolism and papers containing pharmacokinetic/toxicokinetic data were considered and summarized. The implications of toxicokinetics for toxicologic assessment or for interpretation in forensic cases are discussed.

  7. Targeting Cellular Stress Mechanisms and Metabolic Homeostasis by Chinese Herbal Drugs for Neuroprotection

    Directory of Open Access Journals (Sweden)

    Hsiao-Chien Ting

    2018-01-01

    Full Text Available Traditional Chinese medicine has been practiced for centuries in East Asia. Herbs are used to maintain health and cure disease. Certain Chinese herbs are known to protect and improve the brain, memory, and nervous system. To apply ancient knowledge to modern science, some major natural therapeutic compounds in herbs were extracted and evaluated in recent decades. Emerging studies have shown that herbal compounds have neuroprotective effects or can ameliorate neurodegenerative diseases. To understand the mechanisms of herbal compounds that protect against neurodegenerative diseases, we summarize studies that discovered neuroprotection by herbal compounds and compound-related mechanisms in neurodegenerative disease models. Those compounds discussed herein show neuroprotection through different mechanisms, such as cytokine regulation, autophagy, endoplasmic reticulum (ER stress, glucose metabolism, and synaptic function. The interleukin (IL-1β and tumor necrosis factor (TNF-α signaling pathways are inhibited by some compounds, thus attenuating the inflammatory response and protecting neurons from cell death. As to autophagy regulation, herbal compounds show opposite regulatory effects in different neurodegenerative models. Herbal compounds that inhibit ER stress prevent neuronal death in neurodegenerative diseases. Moreover, there are compounds that protect against neuronal death by affecting glucose metabolism and synaptic function. Since the progression of neurodegenerative diseases is complicated, and compound-related mechanisms for neuroprotection differ, therapeutic strategies may need to involve multiple compounds and consider the type and stage of neurodegenerative diseases.

  8. Polyphenols of Salix aegyptiaca modulate the activities of drug metabolizing and antioxidant enzymes, and level of lipid peroxidation.

    Science.gov (United States)

    Nauman, Mohd; Kale, R K; Singh, Rana P

    2018-03-07

    Salix aegyptiaca is known for its medicinal properties mainly due to the presence of salicylate compounds. However, it also contains other beneficial phytochemicals such as gallic acid, quercetin, rutin and vanillin. The aim of the study was to examine the redox potential, antioxidant and anti-inflammatory activity of these phytochemicals along with acetylsalicylic acid. The redox potential and antioxidant activity of gallic acid, quercetin, rutin, vanillin and acetylsalicylic acid were determined by oxidation-reduction potential electrode method and 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay, respectively. In ex vivo studies, antioxidant activity of these phytochemicals was determined by lipid peroxidation and carbonyl content assay in the liver of mice. Anti-inflammatory activity was determined by protein denaturation method. Six-week old C57BL/6 mice treated with gallic acid (100 mg/kg body weight) and acetylsalicylic acid (25 and 50 mg/kg body weight) to investigate their in vivo modulatory effects on the specific activities of drug metabolizing phase I and phase II enzymes, antioxidant enzymes and level of lipid peroxidation in liver. The order of ability to donate electron and antioxidant activity was found to be: gallic acid > quercetin > rutin > vanillin > acetylsalicylic acid. In ex vivo studies, the similar pattern and magnitude of inhibitory effects of these phytochemicals against peroxidative damage in microsomes and protein carbonyl in cytosolic fraction were observed. In in vivo studies, gallic acid and acetylsalicylic acid alone or in combination, enhanced the specific activities of drug metabolizing phase I and phase II enzymes as well as antioxidant enzymes and also inhibited lipid peroxidation in liver. These findings show a close link between the electron donation and antioxidation potential of these phytochemicals, and in turn their biological activity. Gallic acid, quercetin, rutin and vanillin were found to be better electron donors and

  9. Metabolic profile of amphetamine and methamphetamine following administration of the drug famprofazone.

    Science.gov (United States)

    Greenhill, Brandy; Valtier, Sandra; Cody, John T

    2003-10-01

    There are a several drugs that lead to the production of methamphetamine and/or amphetamine in the body which are subsequently excreted in the urine. These drugs raise obvious concerns when interpreting positive amphetamine drug testing results. Famprofazone is an analgesic found in a multi-ingredient medication (Gewodin) used for pain relief. Two Gewodin tablets (50 mg of famprofazone) were administered orally to healthy volunteers with no history of amphetamine, methamphetamine, or famprofazone use. Following administration, urine samples were collected ad lib for up to six days, and pH, specific gravity, and creatinine values were determined. In order to determine the quantitative excretion profile of amphetamine and methamphetamine, samples were extracted using liquid-liquid extraction, derivatized with heptafluorobutyric anhydride, and analyzed by gas chromatography-mass spectrometry (GC-MS). The ions monitored were 91, 118, 240 for amphetamine and 254, 210, 118 for methamphetamine. Amphetamine-d(6) and methamphetamine-d(11) were used as internal standards. Peak concentrations for amphetamine ranged from 148 to 2271 ng/mL and for methamphetamine 615 to 7361 ng/mL. Concentrations of both compounds peaked between 3 and 7 h post-dose. Amphetamine and methamphetamine could be detected (limit of detection = 5 ng/mL) at 121 and 143 h post-dose, respectively. Using a cutoff of 500 ng/mL, all subjects had individual urine samples that tested positive. One subject had 14 samples above the cutoff with the last positive being detected over 48 h post-dose. The profile of methamphetamine and amphetamine enantiomers was also determined using liquid-liquid extraction, derivatization with N-trifluoroacetyl-l-prolyl chloride and analysis by GC-MS. Data showed the famprofazone metabolites amphetamine and methamphetamine to be both d- and l-enantiomers. The proportion of l-methamphetamine exceeded that of its d-enantiomer from the first sample collected. Initially, the

  10. Stable Overexpression of the Constitutive Androstane Receptor Reduces the Requirement for Culture with Dimethyl Sulfoxide for High Drug Metabolism in HepaRG Cells.

    Science.gov (United States)

    van der Mark, Vincent A; Rudi de Waart, D; Shevchenko, Valery; Elferink, Ronald P J Oude; Chamuleau, Robert A F M; Hoekstra, Ruurdtje

    2017-01-01

    Dimethylsulfoxide (DMSO) induces cellular differentiation and expression of drug metabolic enzymes in the human liver cell line HepaRG; however, DMSO also induces cell death and interferes with cellular activities. The aim of this study was to examine whether overexpression of the constitutive androstane receptor (CAR, NR1I3), the nuclear receptor controlling various drug metabolism genes, would sufficiently promote differentiation and drug metabolism in HepaRG cells, optionally without using DMSO. By stable lentiviral overexpression of CAR, HepaRG cultures were less affected by DMSO in total protein content and obtained increased resistance to acetaminophen- and amiodarone-induced cell death. Transcript levels of CAR target genes were significantly increased in HepaRG-CAR cultures without DMSO, resulting in increased activities of cytochrome P450 (P450) enzymes and bilirubin conjugation to levels equal or surpassing those of HepaRG cells cultured with DMSO. Unexpectedly, CAR overexpression also increased the activities of non-CAR target P450s, as well as albumin production. In combination with DMSO treatment, CAR overexpression further increased transcript levels and activities of CAR targets. Induction of CYP1A2 and CYP2B6 remained unchanged, whereas CYP3A4 was reduced. Moreover, the metabolism of low-clearance compounds warfarin and prednisolone was increased. In conclusion, CAR overexpression creates a more physiologically relevant environment for studies on hepatic (drug) metabolism and differentiation in HepaRG cells without the utilization of DMSO. DMSO still may be applied to accomplish higher drug metabolism, required for sensitive assays, such as low-clearance studies and identification of (rare) metabolites, whereas reduced total protein content after DMSO culture is diminished by CAR overexpression. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

  11. Psychedelic 5-Methoxy-N,N-dimethyltryptamine: Metabolism, Pharmacokinetics, Drug Interactions, and Pharmacological Actions

    OpenAIRE

    Shen, Hong-Wu; Jiang, Xi-Ling; Winter, Jerrold C.; Yu, Ai-Ming

    2010-01-01

    5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) belongs to a group of naturally-occurring psychoactive indolealkylamine drugs. It acts as a nonselective serotonin (5-HT) agonist and causes many physiological and behavioral changes. 5-MeO-DMT is O-demethylated by polymorphic cytochrome P450 2D6 (CYP2D6) to an active metabolite, bufotenine, while it is mainly inactivated through the deamination pathway mediated by monoamine oxidase A (MAO-A). 5-MeO-DMT is often used with MAO-A inhibitors such as h...

  12. Long-term exposure to abnormal glucose levels alters drug metabolism pathways and insulin sensitivity in primary human hepatocytes

    Science.gov (United States)

    Davidson, Matthew D.; Ballinger, Kimberly R.; Khetani, Salman R.

    2016-06-01

    Hyperglycemia in type 2 diabetes mellitus has been linked to non-alcoholic fatty liver disease, which can progress to inflammation, fibrosis/cirrhosis, and hepatocellular carcinoma. Understanding how chronic hyperglycemia affects primary human hepatocytes (PHHs) can facilitate the development of therapeutics for these diseases. Conversely, elucidating the effects of hypoglycemia on PHHs may provide insights into how the liver adapts to fasting, adverse diabetes drug reactions, and cancer. In contrast to declining PHH monocultures, micropatterned co-cultures (MPCCs) of PHHs and 3T3-J2 murine embryonic fibroblasts maintain insulin-sensitive glucose metabolism for several weeks. Here, we exposed MPCCs to hypo-, normo- and hyperglycemic culture media for ~3 weeks. While albumin and urea secretion were not affected by glucose level, hypoglycemic MPCCs upregulated CYP3A4 enzyme activity as compared to other glycemic states. In contrast, hyperglycemic MPCCs displayed significant hepatic lipid accumulation in the presence of insulin, while also showing decreased sensitivity to insulin-mediated inhibition of glucose output relative to a normoglycemic control. In conclusion, we show for the first time that PHHs exposed to hypo- and hyperglycemia can remain highly functional, but display increased CYP3A4 activity and selective insulin resistance, respectively. In the future, MPCCs under glycemic states can aid in novel drug discovery and mechanistic investigations.

  13. Regional expression levels of drug transporters and metabolizing enzymes along the pig and human intestinal tract and comparison with Caco-2 cells

    NARCIS (Netherlands)

    Vaessen, S.F.C.; Lipzig, M.M.H. van; Pieters, R.H.H.; Krul, C.A.M.; Wortelboer, H.M.; Steeg, E. van de

    2017-01-01

    Intestinal transporter proteins and metabolizing enzymes play a crucial role in the oral absorption of a wide variety of drugs. The aim of the current study was to characterize better available intestinal in vitro models by comparing expression levels of these proteins and enzymes between porcine

  14. Regional expression levels of drug transporters and metabolizing enzymes along the pig and human intestinal tract and comparison with Caco-2 cells

    NARCIS (Netherlands)

    Vaessen, Stefan F C; van Lipzig, Marola M H; Pieters, Raymond H H; Krul, Cyrille A M; Wortelboer, Heleen M; van de Steeg, Evita

    2017-01-01

    Intestinal transporter proteins and metabolizing enzymes play a crucial role in the oral absorption of a wide variety of drugs. The aim of the current study was to better characterize available intestinal in vitro models by comparing expression levels of these proteins and enzymes between porcine

  15. Comparison of TiO2 photocatalysis, electrochemically assisted Fenton reaction and direct electrochemistry for simulation of phase I metabolism reactions of drugs

    NARCIS (Netherlands)

    Ruokolainen, Miina; Gül, Turan; Permentier, Hjalmar; Sikanen, Tiina; Kostiainen, Risto; Kotiaho, Tapio

    2016-01-01

    The feasibility of titanium dioxide (TiO2) photocatalysis, electrochemically assisted Fenton reaction (EC-Fenton) and direct electrochemical oxidation (EC) for simulation of phase I metabolism of drugs was studied by comparing the reaction products of buspirone, promazine, testosterone and

  16. The potential of inhibitors of endocannabinoid metabolism as anxiolytic and antidepressive drugs--A practical view.

    Science.gov (United States)

    Fowler, Christopher J

    2015-06-01

    The endocannabinoid system, comprising cannabinoid CB1 and CB2 receptors, their endogenous ligands anandamide and 2-arachidonoylglyerol, and their synthetic and metabolic enzymes, are involved in many biological processes in the body, ranging from appetite to bone turnover. Compounds inhibiting the breakdown of anandamide and 2-arachidonoylglycerol increase brain levels of these lipids and thus modulate endocannabinoid signalling. In the present review, the preclinical evidence that these enzymes are good targets for development of novel therapies for anxiety and depression are discussed from a practical, rather than mechanistic, point of view. It is concluded that the preclinical data are promising, albeit tempered by problems of tolerance as well as effects upon learning and memory for irreversible monoacylglycerol lipase inhibitors, and limited by a focus upon male rodents alone. Clinical data so far has been restricted to safety studies with inhibitors of anandamide hydrolysis and a hitherto unpublished study on such a compound in elderly patients with major depressive disorders, but under the dose regimes used, they are well tolerated and show no signs of "cannabis-like" behaviours. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

  17. [Metformin and AMPK: an old drug and a new enzyme in the context of metabolic syndrome].

    Science.gov (United States)

    Santomauro Júnior, Augusto Cézar; Ugolini, Michelle Remião; Santomauro, Ana Teresa; Souto, Ricardo Peres do

    2008-02-01

    Metformin is one of the most commonly prescribed oral antidiabetic agents worldwide. However, its mechanism of action remains unknown. The Diabetes Prevention Program Research Group studies have shown that metformin administration and lifestyle-intervention (diet and exercise) reduce the incidence of Diabetes Mellitus type 2 (DM2). A possible biochemical connection between both therapies may be the AMP-activated protein kinase (AMPK). This enzyme was originally described as a sensor of cellular energy status, being activated in exercise. On the other hand, several experimental evidences indicate that AMPK may be an important target of metformin action. This paper discusses various ways for AMPK regulation, suggesting a possible mechanism for its activation by metformin that involves the production of reactive nitrogen species. AMPK activation determines a wide variety of physiological effects, including enhanced glucose uptake by skeletal muscle and enhanced lipid catabolism. Thus, it may be a key player not only in the prevention and treatment of DM2, but also in the development of new treatments for obesity and the metabolic syndrome. The finding of AMPK activation by metformin draws attention to this enzyme as an important pharmacological target.

  18. A poor metabolizer of both CYP2C19 and CYP2D6 identified by mechanistic pharmacokinetic simulation in a fatal drug poisoning case involving venlafaxine

    DEFF Research Database (Denmark)

    Jornil, J; Nielsen, T S; Rosendal, I

    2013-01-01

    pharmacokinetic simulations suggested that the low metabolite ratio was the result of combined poor metabolizer (PM) status of cytochrome P450 (CYP) 2C19 and CYP2D6. This hypothesis was confirmed by genetic analysis. Simulations revealed that it was likely that the combined missing CYP2D6 and CYP2C19 activity...... would cause higher concentrations of VEN, but the simulations also suggested that there could be additional reasons to explain the high VEN concentration found in this case. Thus, it seems likely that the potentially toxic VEN concentration was caused by reduced metabolic capacity. The simulations...... combined with genotyping were considered very useful in this fatal drug poisoning case. Keywords CYP2D6; CYP2C19; Venlafaxine; Poor metabolizer; Drug poisoning; Mechanistic pharmacokinetic simulation --------------------------------------------------------------------------------...

  19. Biological basis of detoxication

    National Research Council Canada - National Science Library

    Caldwell, John; Jakoby, William B

    1983-01-01

    This volume considers that premise that most of the major patterns of biological conversion of foreign compounds are known and may have predictive value in assessing the biological course for novel compounds...

  20. CNS metabolism in high-risk drug abuse, German version. Insights gained from 1H- and 31P MRS and PET

    International Nuclear Information System (INIS)

    Bodea, S.V.

    2017-01-01

    High-risk drug consumption is a considerable problem for public health actors in industrialised countries. The latest trends show a market tendency towards diversification and increasing demand for high-purity synthetic drugs. Whilst most consumers seek medical help after cannabis use, it is high-risk drugs like cocaine, heroin and amphetamines that account for most of the 1000 drug-related deaths that occur in Germany every year. This article presents the most prominent in vivo cerebral metabolic information in cocaine, heroin and methamphetamine users provided by MRI spectroscopy and PET imaging. We reviewed the literature reporting neuroimaging studies of in vivo metabolic data for methamphetamine, cocaine and heroin consumption published up to March 2017. The search was conducted using PubMed with the following key words: methamphetamine, cocaine, heroin, MR spectroscopy, PET. MRI and PET are indispensable tools in gauging brain metabolic response to illegal drug abuse. Future breakthroughs in this field will most likely come from the investigation of novel neurotransmitter systems in PET and imaging phosphorus and carbon metabolites in MRI. (orig.) [de

  1. [CNS metabolism in high-risk drug abuse, German version : Insights gained from 1H- and 31P MRS and PET].

    Science.gov (United States)

    Bodea, S V

    2017-06-01

    High-risk drug consumption is a considerable problem for public health actors in industrialised countries. The latest trends show a market tendency towards diversification and increasing demand for high-purity synthetic drugs. Whilst most consumers seek medical help after cannabis use, it is high-risk drugs like cocaine, heroin and amphetamines that account for most of the 1000 drug-related deaths that occur in Germany every year. This article presents the most prominent in vivo cerebral metabolic information in cocaine, heroin and methamphetamine users provided by MRI spectroscopy and PET imaging. We reviewed the literature reporting neuroimaging studies of in vivo metabolic data for methamphetamine, cocaine and heroin consumption published up to March 2017. The search was conducted using PubMed with the following key words: methamphetamine, cocaine, heroin, MR spectroscopy, PET. MRI and PET are indispensable tools in gauging brain metabolic response to illegal drug abuse. Future breakthroughs in this field will most likely come from the investigation of novel neurotransmitter systems in PET and imaging phosphorus and carbon metabolites in MRI.

  2. Predicting the Metabolic Sites by Flavin-Containing Monooxygenase on Drug Molecules Using SVM Classification on Computed Quantum Mechanics and Circular Fingerprints Molecular Descriptors.

    Directory of Open Access Journals (Sweden)

    Chien-Wei Fu

    Full Text Available As an important enzyme in Phase I drug metabolism, the flavin-containing monooxygenase (FMO also metabolizes some xenobiotics with soft nucleophiles. The site of metabolism (SOM on a molecule is the site where the metabolic reaction is exerted by an enzyme. Accurate prediction of SOMs on drug molecules will assist the search for drug leads during the optimization process. Here, some quantum mechanics features such as the condensed Fukui function and attributes from circular fingerprints (called Molprint2D are computed and classified using the support vector machine (SVM for predicting some potential SOMs on a series of drugs that can be metabolized by FMO enzymes. The condensed Fukui function fA- representing the nucleophilicity of central atom A and the attributes from circular fingerprints accounting the influence of neighbors on the central atom. The total number of FMO substrates and non-substrates collected in the study is 85 and they are equally divided into the training and test sets with each carrying roughly the same number of potential SOMs. However, only N-oxidation and S-oxidation features were considered in the prediction since the available C-oxidation data was scarce. In the training process, the LibSVM package of WEKA package and the option of 10-fold cross validation are employed. The prediction performance on the test set evaluated by accuracy, Matthews correlation coefficient and area under ROC curve computed are 0.829, 0.659, and 0.877 respectively. This work reveals that the SVM model built can accurately predict the potential SOMs for drug molecules that are metabolizable by the FMO enzymes.

  3. Metabolic and functional MR biomarkers of antiepileptic drug effectiveness: A review.

    Science.gov (United States)

    van Veenendaal, Tamar M; IJff, Dominique M; Aldenkamp, Albert P; Hofman, Paul A M; Vlooswijk, Marielle C G; Rouhl, Rob P W; de Louw, Anton J; Backes, Walter H; Jansen, Jacobus F A

    2015-12-01

    As a large number of patients with epilepsy do not respond favorably to antiepileptic drugs (AEDs), a better understanding of treatment failure and the cause of adverse side effects is required. The working mechanisms of AEDs also alter neurotransmitter concentrations and brain activity, which can be measured using MR spectroscopy and functional MR imaging, respectively. This review presents an overview of clinical research of MR spectroscopy and functional MR imaging studies to the effects of AEDs on the brain. Despite the scarcity of studies associating MR findings to the effectiveness of AEDs, the current research shows clear potential regarding this matter. Several GABAergic AEDs have been shown to increase the GABA concentration, which was related to seizure reductions, while language problems due to topiramate have been associated with altered activation patterns measured with functional MR imaging. MR spectroscopy and functional MR imaging provide biomarkers that may predict individual treatment outcomes, and enable the assessment of mechanisms of treatment failure and cognitive side effects. Copyright © 2015 Elsevier Ltd. All rights reserved.

  4. A microfluidic hepatic coculture platform for cell-based drug metabolism studies.

    Science.gov (United States)

    Novik, Eric; Maguire, Timothy J; Chao, Piyun; Cheng, K C; Yarmush, Martin L

    2010-04-01

    Within the global pharmaceutical and biotech industries, there is significant interest in identifying in vitro screening systems that are more human-relevant-i.e., that offer greater utility in predicting subcellular and cellular physiological responses in humans in vivo-and that thereby allow investigators to reduce the incidence of costly late-stage failures during pharmaceutical clinical trials, as well as to reduce the use of animals in drug testing. Currently incumbent in vitro screening methods, such as culturing human hepatocytes in suspension, while useful, are limited by a lack of long term cellular function. In order to address this limitation, we have established an integrated, microfluidic, in vitro platform that combines the patented HmuREL((R)) microdevice with a hepatic coculture system. In the present report, we use this platform to study clearance and metabolite generation of a battery of molecular entities. The results show that the flow-based coculture system is capable of clearing, with improved resolution and predictive value, compounds with high, medium, and low clearance values. In addition, when coculture is coupled with flow, higher metabolite production rates are obtained than in static systems. Copyright 2009 Elsevier Inc. All rights reserved.

  5. Toxicity of Xanthene Food Dyes by Inhibition of Human Drug-Metabolizing Enzymes in a Noncompetitive Manner

    International Nuclear Information System (INIS)

    Mizutani, T.

    2010-01-01

    The synthetic food dyes studied were rose bengal (RB), phroxine (PL), amaranth, erythrosine B (ET), allura red, new coccine, acid red (AR), tartrazine, sunset yellow FCF, brilliant blue FCF, and indigo carmine. First, data confirmed that these dyes were not substrates for CYP2A6, UGT1A6, and UGT2B7. ET inhibited UGT1A6 (glucuronidation of p-nitrophenol) and UGT2B7 (glucuronidation of androsterone). We showed the inhibitory effect of xanthene dye on human UGT1A6 activity. Basic ET, PL, and RB in those food dyes strongly inhibited UGT1A6 activity, with IC50 values = 0.05, 0.04, and 0.015 mM, respectively. Meanwhile, AR of an acidic xanthene food dye showed no inhibition. Next, we studied the inhibition of CYP3A4 of a major phase I drug-metabolizing enzyme and P-glycoprotein of a major transporter by synthetic food dyes. Human CYP3A4 and P-glycoprotein were also inhibited by basic xanthene food dyes. The IC50 values of these dyes to inhibit CYP3A4 and P-glycoprotein were the same as the inhibition level of UGT1A6 by three halogenated xanthene food dyes (ET, PL, and RB) described above, except AR, like the results with UGT1A6 and UGT2B7. We also confirmed the non inhibition of CYP3A4 and P-gp by other synthetic food dyes. Part of this inhibition depended upon the reaction of O 12 originating on xanthene dyes by light irradiation, because inhibition was prevented by O 12 quenchers. We studied the influence of superoxide dismutase and catalase on this inhibition by dyes and we found prevention of inhibition by superoxide dismutase but not catalase. This result suggests that superoxide anions, originating on dyes by light irradiation, must attack drug-metabolizing enzymes. It is possible that red cosmetics containing phloxine, erythrosine, or rose bengal react with proteins on skin under lighting and may lead to rough skin.

  6. Toxicity of xanthene food dyes by inhibition of human drug-metabolizing enzymes in a noncompetitive manner.

    Science.gov (United States)

    Mizutani, Takaharu

    2009-01-01

    The synthetic food dyes studied were rose bengal (RB), phroxine (PL), amaranth, erythrosine B (ET), allura red, new coccine, acid red (AR), tartrazine, sunset yellow FCF, brilliant blue FCF, and indigo carmine. First, data confirmed that these dyes were not substrates for CYP2A6, UGT1A6, and UGT2B7. ET inhibited UGT1A6 (glucuronidation of p-nitrophenol) and UGT2B7 (glucuronidation of androsterone). We showed the inhibitory effect of xanthene dye on human UGT1A6 activity. Basic ET, PL, and RB in those food dyes strongly inhibited UGT1A6 activity, with IC(50) values = 0.05, 0.04, and 0.015 mM, respectively. Meanwhile, AR of an acidic xanthene food dye showed no inhibition. Next, we studied the inhibition of CYP3A4 of a major phase I drug-metabolizing enzyme and P-glycoprotein of a major transporter by synthetic food dyes. Human CYP3A4 and P-glycoprotein were also inhibited by basic xanthene food dyes. The IC(50) values of these dyes to inhibit CYP3A4 and P-glycoprotein were the same as the inhibition level of UGT1A6 by three halogenated xanthene food dyes (ET, PL, and RB) described above, except AR, like the results with UGT1A6 and UGT2B7. We also confirmed the noninhibition of CYP3A4 and P-gp by other synthetic food dyes. Part of this inhibition depended upon the reaction of (1)O(2) originating on xanthene dyes by light irradiation, because inhibition was prevented by (1)O(2) quenchers. We studied the influence of superoxide dismutase and catalase on this inhibition by dyes and we found prevention of inhibition by superoxide dismutase but not catalase. This result suggests that superoxide anions, originating on dyes by light irradiation, must attack drug-metabolizing enzymes. It is possible that red cosmetics containing phloxine, erythrosine, or rose bengal react with proteins on skin under lighting and may lead to rough skin.

  7. Toxicity of Xanthene Food Dyes by Inhibition of Human Drug-Metabolizing Enzymes in a Noncompetitive Manner

    Science.gov (United States)

    Mizutani, Takaharu

    2009-01-01

    The synthetic food dyes studied were rose bengal (RB), phroxine (PL), amaranth, erythrosine B (ET), allura red, new coccine, acid red (AR), tartrazine, sunset yellow FCF, brilliant blue FCF, and indigo carmine. First, data confirmed that these dyes were not substrates for CYP2A6, UGT1A6, and UGT2B7. ET inhibited UGT1A6 (glucuronidation of p-nitrophenol) and UGT2B7 (glucuronidation of androsterone). We showed the inhibitory effect of xanthene dye on human UGT1A6 activity. Basic ET, PL, and RB in those food dyes strongly inhibited UGT1A6 activity, with IC50 values = 0.05, 0.04, and 0.015 mM, respectively. Meanwhile, AR of an acidic xanthene food dye showed no inhibition. Next, we studied the inhibition of CYP3A4 of a major phase I drug-metabolizing enzyme and P-glycoprotein of a major transporter by synthetic food dyes. Human CYP3A4 and P-glycoprotein were also inhibited by basic xanthene food dyes. The IC50 values of these dyes to inhibit CYP3A4 and P-glycoprotein were the same as the inhibition level of UGT1A6 by three halogenated xanthene food dyes (ET, PL, and RB) described above, except AR, like the results with UGT1A6 and UGT2B7. We also confirmed the noninhibition of CYP3A4 and P-gp by other synthetic food dyes. Part of this inhibition depended upon the reaction of 1O2 originating on xanthene dyes by light irradiation, because inhibition was prevented by 1O2 quenchers. We studied the influence of superoxide dismutase and catalase on this inhibition by dyes and we found prevention of inhibition by superoxide dismutase but not catalase. This result suggests that superoxide anions, originating on dyes by light irradiation, must attack drug-metabolizing enzymes. It is possible that red cosmetics containing phloxine, erythrosine, or rose bengal react with proteins on skin under lighting and may lead to rough skin. PMID:20041016

  8. Acaricide, fungicide and drug interactions in honey bees (Apis mellifera.

    Directory of Open Access Journals (Sweden)

    Reed M Johnson

    Full Text Available BACKGROUND: Chemical analysis shows that honey bees (Apis mellifera and hive products contain many pesticides derived from various sources. The most abundant pesticides are acaricides applied by beekeepers to control Varroa destructor. Beekeepers also apply antimicrobial drugs to control bacterial and microsporidial diseases. Fungicides may enter the hive when applied to nearby flowering crops. Acaricides, antimicrobial drugs and fungicides are not highly toxic to bees alone, but in combination there is potential for heightened toxicity due to interactive effects. METHODOLOGY/PRINCIPAL FINDINGS: Laboratory bioassays based on mortality rates in adult worker bees demonstrated interactive effects among acaricides, as well as between acaricides and antimicrobial drugs and between acaricides and fungicides. Toxicity of the acaricide tau-fluvalinate increased in combination with other acaricides and most other compounds tested (15 of 17 while amitraz toxicity was mostly unchanged (1 of 15. The sterol biosynthesis inhibiting (SBI fungicide prochloraz elevated the toxicity of the acaricides tau-fluvalinate, coumaphos and fenpyroximate, likely through inhibition of detoxicative cytochrome P450 monooxygenase activity. Four other SBI fungicides increased the toxicity of tau-fluvalinate in a dose-dependent manner, although possible evidence of P450 induction was observed at the lowest fungicide doses. Non-transitive interactions between some acaricides were observed. Sublethal amitraz pre-treatment increased the toxicity of the three P450-detoxified acaricides, but amitraz toxicity was not changed by sublethal treatment with the same three acaricides. A two-fold change in the toxicity of tau-fluvalinate was observed between years, suggesting a possible change in the genetic composition of the bees tested. CONCLUSIONS/SIGNIFICANCE: Interactions with acaricides in honey bees are similar to drug interactions in other animals in that P450-mediated detoxication

  9. Acaricide, fungicide and drug interactions in honey bees (Apis mellifera).

    Science.gov (United States)

    Johnson, Reed M; Dahlgren, Lizette; Siegfried, Blair D; Ellis, Marion D

    2013-01-01

    Chemical analysis shows that honey bees (Apis mellifera) and hive products contain many pesticides derived from various sources. The most abundant pesticides are acaricides applied by beekeepers to control Varroa destructor. Beekeepers also apply antimicrobial drugs to control bacterial and microsporidial diseases. Fungicides may enter the hive when applied to nearby flowering crops. Acaricides, antimicrobial drugs and fungicides are not highly toxic to bees alone, but in combination there is potential for heightened toxicity due to interactive effects. Laboratory bioassays based on mortality rates in adult worker bees demonstrated interactive effects among acaricides, as well as between acaricides and antimicrobial drugs and between acaricides and fungicides. Toxicity of the acaricide tau-fluvalinate increased in combination with other acaricides and most other compounds tested (15 of 17) while amitraz toxicity was mostly unchanged (1 of 15). The sterol biosynthesis inhibiting (SBI) fungicide prochloraz elevated the toxicity of the acaricides tau-fluvalinate, coumaphos and fenpyroximate, likely through inhibition of detoxicative cytochrome P450 monooxygenase activity. Four other SBI fungicides increased the toxicity of tau-fluvalinate in a dose-dependent manner, although possible evidence of P450 induction was observed at the lowest fungicide doses. Non-transitive interactions between some acaricides were observed. Sublethal amitraz pre-treatment increased the toxicity of the three P450-detoxified acaricides, but amitraz toxicity was not changed by sublethal treatment with the same three acaricides. A two-fold change in the toxicity of tau-fluvalinate was observed between years, suggesting a possible change in the genetic composition of the bees tested. Interactions with acaricides in honey bees are similar to drug interactions in other animals in that P450-mediated detoxication appears to play an important role. Evidence of non-transivity, year-to-year variation

  10. Accumulation and detoxication responses of the gastropod Lymnaea stagnalis to single and combined exposures to natural (cyanobacteria) and anthropogenic (the herbicide RoundUp® Flash) stressors

    DEFF Research Database (Denmark)

    Lance, Emilie; Desprat, J.; Holbech, B. F.

    2016-01-01

    , and ii) activities of anti-oxidant (catalase CAT) and biotransformation (glutathione-S-transferase GST) enzymes. During the intoxication, the cyanobacterial exposure induced an early increase of CAT activity, independently of the MC content, probably related to the production of secondary cyanobacterial...... metabolites. The GST activity was induced by RoundUp® Flash alone or in combination with non MC-producing cyanobacteria, but was inhibited by MC-producing cyanobacteria with or without RoundUp® Flash. Moreover, MC accumulation in L. stagnalis was 3.2 times increased when snails were concomitantly exposed...... to MC-producing cyanobacteria with RoundUp®, suggesting interacting effects of MCs on biotransformation processes. The potent inhibition of detoxication systems by MCs and RoundUp® Flash was reversible during the depuration, during which CAT and GST activities were significantly higher in snails...

  11. Evaluations of in vitro metabolism, drug-drug interactions mediated by reversible and time-dependent inhibition of CYPs, and plasma protein binding of MMB4 DMS.

    Science.gov (United States)

    Hong, S Peter; Lusiak, Bozena D; Burback, Brian L; Johnson, Jerry D

    2013-01-01

    1,1'-Methylenebis[4-[(hydroxyimino)methyl]-pyridinium] (MMB4) dimethanesulfonate (DMS) is a bisquaternary pyridinium aldoxime that reactivates acetylcholinesterase inhibited by organophosphorus nerve agent. Drug metabolism and plasma protein binding for MMB4 DMS were examined using various techniques and a wide range of species. When (14)C-MMB4 DMS was incubated in liver microsomes, 4-pyridine aldoxime (4-PA) and an additional metabolite were detected in all species tested. Identity of the additional metabolite was postulated to be isonicotinic acid (INA) based on liquid chromatography with a tandem mass spectrometry analysis, which was confirmed by comparison with authentic INA. Formation of INA was dependent on species, with the highest level found in monkey liver microsomes. The MMB4 DMS exhibited reversible inhibition in a concentration-dependent manner toward cytochrome P450 1A2 (CYP1A2), CYP2C9, CYP2C19, CYP2D6, and CYP3A4 in human liver microsomes showing the highest inhibition for CYP2D6. Human recombinant CYPs were used to evaluate inhibitory curves more adequately and determine detailed kinetic constants for reversible inhibition and potential time-dependent inhibition (TDI). The MMB4 DMS exhibited reversible inhibition toward human-recombinant CYP2D6 with an inhibition constant (K i) value of 66.6 µmol/L. Based on the k inact/K I values, MMB4 DMS was found to exhibit the most potent TDI toward CYP2D6. The MMB4 DMS at 5 different concentrations was incubated in plasma for 5 hours using an equilibrium dialysis device. For all species tested, there were no concentration-dependent changes in plasma protein binding, ranging from 10% to 17%. These results suggest that MMB4 was not extensively bound to plasma protein, and there were no overt species-related differences in the extent of MMB4 bound to plasma protein.

  12. Mechanisms of metabonomic for a gateway drug: nicotine priming enhances behavioral response to cocaine with modification in energy metabolism and neurotransmitter level.

    Directory of Open Access Journals (Sweden)

    Hongyu Li

    Full Text Available Nicotine, one of the most commonly used drugs, has become a major concern because tobacco serves as a gateway drug and is linked to illicit drug abuse, such as cocaine and marijuana. However, previous studies mainly focused on certain genes or neurotransmitters which have already been known to participate in drug addiction, lacking endogenous metabolic profiling in a global view. To further explore the mechanism by which nicotine modifies the response to cocaine, we developed two conditioned place preference (CPP models in mice. In threshold dose model, mice were pretreated with nicotine, followed by cocaine treatment at the dose of 2 mg/kg, a threshold dose of cocaine to induce CPP in mice. In high-dose model, mice were only treated with 20 mg/kg cocaine, which induced a significant CPP. (1H nuclear magnetic resonance based on metabonomics was used to investigate metabolic profiles of the nucleus accumbens (NAc and striatum. We found that nicotine pretreatment dramatically increased CPP induced by 2 mg/kg cocaine, which was similar to 20 mg/kg cocaine-induced CPP. Interestingly, metabolic profiles showed considerable overlap between these two models. These overlapped metabolites mainly included neurotransmitters as well as the molecules participating in energy homeostasis and cellular metabolism. Our results show that the reinforcing effect of nicotine on behavioral response to cocaine may attribute to the modification of some specific metabolites in NAc and striatum, thus creating a favorable metabolic environment for enhancing conditioned rewarding effect of cocaine. Our findings provide an insight into the effect of cigarette smoking on cocaine dependence and the underlying mechanism.

  13. Mechanisms of Metabonomic for a Gateway Drug: Nicotine Priming Enhances Behavioral Response to Cocaine with Modification in Energy Metabolism and Neurotransmitter Level

    Science.gov (United States)

    Li, Hongyu; Bu, Qian; Chen, Bo; Shao, Xue; Hu, Zhengtao; Deng, Pengchi; Lv, Lei; Deng, Yi; Zhu, Ruiming; Li, Yan; Zhang, Baolai; Hou, Jing; Du, Changman; Zhao, Qian; Fu, Dengqi; Zhao, Yinglan; Cen, Xiaobo

    2014-01-01

    Nicotine, one of the most commonly used drugs, has become a major concern because tobacco serves as a gateway drug and is linked to illicit drug abuse, such as cocaine and marijuana. However, previous studies mainly focused on certain genes or neurotransmitters which have already been known to participate in drug addiction, lacking endogenous metabolic profiling in a global view. To further explore the mechanism by which nicotine modifies the response to cocaine, we developed two conditioned place preference (CPP) models in mice. In threshold dose model, mice were pretreated with nicotine, followed by cocaine treatment at the dose of 2 mg/kg, a threshold dose of cocaine to induce CPP in mice. In high-dose model, mice were only treated with 20 mg/kg cocaine, which induced a significant CPP. 1H nuclear magnetic resonance based on metabonomics was used to investigate metabolic profiles of the nucleus accumbens (NAc) and striatum. We found that nicotine pretreatment dramatically increased CPP induced by 2 mg/kg cocaine, which was similar to 20 mg/kg cocaine-induced CPP. Interestingly, metabolic profiles showed considerable overlap between these two models. These overlapped metabolites mainly included neurotransmitters as well as the molecules participating in energy homeostasis and cellular metabolism. Our results show that the reinforcing effect of nicotine on behavioral response to cocaine may attribute to the modification of some specific metabolites in NAc and striatum, thus creating a favorable metabolic environment for enhancing conditioned rewarding effect of cocaine. Our findings provide an insight into the effect of cigarette smoking on cocaine dependence and the underlying mechanism. PMID:24489831

  14. Sickle Cell Anemia Patients in Use of Hydroxyurea: Association between Polymorphisms in Genes Encoding Metabolizing Drug Enzymes and Laboratory Parameters

    Directory of Open Access Journals (Sweden)

    Sètondji Cocou Modeste Alexandre Yahouédéhou

    2018-01-01

    Full Text Available This study investigated associations between SNPs in genes encoding metabolizing drug enzymes and laboratory parameters in sickle cell anemia patients under hydroxyurea (SCA-HU+. We evaluated hematologic and biochemical parameters by electronic methods and SNPs by PCR-RFLP and multiplex PCR in 35 SCA-HU+ patients and 67 SCA-HU− patients. The HbS, total cholesterol, lactate dehydrogenase, aspartate aminotransferase, total bilirubin and fractions levels, and leukocyte, eosinophil, monocyte, and erythroblast counts were reduced in SCA-HU+ patients (pA and c1c2 + c2c2 of CYP2E1 −1293G>C/−1053C>T were higher in SCA-HU+ patients (pA, CYP2E1 −1293G>C/−1053C>T, and GSTT1 can be associated with alterations in lipid, inflammatory, renal, hemolytic, and hepatic profiles. However, further studies are needed to elucidate these associations.

  15. Suppression of hepatic cytochrome p450-mediated drug metabolism during the late stage of sepsis in rats.

    Science.gov (United States)

    Lee, Sang-Ho; Lee, Sun-Mee

    2005-02-01

    The effects of polymicrobial sepsis on the activity and gene expression of hepatic microsomal cytochrome P450 (CYP) were examined. Rats were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP). Liver and blood samples were taken 2, 6, and 24 h after CLP. The serum aminotransferase levels and lipid peroxidation increased 24 h after CLP. The hepatic concentrations of reduced glutathione and total CYP content decreased 24 h after CLP. The CYP1A1 activity and its protein level decreased 24 h after CLP. The CYP1A2 activity decreased 2 h and 24 h after CLP. Although the CYP2B1 mRNA expression level decreased 6 h and 24 h after CLP, the CYP2B1 activity and its protein level did not change in any of the experimental groups. The CYP2E1 activity and its protein level decreased 24 h after CLP. The CYP2E1 mRNA levels were lower at both 6 h and 24 h after CLP. The TNF-alpha mRNA expression level increased 2, 6, and 24 h after CLP. The iNOS mRNA expression level increased 24 h after CLP. These findings suggest that sepsis causes abnormalities in the microsomal drug-metabolizing function, particularly in the late stage, which is associated with higher level of oxidant stress and lipid peroxidation.

  16. Application of a novel regulatable Cre recombinase system to define the role of liver and gut metabolism in drug oral bioavailability.

    Science.gov (United States)

    Henderson, Colin J; McLaughlin, Lesley A; Osuna-Cabello, Maria; Taylor, Malcolm; Gilbert, Ian; McLaren, Aileen W; Wolf, C Roland

    2015-02-01

    The relative contribution of hepatic compared with intestinal oxidative metabolism is a crucial factor in drug oral bioavailability and therapeutic efficacy. Oxidative metabolism is mediated by the cytochrome P450 mono-oxygenase system to which cytochrome P450 reductase (POR) is the essential electron donor. In order to study the relative importance of these pathways in drug disposition, we have generated a novel mouse line where Cre recombinase is driven off the endogenous Cyp1a1 gene promoter; this line was then crossed on to a floxed POR mouse. A 40 mg/kg dose of the Cyp1a1 inducer 3-methylcholanthrene (3MC) eliminated POR expression in both liver and small intestine, whereas treatment at 4 mg/kg led to a more targeted deletion in the liver. Using this approach, we have studied the pharmacokinetics of three probe drugs--paroxetine, midazolam, nelfinavir--and show that intestinal metabolism is a determinant of oral bioavailability for the two latter compounds. The Endogenous Reductase Locus (ERL) mouse represents a significant advance on previous POR deletion models as it allows direct comparison of hepatic and intestinal effects on drug and xenobiotic clearance using lower doses of a single Cre inducing agent, and in addition minimizes any cytotoxic effects, which may compromise interpretation of the experimental data.

  17. Metabolic profiling of urine and blood plasma in rat models of drug addiction on the basis of morphine, methamphetamine, and cocaine-induced conditioned place preference.

    Science.gov (United States)

    Zaitsu, Kei; Miyawaki, Izuru; Bando, Kiyoko; Horie, Hiroshi; Shima, Noriaki; Katagi, Munehiro; Tatsuno, Michiaki; Bamba, Takeshi; Sato, Takako; Ishii, Akira; Tsuchihashi, Hitoshi; Suzuki, Koichi; Fukusaki, Eiichiro

    2014-02-01

    The metabolic profiles of urine and blood plasma in drug-addicted rat models based on morphine (MOR), methamphetamine (MA), and cocaine (COC)-induced conditioned place preference (CPP) were investigated. Rewarding effects induced by each drug were assessed by use of the CPP model. A mass spectrometry (MS)-based metabolomics approach was applied to urine and plasma of MOR, MA, and COC-addicted rats. In total, 57 metabolites in plasma and 70 metabolites in urine were identified by gas chromatography-MS. The metabolomics approach revealed that amounts of some metabolites, including tricarboxylic acid cycle intermediates, significantly changed in the urine of MOR-addicted rats. This result indicated that disruption of energy metabolism is deeply relevant to MOR addiction. In addition, 3-hydroxybutyric acid, L-tryptophan, cystine, and n-propylamine levels were significantly changed in the plasma of MOR-addicted rats. Lactose, spermidine, and stearic acid levels were significantly changed in the urine of MA-addicted rats. Threonine, cystine, and spermidine levels were significantly increased in the plasma of COC-addicted rats. In conclusion, differences in the metabolic profiles were suggestive of different biological states of MOR, MA, and COC addiction; these may be attributed to the different actions of the drugs on the brain reward circuitry and the resulting adaptation. In addition, the results showed possibility of predict the extent of MOR addiction by metabolic profiling. This is the first study to apply metabolomics to CPP models of drug addiction, and we demonstrated that metabolomics can be a multilateral approach to investigating the mechanism of drug addiction.

  18. Simulation of Metabolic Drug-Drug Interactions Perpetrated by Fluvoxamine Using Hybridized Two-Compartment Hepatic Drug-Pool-Based Tube Modeling and Estimation of In Vivo Inhibition Constants.

    Science.gov (United States)

    Iga, Katsumi

    2015-10-01

    Co-administration of fluvoxamine (FLV) (perpetrator) and ramelteon (victim, high-clearance CYP1A2 substrate) reportedly showed a 130-fold increase in the area under blood-ramelteon-levels curve (AUCR), which is unpredictable by any method assuming the traditional well-stirred hepatic extraction (Eh ) model. Thus, in order to predict this drug interaction (DDI), a mathematical method that allows simulation of dynamic changes in blood victim levels in response to metabolic inhibition by a perpetrator, without the use of any specialized tools, was derived using hybridized two-compartment hepatic drug-pool-based tube modeling. Using this method, the ramelteon-victimized DDI could be simulated in comparison with other victim DDIs, assuming a consistent FLV dosing regimen. Despite large differences in AUCRs, CYP1A2 or CYP2C19 substrate-victimized DDIs resulted in equivalent inhibition constants (Ki , around 3 nM) and net enzymatic inhibitory activities calculated by eliminating hepatic availability increases for victims. Thus, the unusually large ramelteon DDI could be attributed to the Eh of ramelteon itself. This DDI risk could also be accurately predicted from Ki s estimated in the other CYP1A2 or CYP2C19-substrate interactions. Meanwhile, dynamic changes in blood perpetrator levels were demonstrated to have a small effect on DDI, thus suggesting the usefulness of a tube-based static method for DDI prediction. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

  19. Gene-gene-environment interactions between drugs, transporters, receptors, and metabolizing enzymes: Statins, SLCO1B1, and CYP3A4 as an example.

    Science.gov (United States)

    Sadee, Wolfgang

    2013-09-01

    Pharmacogenetic biomarker tests include mostly specific single gene-drug pairs, capable of accounting for a portion of interindividual variability in drug response and toxicity. However, multiple genes are likely to contribute, either acting independently or epistatically, with the CYP2C9-VKORC1-warfarin test panel, an example of a clinically used gene-gene-dug interaction. I discuss here further instances of gene-gene-drug interactions, including a proposed dynamic effect on statin therapy by genetic variants in both a transporter (SLCO1B1) and a metabolizing enzyme (CYP3A4) in liver cells, the main target site where statins block cholesterol synthesis. These examples set a conceptual framework for developing diagnostic panels involving multiple gene-drug combinations. Copyright © 2013 Wiley Periodicals, Inc.

  20. Drug-DNA adducts as biomarkers for metabolic activation of the nitro-aromatic nitrogen mustard prodrug PR-104A.

    Science.gov (United States)

    Stornetta, Alessia; Deng, Kai-Cheng Kieren; Danielli, Sara; Liyanage, H D Sarath; Sturla, Shana J; Wilson, William R; Gu, Yongchuan

    2018-04-07

    PR-104A is a clinical-stage nitrogen mustard prodrug that is activated for DNA alkylation by reduction of a nitro group to the corresponding hydroxylamine (PR-104H) or amine (PR-104M). Metabolic reduction is catalysed by flavoreductases such as cytochrome P450 oxidoreductase (POR) under hypoxia, or by aldo-ketoreductase 1C3 (AKR1C3) independently of hypoxia. The unstable reduced metabolites are challenging to measure in biological samples, and biomarkers of the metabolic activation of PR-104A have not been used in the clinical evaluation of PR-104 to date. Here, we employ a selected reaction monitoring mass spectrometry assay for DNA crosslinks to assess the capacity of human cancer cells to bioactivate PR-104A. We also test whether the more abundant DNA monoadducts could be used for the same purpose. DNA monoadducts and crosslinks from PR-104A itself, and from its reduced metabolites, accumulated over 4 h in AKR1C3-expressing TF1 erythroleukaemia cells under hypoxia, whereas intracellular concentrations of unstable PR-104H and PR-104M reached steady state within 1 h. We then varied rates of PR-104A reduction by manipulating hypoxia or reductase expression in a panel of cell lines, in which AKR1C3 and POR were quantified by targeted proteomics. Hypoxia or reductase overexpression induced large increases in PR-104A sensitivity (inhibition of proliferation), DNA damage response (γH2AX formation), steady-state concentrations of PR-104H/M and formation of reduced drug-DNA adducts but not DNA adducts retaining the dinitro groups of PR-104A. The fold-change in the sum of PR-104H and PR-104M correlated with the fold-change in reduced crosslinks or monoadducts (R 2  = 0.87 for both), demonstrating their potential for assessing the capacity of cancer cells to bioactivate PR-104A. Copyright © 2018 Elsevier Inc. All rights reserved.

  1. Real Time Extraction Kinetics of Electro Membrane Extraction Verified by Comparing Drug Metabolism Profiles Obtained from a Flow-Flow Electro Membrane Extraction-Mass Spectrometry System with LC-MS

    DEFF Research Database (Denmark)

    Fuchs, David; Jensen, Henrik; Pedersen-Bjergaard, Stig

    2015-01-01

    A simple to construct and operate, "dip-in" electromembrane extraction (EME) probe directly coupled to electrospray ionization-mass spectrometry (ESI-MS) for rapid extraction and real time analysis of various analytes was developed. The setup demonstrated that EME-MS can be used as a viable...... alternative to conventional protein precipitation followed by liquid chromatography-mass spectrometry (LC-MS) for studying drug metabolism. Comparison of EME-MS with LC-MS for drug metabolism analysis demonstrated for the first time that real time extraction of analytes by EME is possible. Metabolism kinetics...... were investigated for three different drugs: amitriptyline, promethazine, and methadone. By comparing the EME-MS extraction profiles of the drug substances and formed drug metabolites with the metabolism profiles obtained by conventional protein precipitation followed by LC-MS good correlation...

  2. Anti-hypertensive drug treatment of patients with and the metabolic syndrome and obesity: a review of evidence, meta-analysis, post hoc and guidelines publications.

    Science.gov (United States)

    Owen, Jonathan G; Reisin, Efrain

    2015-06-01

    Epidemiological studies have shown an increasing prevalence of obesity and the metabolic syndrome worldwide. Lifestyle modifications that include dietary changes, weight reduction, and exercise are the cornerstones in the treatment of this pathology. However, adherence to this approach often meets with failure in clinical practice; therefore, drug therapy should not be delayed. The ideal pharmacological antihypertensive regimen should target the underlying mechanisms involved in this syndrome, including sympathetic activation, increased renal tubular sodium reabsorption, and overexpression of the renin-angiotensin-aldosterone system by the adipocyte. Few prospective trials have been conducted in the search of the ideal antihypertensive regimen in patients with obesity and the metabolic syndrome. We summarize previously published ad hoc studies, prospective studies, and guideline publications regarding the treatment of hypertension in patients with obesity and the metabolic syndrome. We conclude that the optimal antihypertensive drug therapy in these patients has not been defined. Though caution exists regarding the use of thiazide diuretics due to potential metabolic derangements, there is insufficient data to show worsened cardiovascular or renal outcomes in patients treated with these drugs. In regard to beta blockers, the risk of accelerating conversion to diabetes and worsening of inflammatory mediators described in patients treated with traditional beta blockers appears much less pronounced or absent when using the vasodilating beta blockers. Renin-angiotensin-aldosterone system (RAAS) inhibition with an ACE or an ARB and treatment with calcium channel blockers appears safe and well tolerated in obesity-related hypertension and in patients with metabolic syndrome. Future prospective pharmacological studies in this population are needed.

  3. The efficacy of black cumin seed (Nigella sativa) oil and hypoglycemic drug combination to reduce HbA1c level in patients with metabolic syndrome risk

    Science.gov (United States)

    Rachman, P. N. R.; Akrom; Darmawan, E.

    2017-11-01

    Metabolic syndrome is a conditions caused by metabolic abnormalities include central obesity, atherogenic dyslipidemia, hypertension, and insulin resistance. HbA1c examination is required to study the long-term glycemic status and to prevent diabetic complications of metabolic syndrome. The purpose of this study is to determine the efficacy of black cumin seed (Nigella sativa) oil and hypoglycemic drug combination to reduce HbA1c level in patients with metabolic syndrome risk. This research performed using an experimental randomized single - blind controlled trial design. A total of 99 outpatients at the Jetis I Public Health Center, Yogyakarta, Indonesia with metabolic syndrome risk were divided into three groups: The control group received placebo and two treatment groups received black seed oil orally at dose of 1.5 mL/day and 3 mL/day, respectively, for 20 days. The clinical conditions such as blood pressure, pulse rate, BMI, blood glucose serum and HbA1c levels were examined on day 0 and 21. The results obtained were analyzed with one-way ANOVA test. The mean of HbA1c levels of all groups before treatment was higher than the normal values and there was no significant difference in HbA1c value on day 0. Administration of 1.5 and 3 mL/day of black seed oil for 20 days decreased (p<0.05) HbA1c levels. It can be concluded that administration of black cumin seed oil and hypoglycemic drug combination for 20 days in patients at risk of metabolic syndrome may reduce to HbA1c levels.

  4. The effects of anticholinergic drugs on regional cerebral blood flow, and oxygen metabolism in previously untreated patients with Parkinson's disease

    International Nuclear Information System (INIS)

    Obara, Satoko; Takahashi, Satoshi; Yonezawa, Hisashi; Sato, Yoshitomo

    1998-01-01

    Regional cerebral blood flow (rCBF) and oxygen metabolism (rCMRO 2 ) were measured using the steady-state 15 O technique and positron emission tomography (PET) in six previously untreated patients with Parkinson's disease before and after trihexyphenidyl (THP) treatment. The patients comprised of 4 men and 2 women with Hoehn-Yahr stage II-III. Their ages at the onset of the study ranged from 46 to 57 years (mean±SD, 51.8±3.7) and the duration of the illness ranged from 10 to 48 months (mean±SD, 28.8±15.5). The PET study, assessments of the disability and cognitive function were undergone twice. The first time assessments were done was when the patients were not receiving any drugs, and the second time was one to three months after administration of 6 mg THP. All patients showed clinical improvement after THP treatment. The mean disability score of Unified Parkinson's Disease Rating Scale decreased from 35.1 (SD±11.3) to 25.7 (SD±11.6). The cognitive function assessed by Hasegawa's dementia rating scale-revised, Mini-Mental State Examination, Wechsler Adult Intelligence Scale-Revised, and Wechsler Memory Scale-Revised, were not significantly different before and after the THP treatment. After the THP treatment, rCBF and rCMRO 2 decreased significantly in the striatum (about 15%) and all cerebral cortices (about 10%) on both sides contralateral and ipsilateral to the predominantly symptomatic limbs. We conclude that an anticholinergic THP decreases the rCBF and rCMRO 2 significantly in the cerebral cortices without cognitive impairment in early untreated patients with Parkinson's disease. (author)

  5. Influence of Sulforaphane Metabolites on Activities of Human Drug-Metabolizing Cytochrome P450 and Determination of Sulforaphane in Human Liver Cells.

    Science.gov (United States)

    Vanduchova, Alena; Tomankova, Veronika; Anzenbacher, Pavel; Anzenbacherova, Eva

    2016-12-01

    The influence of metabolites of sulforaphane, natural compounds present in broccoli (Brassica oleracea var. botrytis italica) and in other cruciferous vegetables, on drug-metabolizing cytochrome P450 (CYP) enzymes in human liver microsomes and possible entry of sulforaphane into human hepatic cells were investigated. Metabolites studied are compounds derived from sulforaphane by the mercapturic acid pathway (conjugation with glutathione and by following reactions), namely sulforaphane glutathione and sulforaphane cysteine conjugates and sulforaphane-N-acetylcysteine. Their possible effect on four drug-metabolizing CYP enzymes, CYP3A4 (midazolam 1'-hydroxylation), CYP2D6 (bufuralol 1'-hydroxylation), CYP1A2 (7-ethoxyresorufin O-deethylation), and CYP2B6 (7-ethoxy-4-(trifluoromethyl)coumarin O-deethylation), was tested. Inhibition of four prototypical CYP activities by sulforaphane metabolites was studied in pooled human liver microsomes. Sulforaphane metabolites did not considerably affect biological function of drug-metabolizing CYPs in human liver microsomes except for CYP2D6, which was found to be inhibited down to 73-78% of the original activity. Analysis of the entry of sulforaphane into human hepatocytes was done by cell disruption by sonication, methylene chloride extraction, and modified high-performance liquid chromatography method. The results have shown penetration of sulforaphane into the human hepatic cells.

  6. Evaluation of the synergistic effect of Allium sativum, Eugenia jambolana, Momordica charantia, Ocimum sanctum and Psidium guajav on hepatic and intestinal drug metabolizing enzymes in rats

    Directory of Open Access Journals (Sweden)

    Devendra Kumar

    2016-12-01

    Full Text Available Aims/Background: Present study investigated the synergistic effect of polyherbal formulations (PHF of Allium sativum L Eugenia jambolana Lam., Momordica charantia L., Ocimum sanctum Linn and Psidium guajava L. in the inhibition/induction of hepatic and intestinal CYPs and Phase-II conjugated drug metabolizing enzymes. Consumption of these herbal remedy has been extensively documented for diabetes treatment in Auyureda. Methodology: PHF of these five herbs was prepared and different doses were orally administered to Sprague Dawley rats of different groups except control group. Expression of mRNA and activity of drug metabolizing enzymes were examined by RT-PCR and HPLC in isolated liver and intestine microsomes in PHF pretreated rats. Results: Activities of hepatic and intestinal Phase-II enzyme levels increased along with mRNA levels except CYP3A mRNA level. PHF administration increases the activity of hepatic and intestinal UDPGT and GST in response to dose and time; however, activity of hepatic SULT increased at higher doses. Conclusions: CYPs and Phase-II conjugated enzymes levels can be modulated in dose and time dependent manner. Observations suggest that poly herbal formulation might be a possible cause of herb-drug interaction, due to changes in pharmacokinetic of crucial CYPs and Phase-II substrate drug. [J Complement Med Res 2016; 5(4.000: 372-382

  7. From Omics to Drug Metabolism and High Content Screen of Natural Product in Zebrafish: A New Model for Discovery of Neuroactive Compound

    Directory of Open Access Journals (Sweden)

    Ming Wai Hung

    2012-01-01

    Full Text Available The zebrafish (Danio rerio has recently become a common model in the fields of genetics, environmental science, toxicology, and especially drug screening. Zebrafish has emerged as a biomedically relevant model for in vivo high content drug screening and the simultaneous determination of multiple efficacy parameters, including behaviour, selectivity, and toxicity in the content of the whole organism. A zebrafish behavioural assay has been demonstrated as a novel, rapid, and high-throughput approach to the discovery of neuroactive, psychoactive, and memory-modulating compounds. Recent studies found a functional similarity of drug metabolism systems in zebrafish and mammals, providing a clue with why some compounds are active in zebrafish in vivo but not in vitro, as well as providing grounds for the rationales supporting the use of a zebrafish screen to identify prodrugs. Here, we discuss the advantages of the zebrafish model for evaluating drug metabolism and the mode of pharmacological action with the emerging omics approaches. Why this model is suitable for identifying lead compounds from natural products for therapy of disorders with multifactorial etiopathogenesis and imbalance of angiogenesis, such as Parkinson's disease, epilepsy, cardiotoxicity, cerebral hemorrhage, dyslipidemia, and hyperlipidemia, is addressed.

  8. Development and characterization of a small electromembrane extraction probe coupled with mass spectrometry for real-time and online monitoring of in vitro drug metabolism

    DEFF Research Database (Denmark)

    Dugstad, Helene Bonkerud; Petersen, Nickolaj J.; Jensen, Henrik

    2014-01-01

    A small and very simple electromembrane extraction probe (EME-probe) was developed and coupled directly to electrospray ionization mass spectrometry (ESI-MS), and this system was used to monitor in real time in vitro metabolism by rat liver microsomes of drug substances from a small reaction...... (incubation) chamber (37 °C). The drug-related substances were continuously extracted from the 1.0 mL metabolic reaction mixture and into the EME-probe by an electrical potential of 2.5 V. The extraction probe consisted of a 1-mm long and 350-μm ID thin supported liquid membrane (SLM) of 2-nitrophenyl octyl...... ether. The drugs and formed metabolites where extracted through the SLM and directly into a 3 μL min(-1) flow of 60 mM HCOOH inside the probe serving as the acceptor solution. The acceptor solution was directed into the ESI-MS-system, and the MS continuously monitored the drug-related substances...

  9. Effects of meal composition and meal timing on the expression of genes involved in hepatic drug metabolism in rats

    NARCIS (Netherlands)

    de Vries, E M; Oosterman, Johanneke E; Eggink, Hannah M; de Goede, P; Sen, Satish; Foppen, E; Boudzovitch-Surovtseva, Olga; Boelen, A.; Romijn, Johannes A; La Fleur, S.E.; Kalsbeek, A

    2017-01-01

    INTRODUCTION: With chronotherapy, drug administration is synchronized with daily rhythms in drug clearance and pharmacokinetics. Daily rhythms in gene expression are centrally mastered by the suprachiasmatic nucleus of the hypothalamus as well as by tissue clocks containing similar molecular

  10. Effects of meal composition and meal timing on the expression of genes involved in hepatic drug metabolism in rats

    NARCIS (Netherlands)

    de Vries, E. M.; Oosterman, J. E.; Eggink, H. M.; de Goede, P.; Sen, S.; Foppen, E.; Boudzovitch-Surovtseva, O.; Boelen, A.; Romijn, J. A.; laFleur, S. E.; Kalsbeek, A.

    2017-01-01

    With chronotherapy, drug administration is synchronized with daily rhythms in drug clearance and pharmacokinetics. Daily rhythms in gene expression are centrally mastered by the suprachiasmatic nucleus of the hypothalamus as well as by tissue clocks containing similar molecular mechanisms in

  11. Metabolically active extracellular vesicles released from hepatocytes under drug-induced liver-damaging conditions modify serum metabolome and might affect different pathophysiological processes.

    Science.gov (United States)

    Royo, Felix; Palomo, Laura; Mleczko, Justyna; Gonzalez, Esperanza; Alonso, Cristina; Martínez, Ibon; Pérez-Cormenzana, Miriam; Castro, Azucena; Falcon-Perez, Juan M

    2017-02-15

    Hepatocytes are involved in the endogenous and drug metabolism; many of the enzymes involved in those processes are incorporated into extracellular vesicles and secreted into the bloodstream. Liver-damaging conditions modify the molecular cargo of those vesicles significantly. However, no information about the effect of these hepatic vesicles on the extracellular environment is available. Drug-induced liver damage increases the number of circulating extracellular vesicles and affects the release and content of hepatocyte-derived vesicles. In this work, we evaluated the metabolic effect of these vesicles on the composition of the serum. We performed a targeted ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) metabolomics analysis of serum samples. The samples had been first incubated with hepatic extracellular vesicles from hepatocytes challenged with acetaminophen or diclofenac. The incubation affected the serum levels of 67 metabolites, such as amino acids and different species of lipids. The metabolites included various species of phosphatidylcholines and phosphatidylethanolamines. These compounds are the components of biological membranes; our observations suggest that the vesicles might take part in remodelling and maintenance of the membranes. Alterations in the levels of some other serum metabolites might have deleterious consequences, for example, the tetracosanoic acid with its cardiovascular effects. However, some of the metabolites whose levels were increased, including alpha-linoleic and tauroursodeoxycholic acids, have been reported to have a protective effect. Our targeted metabolomics analysis indicated that the hepatic extracellular vesicles act as nano-metabolic machines supplying the extracellular environment with the means to integrate diverse tissue responses. In conclusion, we show that the hepatic extracellular vesicles are metabolically active and might play a role in the physiopathological response to hepatic insults

  12. Combining Potent Statin Therapy with Other Drugs to Optimize Simultaneous Cardiovascular and Metabolic Benefits while Minimizing Adverse Events

    OpenAIRE

    Koh, Kwang Kon; Sakuma, Ichiro; Shimada, Kazunori; Hayashi, Toshio; Quon, Michael J.

    2017-01-01

    Hypercholesterolemia and hypertension are among the most important risk factors for cardiovascular (CV) disease. They are also important contributors to metabolic diseases including diabetes that further increase CV risk. Updated guidelines emphasize targeted reduction of overall CV risks but do not explicitly incorporate potential adverse metabolic outcomes that also influence CV health. Hypercholesterolemia and hypertension have synergistic deleterious effects on interrelated insulin resist...

  13. Human carbonyl reductase 1 participating in intestinal first-pass drug metabolism is inhibited by fatty acids and acyl-CoAs.

    Science.gov (United States)

    Hara, Akira; Endo, Satoshi; Matsunaga, Toshiyuki; El-Kabbani, Ossama; Miura, Takeshi; Nishinaka, Toru; Terada, Tomoyuki

    2017-08-15

    Human carbonyl reductase 1 (CBR1), a member of the short-chain dehydrogenase/reductase (SDR) superfamily, reduces a variety of carbonyl compounds including endogenous isatin, prostaglandin E 2 and 4-oxo-2-nonenal. It is also a major non-cytochrome P450 enzyme in the phase I metabolism of carbonyl-containing drugs, and is highly expressed in the intestine. In this study, we found that long-chain fatty acids and their CoA ester derivatives inhibit CBR1. Among saturated fatty acids, myristic, palmitic and stearic acids were inhibitory, and stearic acid was the most potent (IC 50 9µM). Unsaturated fatty acids (oleic, elaidic, γ-linolenic and docosahexaenoic acids) and acyl-CoAs (palmitoyl-, stearoyl- and oleoyl-CoAs) were more potent inhibitors (IC 50 1.0-2.5µM), and showed high inhibitory selectivity to CBR1 over its isozyme CBR3 and other SDR superfamily enzymes (DCXR and DHRS4) with CBR activity. The inhibition by these fatty acids and acyl-CoAs was competitive with respect to the substrate, showing the K i values of 0.49-1.2µM. Site-directed mutagenesis of the substrate-binding residues of CBR1 suggested that the interactions between the fatty acyl chain and the enzyme's Met141 and Trp229 are important for the inhibitory selectivity. We also examined CBR1 inhibition by oleic acid in cellular levels: The fatty acid effectively inhibited CBR1-mediated 4-oxo-2-nonenal metabolism in colon cancer DLD1 cells and increased sensitivity to doxorubicin in the drug-resistant gastric cancer MKN45 cells that highly express CBR1. The results suggest a possible new food-drug interaction through inhibition of CBR1-mediated intestinal first-pass drug metabolism by dietary fatty acids. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Real Time Extraction Kinetics of Electro Membrane Extraction Verified by Comparing Drug Metabolism Profiles Obtained from a Flow-Flow Electro Membrane Extraction-Mass Spectrometry System with LC-MS.

    Science.gov (United States)

    Fuchs, David; Jensen, Henrik; Pedersen-Bjergaard, Stig; Gabel-Jensen, Charlotte; Hansen, Steen Honoré; Petersen, Nickolaj Jacob

    2015-06-02

    A simple to construct and operate, "dip-in" electromembrane extraction (EME) probe directly coupled to electrospray ionization-mass spectrometry (ESI-MS) for rapid extraction and real time analysis of various analytes was developed. The setup demonstrated that EME-MS can be used as a viable alternative to conventional protein precipitation followed by liquid chromatography-mass spectrometry (LC-MS) for studying drug metabolism. Comparison of EME-MS with LC-MS for drug metabolism analysis demonstrated for the first time that real time extraction of analytes by EME is possible. Metabolism kinetics were investigated for three different drugs: amitriptyline, promethazine, and methadone. By comparing the EME-MS extraction profiles of the drug substances and formed drug metabolites with the metabolism profiles obtained by conventional protein precipitation followed by LC-MS good correlation was obtained with only very limited time delay in the extraction. The results indicate that, by tuning the electromembrane properties, for example, by optimizing the extraction voltage, extremely fast extraction kinetics can be obtained. A metabolic profile could be generated while the drug was metabolized offering a significant time saving as compared to conventional LC-MS where laborious protein precipitation or other sample pretreatments are required before analysis. This makes the developed EME-MS setup a highly promising sample preparation method for various kinds of applications where fast and real-time analysis of analytes is of interest.

  15. Metabolism of a novel side chain modified Δ8(14)-15-ketosterol, a potential cholesterol lowering drug: 28-hydroxylation by CYP27A1

    Science.gov (United States)

    Pettersson, Hanna; Norlina, Maria; Andersson, Ulla; Pikuleva, Irina; Björkhem, Ingemar; Misharin, Alexander Yu.; Wikvall, Kjell

    2009-01-01

    The synthetic inhibitors of sterol biosynthesis, 3β-hydroxy-5α-cholest-8(14)-en-15-one and 3β-hydroxy-24S-methyl-5α-cholesta-8(14),22-dien-15-one, are of interest as potential cholesterol lowering drugs. Rapid metabolism of synthetic 15-ketosterols may lead to a decrease, or loss, of their potency to affect lipid metabolism. 3β-Hydroxy-5α-cholest-8(14)-en-15-one is reported to be rapidly side chain oxygenated by rat liver mitochondria. In an attempt to reduce this metabolism, the novel side-chain modified 15-ketosterol 3β-Hydroxy-24S-methyl-5α-cholesta-8(14),22-dien-15-one was synthesized. We have examined the metabolism by recombinant human CYP27A1 of this novel side-chain modified 3β-hydroxy-24S-methyl-5α-cholesta-8(14),22-dien-15-one and compared the rate of metabolism with that of the previously described 3β-hydroxy-5α-cholest-8(14)-en-15-one. Both sterols were found to be efficiently metabolized by recombinant human CYP27A1. None of the two 15-ketosterols was significantly metabolized by microsomal 7α-hydroxylation. Interestingly, CYP27A1-mediated product formation was much lower with the side-chain modified 3β-hydroxy-24S-methyl-5α-cholesta-8(14),22-dien-15-one than with the previously described 3β-hydroxy-5α-cholest-8(14)-en-15-one. A surprising finding was that this novel side-chain modified sterol was metabolized mainly in the C-28 position by CYP27A1. The data on 28-hydroxylation by human CYP27A1 provide new insights on the catalytic properties and substrate specificity of this enzyme. The finding that 3β-hydroxy-24S-methyl-5α-cholesta-8(14),22-dien-15-one with a modified side chain is metabolized at a dramatically slower rate than the previously described 15-ketosterol with unmodified side chain may be important for future development of synthetic cholesterol lowering sterols. PMID:18603016

  16. Metabolism of a novel side chain modified Delta8(14)-15-ketosterol, a potential cholesterol lowering drug: 28-hydroxylation by CYP27A1.

    Science.gov (United States)

    Pettersson, Hanna; Norlin, Maria; Andersson, Ulla; Pikuleva, Irina; Björkhem, Ingemar; Misharin, Alexander Yu; Wikvall, Kjell

    2008-08-01

    The synthetic inhibitors of sterol biosynthesis, 3beta-hydroxy-5alpha-cholest-8(14)-en-15-one and 3beta-hydroxy-24S-methyl-5alpha-cholesta-8(14),22-dien-15-one, are of interest as potential cholesterol lowering drugs. Rapid metabolism of synthetic 15-ketosterols may lead to a decrease, or loss, of their potency to affect lipid metabolism. 3beta-Hydroxy-5alpha-cholest-8(14)-en-15-one is reported to be rapidly side chain oxygenated by rat liver mitochondria. In an attempt to reduce this metabolism, the novel side chain modified 15-ketosterol 3beta-Hydroxy-24S-methyl-5alpha-cholesta-8(14),22-dien-15-one was synthesized. We have examined the metabolism by recombinant human CYP27A1 of this novel side chain modified 3beta-hydroxy-24S-methyl-5alpha-cholesta-8(14),22-dien-15-one and compared the rate of metabolism with that of the previously described 3beta-hydroxy-5alpha-cholest-8(14)-en-15-one. Both sterols were found to be efficiently metabolized by recombinant human CYP27A1. None of the two 15-ketosterols was significantly metabolized by microsomal 7alpha-hydroxylation. Interestingly, CYP27A1-mediated product formation was much lower with the side chain modified 3beta-hydroxy-24S-methyl-5alpha-cholesta-8(14),22-dien-15-one than with the previously described 3beta-hydroxy-5alpha-cholest-8(14)-en-15-one. A surprising finding was that this novel side chain modified sterol was metabolized mainly in the C-28 position by CYP27A1. The data on 28-hydroxylation by human CYP27A1 provide new insights on the catalytic properties and substrate specificity of this enzyme. The finding that 3beta-hydroxy-24S-methyl-5alpha-cholesta-8(14),22-dien-15-one with a modified side chain is metabolized at a dramatically slower rate than the previously described 15-ketosterol with unmodified side chain may be important for future development of synthetic cholesterol lowering sterols.

  17. The METEOR study: frequency of metabolic disorders in patients with schizophrenia. Focus on first and second generation and level of risk of antipsychotic drugs.

    Science.gov (United States)

    Falissard, Bruno; Mauri, Mauro; Shaw, Ken; Wetterling, Tilman; Doble, Adam; Giudicelli, Agnès; De Hert, Marc

    2011-11-01

    The objective of this crosssectional study was to estimate the prevalence of metabolic disorders and hypertension in patients with schizophrenia and to compare prevalence between patients treated with first-generation (FGA) and second-generation (SGA) antipsychotic drugs. The study included 2270 adults with schizophrenia. Patients were assigned to an FGA or SGA stratum on the basis of current treatment. Data were collected on sociodemographic, lifestyle and clinical variables. Blood pressure, waist and hip circumference, blood glucose, triglycerides and cholesterol were measured. The primary evaluation criterion was the prevalence of a glycaemic disorder. Secondary criteria were the prevalence of dyslipidaemia, obesity, hypertension and metabolic syndrome. A propensity score was used to control imbalance between strata. The prevalence of glycaemic disorders was 31.1% (FGA) and 27.6% (SGA). No between-strata difference in prevalence was observed for glycaemic disorders, dyslipidaemia or metabolic syndrome. The prevalence of hypertension was higher (P=0.033) in the FGA group. The proportion of women (but not men) who were overweight or obese was higher in the SGA group (P=0.035), as was the proportion reporting weight gain of more than 5 kg (P<0.001). In an exploratory unadjusted post-hoc analysis, significantly higher frequencies of dysglycaemia (28.5 vs. 22.0%; P=0.006), low HDL cholesterol (35.3 vs. 29.7%; P=0.023) and metabolic syndrome (36.7 vs. 30.7%; P=0.021) were observed in patients taking SGAs considered to carry high metabolic risk compared with those taking low-risk agents. In conclusion, metabolic disorders are prevalent in patients with schizophrenia treated with antipsychotics and are under-diagnosed and under-treated.

  18. Inflammation's Association with Metabolic Profiles before and after a Twelve-Week Clinical Trial in Drug-Naïve Patients with Bipolar II Disorder.

    Directory of Open Access Journals (Sweden)

    Sheng-Yu Lee

    Full Text Available Inflammation is thought to be involved in the pathophysiology of bipolar disorder (BP and metabolic syndrome. Prior studies evaluated the association between metabolic profiles and cytokines only during certain mood states instead of their changes during treatment. We enrolled drug-naïve patients with BP-II and investigated the correlation between changes in mood symptoms and metabolic indices with changes in plasma cytokine levels after 12 weeks of pharmacological treatment. Drug-naïve patients (n = 117 diagnosed with BP-II according to DSM-IV criteria were recruited. Metabolic profiles (cholesterol, triglyceride, HbA1C, fasting serum glucose, body mass index (BMI and plasma cytokines (TNF-α, CRP, IL-6, and TGF-β were measured at baseline and 2, 8, and 12 weeks post-treatment. To adjust within-subject dependence over repeated assessments, multiple linear regressions with generalized estimating equation methods were used. Seventy-six (65.0% patients completed the intervention. Changes in plasma CRP were significantly associated with changes in BMI (P = 1.7E-7 and triglyceride (P = 0.005 levels. Changes in plasma TGF-β1 were significantly associated with changes in BMI (P = 8.2E-6, cholesterol (P = 0.004, and triglyceride (P = 0.006 levels. However, changes in plasma TNF-α and IL-6 were not associated with changes in any of the metabolic indices. Changes in Hamilton Depression Rating Scale scores were significantly associated with changes in IL-6 (P = 0.003 levels; changes in Young Mania Rating Scale scores were significantly associated with changes in CRP (P = 0.006 and TNF-α (P = 0.039 levels. Plasma CRP and TGF-β1 levels were positively correlated with several metabolic indices in BP-II after 12 weeks of pharmacological intervention. We also hypothesize that clinical symptoms are correlated with certain cytokines. These new findings might be important evidence that inflammation is the pathophysiology

  19. Genetic polymorphisms of drug-metabolizing cytochrome P450 enzymes in cynomolgus and rhesus monkeys and common marmosets in preclinical studies for humans.

    Science.gov (United States)

    Uno, Yasuhiro; Uehara, Shotaro; Yamazaki, Hiroshi

    2017-12-23

    Cynomolgus monkeys (Macaca fascicularis, Old World Monkeys) and common marmosets (Callithrix jacchus, New World Monkeys) have been widely, and expectedly, used as non-human primate models in drug development studies. Major drug-metabolizing cytochrome P450 (P450) enzymes information is now available that supports these primate species as animal models, and it is established that multiple forms of cynomolgus monkey and common marmoset P450 enzymes have generally similar substrate recognition functionality to human P450 enzymes. This research update provides information on genetic polymorphisms of P450 enzymes in cynomolgus monkey and common marmoset like human P450 enzymes. Information on rhesus monkeys (Macaca mulatta), another macaque species used in drug metabolism studies, is also included for comparison. Among a variety of cynomolgus monkey P450 variants investigated, typical examples include individual pharmacokinetic data for efavirenz and R-warfarin associated with cynomolgus monkey P450 2C9 (formerly 2C43) and 2C19 (2C75) variants, respectively, and for R-omeprazole and S-warfarin associated with marmoset P450 2C19 variants. These findings provide a foundation for understanding the individual pharmacokinetic and toxicological results in non-human primates as preclinical models and will help to further support understanding of molecular mechanisms of human P450 function. In addition to these polymorphic P450 enzymes, effects of aging on some drug clearances mediated by cynomolgus monkey and common marmoset P450 enzymes were found in elder animals or animals pretreated with rifampicin. This review describes genetic and acquired individual differences in cynomolgus monkey and common marmoset P450 enzymes involved in drug oxidation associated with pharmacological and/or toxicological effects. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Investigating the metabolic capabilities of Mycobacterium tuberculosis H37Rv using the in silico strain iNJ661 and proposing alternative drug targets

    Directory of Open Access Journals (Sweden)

    Palsson Bernhard Ø

    2007-06-01

    Full Text Available Abstract Background: Mycobacterium tuberculosis continues to be a major pathogen in the third world, killing almost 2 million people a year by the most recent estimates. Even in industrialized countries, the emergence of multi-drug resistant (MDR strains of tuberculosis hails the need to develop additional medications for treatment. Many of the drugs used for treatment of tuberculosis target metabolic enzymes. Genome-scale models can be used for analysis, discovery, and as hypothesis generating tools, which will hopefully assist the rational drug development process. These models need to be able to assimilate data from large datasets and analyze them. Results: We completed a bottom up reconstruction of the metabolic network of Mycobacterium tuberculosis H37Rv. This functional in silico bacterium, iNJ661, contains 661 genes and 939 reactions and can produce many of the complex compounds characteristic to tuberculosis, such as mycolic acids and mycocerosates. We grew this bacterium in silico on various media, analyzed the model in the context of multiple high-throughput data sets, and finally we analyzed the network in an 'unbiased' manner by calculating the Hard Coupled Reaction (HCR sets, groups of reactions that are forced to operate in unison due to mass conservation and connectivity constraints. Conclusion: Although we observed growth rates comparable to experimental observations (doubling times ranging from about 12 to 24 hours in different media, comparisons of gene essentiality with experimental data were less encouraging (generally about 55%. The reasons for the often conflicting results were multi-fold, including gene expression variability under different conditions and lack of complete biological knowledge. Some of the inconsistencies between in vitro and in silico or in vivo and in silico results highlight specific loci that are worth further experimental investigations. Finally, by considering the HCR sets in the context of known

  1. Metabolic Diseases Drug Discovery-Strategic Research Institute's Third International World Summit. Dipeptidyl peptidase-IV inhibitors 26-27 July 2004, San Diego, CA, USA.

    Science.gov (United States)

    Xu, Jing

    2004-09-01

    The majority of the presentations a the conference were on three highly sought-after targets for type 2 diabetes mellitus, namely PTP1B, PPARs and DPP-IV, reflecting the current focus and trend in the industry. A couple of novel targets were discussed, including the potential of myostatin as a type 2 diabetes mellitus target and a novel GPCR target. While small molecules were dominant, several biological-based approaches were covered: antibody therapeutics and oligonucleotide-based approaches (ASO and siRNA). In searching for small-molecule leads, structure-based rational design and focused combination chemistry appear to produce better results than a random high-throughput approach over the entire chemical library. The biggest challenges for diabetes and obesity drugs remain similar to those mentioned in previous meetings: increasing specificity to reduce side effects and maintaining long-term effect while maintaining or increasing efficacy. Due to the tremendous interest of the pharmaceutical industry in metabolic disease drug development, our knowledge of food intake and metabolism regulation has increased exponentially. Overall, the prospect of better drugs for, and better control of, type 2 diabetes mellitus and obesity is promising.

  2. UPLC/ESI-QTOF-MS-based metabolomics survey on the toxicity of triptolide and detoxication of licorice.

    Science.gov (United States)

    Wang, Zhuo; Liu, Jian-Qun; Xu, Jin-Di; Zhu, He; Kong, Ming; Zhang, Guo-Hua; Duan, Su-Min; Li, Xiu-Yang; Li, Guang-Fu; Liu, Li-Fang; Li, Song-Lin

    2017-06-01

    Triptolide (TP) from Tripterygium wilfordii has been demonstrated to possess anti-inflammatory, immunosuppressive, and anticancer activities. TP is specially used for the treatment of awkward rheumatoid arthritis, but its clinical application is confined by intense side effects. It is reported that licorice can obviously reduce the toxicity of TP, but the detailed mechanisms involved have not been comprehensively investigated. The current study aimed to explore metabolomics characteristics of the toxic reaction induced by TP and the intervention effect of licorice water extraction (LWE) against such toxicity. Obtained urine samples from control, TP and TP + LWE treated rats were analyzed by UPLC/ESI-QTOF-MS. The metabolic profiles of the control and the TP group were well differentiated by the principal component analysis and orthogonal partial least squares-discriminant analysis. The toxicity of TP was demonstrated to be evolving along with the exposure time of TP. Eight potential biomarkers related to TP toxicity were successfully identified in urine samples. Furthermore, LWE treatment could attenuate the change in six of the eight identified biomarkers. Functional pathway analysis revealed that the alterations in these metabolites were associated with tryptophan, pantothenic acid, and porphyrin metabolism. Therefore, it was concluded that LWE demonstrated interventional effects on TP toxicity through regulation of tryptophan, pantothenic acid, and porphyrin metabolism pathways, which provided novel insights into the possible mechanisms of TP toxicity as well as the potential therapeutic effects of LWE against such toxicity. Copyright © 2017 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

  3. [The effect of polymorphism of genes of xenobiotics detoxication on the frequencies of spontaneous and induced chromosome aberrations in human lymphocytes].

    Science.gov (United States)

    Sal'nikova, L E; Akaeva, E A; Elisova, T V; Kuznetsova, G I; Kuz'mina, N S; Vesnina, I N; Lapteva, N Sh; Chumachenko, A G; Romanchuk, V A; Rubanovich, A V

    2009-01-01

    Here presented the data on the frequencies of chromosome aberrations in lymphocytes of peripheral blood of 97 volunteers depending on genotypes by genes of xenobiotics detoxication before and after gamma-irradiation with dose of 1 Gy in vitro. The frequencies of aberrations were estimated by analyzing not less than 500-1000 metaphases per person. The data of cytogenetic analysis were compared with the results of PCR-genotyping of loci GSTM1, GSTT1, GSTP1, CYP1A1, CYP2D6, NAT2, and MTHFR. The significant differences by the frequencies of aberrations between "single-locus" genotypes were not found except for GSTM1 locus, for which the enhanced frequency of spontaneous aberrations of chromosome type in "positive" genotypes compared to "zero" ones, i.e., homozygotes by deletion (p = 0.04) was observed. The minimum frequency of spontaneous aberrations of chromosome type was recorded for carriers of double homozygotes by deletion of GSTM1-GSTT1: 0.0006 +/- 0.0003 against 0.0027 +/- 0.0003 for the rest of genotypes (p = 0.016 by the Mann-Witney test). The frequency of gamma-induced chromosome aberrations was correlated with the total amount of minor alleles in loci GSTP1, NAT2, and MTHFR (r = 0.25 at p = 0.0065).

  4. Effect of the acquisition enhancing drug piracetam on rat cerebral energy metabolism. Comparison with naftidrofuryl and methamphetamine

    NARCIS (Netherlands)

    Nickolson, V.J.; Wolthuis, O.L.

    1976-01-01

    The effects of Piracetam, Naftidrofuryl and methamphetamine on several parameters of cerebral energy metabolism have been studied. At variance with some reports in the literature neither Piracetam nor Naftidrofuryl affected the cerebral contents of adenine nucleotides and, accordingly, both

  5. 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

    2017-12-14

    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.

  6. Immobilization of β-Cyclodextrin-Conjugated Lactoferrin onto Polymer Monolith for Enrichment of Ga in Metabolic Residues of Ga-Based Anticancer Drugs.

    Science.gov (United States)

    Zheng, Haijiao; Zhu, Tenggao; Li, Xiqian; Wang, Guan; Jia, Qiong

    2017-12-11

    Biological-material-functionalized porous monoliths were prepared with lactoferrin and β-cyclodextrin via a click reaction. With the monolith as an extraction medium, a method combined with ICP-MS was developed for the determination of total gallium originating from metabolic residues of orally bioavailable gallium complexes with tris(8-quinolinolato)gallium (GaQ 3 ) as a representative. The method exhibited favorable adsorption behaviors for gallium with high selectivity, low detection limit (2 ng L -1 ), and an enrichment factor of 29-fold with the sample throughput of 30 min -1 . The developed approach was validated by the analysis of gallium from GaQ 3 metabolic residues in a human cell line. Additionally, the practical applicability of this method was evaluated by the determination of gallium in human blood and urine samples from cancer patients. Results illustrated that the prepared monolith had potential in Ga-based anticancer drug analysis in complex biological samples.

  7. Studies on the metabolism and the toxicological analysis of the nootropic drug fipexide in rat urine using gas chromatography-mass spectrometry.

    Science.gov (United States)

    Staack, Roland F; Maurer, Hans H

    2004-05-25

    Qualitative studies are described on the metabolism and the toxicological analysis of the nootropic fipexide (FIP) in rat urine using gas chromatography-mass spectrometry (GC-MS). FIP was extensively metabolized to 1-(3,4-methylenedioxybenzyl)piperazine (MDBP), 4-chlorophenoxyacetic acid, 1-[2-(4-chlorophenoxy)acetyl]piperazine, N-(4-hydroxy-3-methoxy-benzyl)piperazine, piperazine, N-(3,4-methylenedioxybenzyl)ethylenediamine, and N-[2-(4-chlorophenoxy)acetyl]ethylenediamine. The authors' systematic toxicological analysis (STA) procedure using full-scan GC-MS after acid hydrolysis of one urine aliquot, liquid-liquid extraction and acetylation allowed the detection of FIP via its metabolites in rat urine after administration of a common FIP dose. Therefore, this qualitative procedure should also be suitable for detection of a FIP intake in human urine. Differentiation of an intake of FIP from that of other drugs which form common metabolites is discussed.

  8. Validation of in vitro cell models used in drug metabolism and transport studies; genotyping of cytochrome P450, phase II enzymes and drug transporter polymorphisms in the human hepatoma (HepG2), ovarian carcinoma (IGROV-1) and colon carcinoma (CaCo-2, LS180) cell lines

    International Nuclear Information System (INIS)

    Brandon, Esther F.A.; Bosch, Tessa M.; Deenen, Maarten J.; Levink, Rianne; Wal, Everdina van der; Meerveld, Joyce B.M. van; Bijl, Monique; Beijnen, Jos H.; Schellens, Jan H.M.; Meijerman, Irma

    2006-01-01

    Human cell lines are often used for in vitro biotransformation and transport studies of drugs. In vivo, genetic polymorphisms have been identified in drug-metabolizing enzymes and ABC-drug transporters leading to altered enzyme activity, or a change in the inducibility of these enzymes. These genetic polymorphisms could also influence the outcome of studies using human cell lines. Therefore, the aim of our study was to pharmacogenotype four cell lines frequently used in drug metabolism and transport studies, HepG2, IGROV-1, CaCo-2 and LS180, for genetic polymorphisms in biotransformation enzymes and drug transporters. The results indicate that, despite the presence of some genetic polymorphisms, no real effects influencing the activity of metabolizing enzymes or drug transporters in the investigated cell lines are expected. However, this characterization will be an aid in the interpretation of the results of biotransformation and transport studies using these in vitro cell models

  9. An enhanced in vivo stable isotope labeling by amino acids in cell culture (SILAC) model for quantification of drug metabolism enzymes.

    Science.gov (United States)

    MacLeod, A Kenneth; Fallon, Padraic G; Sharp, Sheila; Henderson, Colin J; Wolf, C Roland; Huang, Jeffrey T-J

    2015-03-01

    Many of the enzymes involved in xenobiotic metabolism are maintained at a low basal level and are only synthesized in response to activation of upstream sensor/effector proteins. This induction can have implications in a variety of contexts, particularly during the study of the pharmacokinetics, pharmacodynamics, and drug-drug interaction profile of a candidate therapeutic compound. Previously, we combined in vivo SILAC material with a targeted high resolution single ion monitoring (tHR/SIM) LC-MS/MS approach for quantification of 197 peptide pairs, representing 51 drug metabolism enzymes (DME), in mouse liver. However, as important enzymes (for example, cytochromes P450 (Cyp) of the 1a and 2b subfamilies) are maintained at low or undetectable levels in the liver of unstimulated metabolically labeled mice, quantification of these proteins was unreliable. In the present study, we induced DME expression in labeled mice through synchronous ligand-mediated activation of multiple upstream nuclear receptors, thereby enhancing signals for proteins including Cyps 1a, 2a, 2b, 2c, and 3a. With this enhancement, 115 unique, lysine-containing, Cyp-derived peptides were detected in the liver of a single animal, as opposed to 56 in a pooled sample from three uninduced animals. A total of 386 peptide pairs were quantified by tHR/SIM, representing 68 Phase I, 30 Phase II, and eight control proteins. This method was employed to quantify changes in DME expression in the hepatic cytochrome P450 reductase null (HRN) mouse. We observed compensatory induction of several enzymes, including Cyps 2b10, 2c29, 2c37, 2c54, 2c55, 2e1, 3a11, and 3a13, carboxylesterase (Ces) 2a, and glutathione S-transferases (Gst) m2 and m3, along with down-regulation of hydroxysteroid dehydrogenases (Hsd) 11b1 and 17b6. Using DME-enhanced in vivo SILAC material with tHR/SIM, therefore, permits the robust analysis of multiple DME of importance to xenobiotic metabolism, with improved utility for the study of

  10. Impact of Metabolic Diseases, Drugs, and Dietary Factors on Prostate Cancer Risk, Recurrence, and Survival: A Systematic Review by the European Association of Urology Section of Oncological Urology.

    Science.gov (United States)

    Campi, Riccardo; Brookman-May, Sabine D; Subiela Henríquez, Jose Daniel; Akdoğan, Bülent; Brausi, Maurizio; Klatte, Tobias; Langenhuijsen, Johan F; Linares-Espinos, Estefania; Marszalek, Martin; Roupret, Morgan; Stief, Christian G; Volpe, Alessandro; Minervini, Andrea; Rodriguez-Faba, Oscar

    2018-04-13

    To date, established risk factors for prostate cancer (PCa) are limited to age, race, family history, and certain genetic polymorphisms. Despite great research efforts, available evidence on potentially modifiable risk factors is conflicting. Moreover, most studies on PCa risk factors did not consider the impact of prostate-specific antigen (PSA) testing on PCa diagnosis. To provide a detailed overview of the latest evidence on the role of metabolic diseases, drugs, and dietary factors for risk of PCa incidence, recurrence, and survival in men exposed to PSA testing. A systematic review of the English-language literature was performed using the MEDLINE, Cochrane Central Register of Controlled Trials, and Web of Science databases according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses recommendations. Randomized, case-control, or cohort studies published during the periods 2008-2017 (on drugs and metabolic diseases) and 2003-2017 (on dietary factors), with extensive follow-up (≥8-10yr for studies on PCa risk; ≥2-5yr for studies on PCa recurrence, progression, and survival, depending on the review subtopic) and adjusting of the analyses, beyond established risk factors, for either rate of PSA testing (for risk analyses) or PCa stage and primary treatment (for survival analyses), were eligible for inclusion. Overall, 39 reports from 22 observational studies were included. Studies were heterogeneous regarding definitions of exposure or outcomes, length of follow-up, risk of bias, and confounding. For some risk factors, evidence was insufficient to assess potential effects, while for others there was no evidence of an effect. For selected risk factors, namely metformin, aspirin and statin use, diabetes, obesity, and specific dietary intakes, there was low-quality evidence of modest effects on PCa risk. Current evidence from long-term observational studies evaluating the effect of drugs, metabolic diseases, and dietary factors for PCa risk

  11. CYTOCHROMES P450,NUCLEAR RECEPTORS AND FIBROBLAST GROWTH FACTORS- NEW ENDOCRINE AXES AS POTENCIAL DRUG TARGETS TO TREAT METABOLIC DISORDERS

    Directory of Open Access Journals (Sweden)

    Klementina Fon Tacer

    2009-06-01

    Full Text Available background Coordinate action of endocrine and nervous system enables adaptation of higher organisms to constant changes in the environment. Fibroblast growth factors (FGFs primarily regulate embryonic and organ development, however, FGF19 subfamily members despite the name act in an endocrine fashion. The studies of endocrine FGFs resulted in the discovery of new endocrine axes, composed of small lipophilic molecules and members of three protein families: cytochromes P450, nuclear receptors, and FGFs. Cytochromes P450 are enzymes responsible for metabolism of different lipid molecules. Nuclear receptors bind lipid metabolites and act as metabolic sensors. They become activated and as transcriptional factors turn on expression of endocrine FGFs. eFGFs regulate metabolic pathways in target organs that express specific FGF receptor/coreceptor pair. FGF15/19 is expressed in the small intestine and is involved in the postprandial bile acid negative feedback loop in the liver. FGF21 is liver-borne fasting hormone that induces fat utilization. FGF23 is expressed in bone and acts on kidney to regulate phosphate and vitamin D metabolism.Conclusions We describe herein three new endocrine axes that were probably developed for fine tuning metabolite concentration within narrow physiological limits and prevent their toxicity in excess. They play important role in the pathophysiology underlying diverse metabolic disorders and are expected to be potential targets for therapeutic interventions.

  12. Software-aided approach to investigate peptide structure and metabolic susceptibility of amide bonds in peptide drugs based on high resolution mass spectrometry.

    Directory of Open Access Journals (Sweden)

    Tatiana Radchenko

    Full Text Available Interest in using peptide molecules as therapeutic agents due to high selectivity and efficacy is increasing within the pharmaceutical industry. However, most peptide-derived drugs cannot be administered orally because of low bioavailability and instability in the gastrointestinal tract due to protease activity. Therefore, structural modifications peptides are required to improve their stability. For this purpose, several in-silico software tools have been developed such as PeptideCutter or PoPS, which aim to predict peptide cleavage sites for different proteases. Moreover, several databases exist where this information is collected and stored from public sources such as MEROPS and ExPASy ENZYME databases. These tools can help design a peptide drug with increased stability against proteolysis, though they are limited to natural amino acids or cannot process cyclic peptides, for example. We worked to develop a new methodology to analyze peptide structure and amide bond metabolic stability based on the peptide structure (linear/cyclic, natural/unnatural amino acids. This approach used liquid chromatography / high resolution, mass spectrometry to obtain the analytical data from in vitro incubations. We collected experimental data for a set (linear/cyclic, natural/unnatural amino acids of fourteen peptide drugs and four substrate peptides incubated with different proteolytic media: trypsin, chymotrypsin, pepsin, pancreatic elastase, dipeptidyl peptidase-4 and neprilysin. Mass spectrometry data was analyzed to find metabolites and determine their structures, then all the results were stored in a chemically aware manner, which allows us to compute the peptide bond susceptibility by using a frequency analysis of the metabolic-liable bonds. In total 132 metabolites were found from the various in vitro conditions tested resulting in 77 distinct cleavage sites. The most frequent observed cleavage sites agreed with those reported in the literature. The

  13. Software-aided approach to investigate peptide structure and metabolic susceptibility of amide bonds in peptide drugs based on high resolution mass spectrometry

    Science.gov (United States)

    Fontaine, Fabien; Morettoni, Luca; Zamora, Ismael

    2017-01-01

    Interest in using peptide molecules as therapeutic agents due to high selectivity and efficacy is increasing within the pharmaceutical industry. However, most peptide-derived drugs cannot be administered orally because of low bioavailability and instability in the gastrointestinal tract due to protease activity. Therefore, structural modifications peptides are required to improve their stability. For this purpose, several in-silico software tools have been developed such as PeptideCutter or PoPS, which aim to predict peptide cleavage sites for different proteases. Moreover, several databases exist where this information is collected and stored from public sources such as MEROPS and ExPASy ENZYME databases. These tools can help design a peptide drug with increased stability against proteolysis, though they are limited to natural amino acids or cannot process cyclic peptides, for example. We worked to develop a new methodology to analyze peptide structure and amide bond metabolic stability based on the peptide structure (linear/cyclic, natural/unnatural amino acids). This approach used liquid chromatography / high resolution, mass spectrometry to obtain the analytical data from in vitro incubations. We collected experimental data for a set (linear/cyclic, natural/unnatural amino acids) of fourteen peptide drugs and four substrate peptides incubated with different proteolytic media: trypsin, chymotrypsin, pepsin, pancreatic elastase, dipeptidyl peptidase-4 and neprilysin. Mass spectrometry data was analyzed to find metabolites and determine their structures, then all the results were stored in a chemically aware manner, which allows us to compute the peptide bond susceptibility by using a frequency analysis of the metabolic-liable bonds. In total 132 metabolites were found from the various in vitro conditions tested resulting in 77 distinct cleavage sites. The most frequent observed cleavage sites agreed with those reported in the literature. The main advantages of

  14. Summary of information on the effects of ionizing and non-ionizing radiation on cytochrome P450 and other drug metabolizing enzymes and transporters.

    Science.gov (United States)

    Rendic, Slobodan; Guengerich, F Peter

    2012-07-01

    The present paper is an update of data on the effects of ionizing radiation (γ-rays, X-rays, high energy UV, fast neutron) caused by environmental pollution or clinical treatments and the effects of non-ionizing radiation (low energy UV) on the expression and/or activity of drug metabolism (e.g., cytochrome P450 (CYP), glutathione transferase (GST)), enzymes involved in oxidative stress (e.g., peroxidases, catalase (CAT), aconitase (ACO), superoxide dismutase (SOD)), and transporters. The data are presented in tabular form (Tables 1-3) and are a continuation of previously published summaries on the effects of drugs and other chemicals on cytochrome P450 enzymes (Rendic, S.; Di Carlo, F. Drug Metab. Rev., 1997, 29 (1-2), 413-580, Rendic, S. Drug Metab. Rev., 2002, 34 (1-2), 83- 448) and of the data on the effects of diseases and environmental factors on the expression and/or activity of human cytochrome P450 enzymes and transporters (Guengerich, F.P.; Rendic, S. Curr. Drug Metab., 2010, 11(1), 1-3, Rendic, S.; Guengerich, F.P. Curr. Drug Metab., 2010, 11 (1), 4-84). The collective information is as presented by the cited author(s) in cases where several references are cited the latest published information is included. Remarks and conclusions suggesting clinically important impacts are highlighted, followed by discussion of the major findings. The searchable database is available as an Excel file (for information about file availability contact the corresponding author).

  15. Toxicokinetics of novel psychoactive substances: characterization of N-acetyltransferase (NAT) isoenzymes involved in the phase II metabolism of 2C designer drugs.

    Science.gov (United States)

    Meyer, Markus R; Robert, Anja; Maurer, Hans H

    2014-06-05

    The 2,5-dimethoxyphenethylamine-derived designer drugs (so-called "2Cs") recently became of great importance on the illicit drug market as stimulating hallucinogens. They are distributed and consumed as "novel psychoactive substances" (NPS) without any safety testing at the forefront. As previous studies have shown, the 2Cs are mainly metabolized by O-demethylation, N-acetylation, or deamination. Therefore, the aim of this study was to elucidate the role of the recombinant human N-acetyltransferase (NAT) isoforms 1 and 2 in the phase II metabolism of 2Cs. For these studies, cDNA-expressed recombinant human NATs were used and formation of metabolites after incubation was measured using GC-MS. NAT2 could be shown to be the only isoform catalyzing the reaction in vitro, hence it should be the only relevant enzyme for in vivo acetylation. In general, all metabolite formation reactions followed classic Michaelis-Menten kinetics and the affinity to human NAT2 was increasing with the volume of the 4-substituent. In consequence, a slow acetylator phenotype or inhibition of NAT2 could lead to decreased N-acetylation and might lead to an increased risk of side effects caused by these novel psychoactive substances. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  16. Effects of the antitumor agents from various natural sources on drug-metabolizing system, phagocytic activity and complement system in sarcoma 180-bearing mice.

    Science.gov (United States)

    Ito, H

    1986-03-01

    Correlation between antitumor activity and effects on some biological properties, such as phagocytic activity of the reticuloendothelial system, the third component of complement (C3) activation, hepatic drug-metabolizing activities and pentobarbital-induced narcosis, of antitumor agents from various natural sources such as B B (Broncasma Berna), GU-P (Grifora umbellata polysaccharide), OK-432, PS-K (Polysaccharide Kureha), and RA-P (Rumex acetosa polysaccharide) were studied with female ICR mice implanted with Sarcoma 180 solid tumor. All of these agents depressed aniline hydroxylase and aminopyrine demethylase activities, prolonged the duration of pentobarbital-induced narcosis, and significantly enhanced the phagocytic activity and C3 activity. Especially, RA-P which has the strongest antitumor activity was the most effective in changing these activities. The biological activities of GU-P at a dose of 10 mg/kg reached the same level as that found with PS-K at a dose of 100 mg/kg. a possible mechanism of inhibition of Sarcoma 180 solid tumor growth by the treatment with the antitumor agents could be interpreted as due to the C3 activation, the stimulation of phagocytic activity and depression of the hepatic microsomal drug-metabolizing system in tumor-bearing mice.

  17. Maintenance of drug metabolism and transport functions in human precision-cut liver slices during prolonged incubation for 5 days

    NARCIS (Netherlands)

    Starokozhko, Viktoriia; Vatakuti, Suresh; Schievink, Bauke; Merema, Marjolijn T.; Asplund, Annika; Synnergren, Jane; Aspegren, Anders; Groothuis, Geny M. M.

    Human precision-cut liver slices (hPCLS) are a valuable ex vivo model that can be used in acute toxicity studies. However, a rapid decline in metabolic enzyme activity limits their use in studies that require a prolonged xenobiotic exposure. The aim of the study was to extend the viability and

  18. Comparison of TiO2 photocatalysis, electrochemically assisted Fenton reaction and direct electrochemistry for simulation of phase I metabolism reactions of drugs.

    Science.gov (United States)

    Ruokolainen, Miina; Gul, Turan; Permentier, Hjalmar; Sikanen, Tiina; Kostiainen, Risto; Kotiaho, Tapio

    2016-02-15

    The feasibility of titanium dioxide (TiO2) photocatalysis, electrochemically assisted Fenton reaction (EC-Fenton) and direct electrochemical oxidation (EC) for simulation of phase I metabolism of drugs was studied by comparing the reaction products of buspirone, promazine, testosterone and 7-ethoxycoumarin with phase I metabolites of the same compounds produced in vitro by human liver microsomes (HLM). Reaction products were analysed by UHPLC-MS. TiO2 photocatalysis simulated the in vitro phase I metabolism in HLM more comprehensively than did EC-Fenton or EC. Even though TiO2 photocatalysis, EC-Fenton and EC do not allow comprehensive prediction of phase I metabolism, all three methods produce several important metabolites without the need for demanding purification steps to remove the biological matrix. Importantly, TiO2 photocatalysis produces aliphatic and aromatic hydroxylation products where direct EC fails. Furthermore, TiO2 photocatalysis is an extremely rapid, simple and inexpensive way to generate oxidation products in a clean matrix and the reaction can be simply initiated and quenched by switching the UV lamp on/off. Copyright © 2015 Elsevier B.V. All rights reserved.

  19. Accumulation and detoxication responses of the gastropod Lymnaea stagnalis to single and combined exposures to natural (cyanobacteria) and anthropogenic (the herbicide RoundUp(®) Flash) stressors.

    Science.gov (United States)

    Lance, Emilie; Desprat, Julia; Holbech, Bente Frost; Gérard, Claudia; Bormans, Myriam; Lawton, Linda A; Edwards, Christine; Wiegand, Claudia

    2016-08-01

    Freshwater gastropods are increasingly exposed to multiple stressors in the field such as the herbicide glyphosate in Roundup formulations and cyanobacterial blooms either producing or not producing microcystins (MCs), potentially leading to interacting effects. Here, the responses of Lymnaea stagnalis to a 21-day exposure to non-MC or MC-producing (33μgL(-1)) Planktothrix agardhii alone or in combination with the commercial formulation RoundUp(®) Flash at a concentration of 1μgL(-1) glyphosate, followed by 14days of depuration, were studied via i) accumulation of free and bound MCs in tissues, and ii) activities of anti-oxidant (catalase CAT) and biotransformation (glutathione-S-transferase GST) enzymes. During the intoxication, the cyanobacterial exposure induced an early increase of CAT activity, independently of the MC content, probably related to the production of secondary cyanobacterial metabolites. The GST activity was induced by RoundUp(®) Flash alone or in combination with non MC-producing cyanobacteria, but was inhibited by MC-producing cyanobacteria with or without RoundUp(®) Flash. Moreover, MC accumulation in L. stagnalis was 3.2 times increased when snails were concomitantly exposed to MC-producing cyanobacteria with RoundUp(®), suggesting interacting effects of MCs on biotransformation processes. The potent inhibition of detoxication systems by MCs and RoundUp(®) Flash was reversible during the depuration, during which CAT and GST activities were significantly higher in snails previously exposed to MC-producing cyanobacteria with or without RoundUp(®) Flash than in other conditions, probably related to the oxidative stress caused by accumulated MCs remaining in tissues. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. Mass spectrometric studies on the in vivo metabolism and excretion of SIRT1 activating drugs in rat urine, dried blood spots, and plasma samples for doping control purposes.

    Science.gov (United States)

    Höppner, Sebastian; Delahaut, Philippe; Schänzer, Wilhelm; Thevis, Mario

    2014-01-01

    The NAD(+) depending enzyme SIRT1 regulates the mitochondrial biogenesis, fat and glucose metabolism through catalyzing the deacetylation of several metabolism-related protein-substrates. Recently, synthetic activators of SIRT1 referred to as STACs (Sirtuin activating compounds, e.g. SRT2104) were identified and tested in clinical studies for the treatment of aging-related diseases such as type 2 diabetes, Alzheimer's and obesity. Although the mechanism of SIRT1 activation by small molecules has caused considerable controversy, STACs demonstrated a significant performance enhancement in mice experiments including an improvement of endurance, muscle strength, and locomotor behavior. Due to their potential to increase exercise tolerance in healthy individuals, SIRT1 activators are currently being monitored by anti-doping authorities. In the present study, the in vivo metabolic clearance of three SIRT1 activators was investigated in rats by the collection of urine, DBS (dried blood spots) and plasma samples following a single oral administration. The resulting metabolic products were studied by positive electrospray ionization - (tandem) mass spectrometry and confirmed by the comparison with in vitro generated metabolites using human and rat liver microsomal preparations. Subsequently, a screening procedure for five SIRT1 activators and the metabolite M1-SRT1720 in DBS specimens was developed. Liquid-liquid-extraction and liquid chromatography/tandem mass spectrometry was employed based on diagnostic ion transitions recorded in multiple reaction monitoring mode and two deuterated internal standards namely d8-SRT1720 and d8-M1-SRT1720 were utilized. The doping control assay was characterized with regard to specificity, limit of detection (10-50ng/ml), recovery (65-83%) and imprecision (7-20%) and ion suppression/enhancement effects (drug testing applications. Copyright © 2013 Elsevier B.V. All rights reserved.

  1. Fast detoxication of 2-chloro ethyl ethyl sulfide by p-type Ag{sub 2}O semiconductor nanoparticle-loaded Al{sub 2}O{sub 3}-based supports

    Energy Technology Data Exchange (ETDEWEB)

    Ma, Meng-Wei [Graduate Institute of Applied Science and Technology, National Taiwan University of Science and Technology, Taipei 10607, Taiwan (China); Kuo, Dong-Hau, E-mail: dhkuo@mail.ntust.edu.tw [Department of Materials Science and Engineering, National Taiwan University of Science and Technology, Taipei 10607, Taiwan (China)

    2016-01-15

    Highlights: • Detoxication of CWA surrogate of 2-chloro ethyl ethyl sulfide is investigated. • A small amount of Ag{sub 2}O on Al{sub 2}O{sub 3}-base support is sufficient to degrade 2-CEES. • Detoxication conversion >82% in 15 min is achieved for >2.5% Ag{sub 2}O/Na{sub 2}SiO{sub 3}/Al{sub 2}O{sub 3}. • Na{sub 2}SiO{sub 3} modified Al{sub 2}O{sub 3} to have the valley-like line pattern for depositing Ag{sub 2}O. • 2-CEES oxidation is initiated from the dominant electronic holes in p-type Ag{sub 2}O. - Abstract: p-type Ag{sub 2}O semiconductor nanoparticle-loaded Al{sub 2}O{sub 3} or Na{sub 2}SiO{sub 3}/Al{sub 2}O{sub 3} powders used for detoxicating the surrogate of sulfur mustard of 2-chloro ethyl ethyl sulfide (C{sub 2}H{sub 5}SCH{sub 2}CH{sub 2}Cl, 2-CEES) were investigated. Different amounts of Ag{sub 2}O and Na{sub 2}SiO{sub 3} on catalyst supports were evaluated. Gas chromatography with a pulsed flame photometric detector (GC–PFPD) and gas chromatography coupled with a mass spectroscopy (GC–MS) were used to monitor and identify the catalytic reactions, together with reaction products analysis. The GC analyses showed that the decontamination of 2-CEES in isopropanol solvent for 15 min was above 82% efficiency for the 0.5% Na{sub 2}SiO{sub 3}/Al{sub 2}O{sub 3} support deposited with a Ag{sub 2}O content above 2.5%. 2-(ethylthio)ethanol and 2-(ethylthio)ethanoic acid were identified as the major products after catalytic reactions. The electronic holes dominating in p-type Ag{sub 2}O is proposed to provide the key component and to initiate the catalytic reactions. The electronic hole-based detoxication mechanism is proposed.

  2. Protective/detoxicative function of metallothionein in the rat brain and blood induced by controlled cadmium doses

    Directory of Open Access Journals (Sweden)

    H. N. Shiyntum

    2015-09-01

    Full Text Available Cadmiumclassified as a major carcinogen is considered a poisonous and unwanted heavy metal to a lot of tissues in many organisms. Of many publications already available, the general consensus is that the cadmium attenuating element is metallothionein (MT through its interchangeable mechanism with Zn triggered by the presence of Cd, providing binding sites for Cd ions. MT was first discovered in the kidney cortex of the horse; it represents a low molecular weight protein, rich in cysteine residues which effectively bind with metals. Its functions consist in detoxification of heavy metals like mercury, arsenic, cadmium, homeostasis of essential metals including copper and zinc, anti-oxidation against reactive oxygen species, protection against DNA damage, oxidative stress, cell survival, angiogenesis, apoptosis, and increase of proliferation. In this work, we sought to highlight the protective function of MT in the brain and serum of rats by means of detoxification under induced effects of controlled Cd doses. We have done this by exposing Wistar rats to Cd at different doses in drinking water at different time intervals. In two independent experiments, 58 rats were subjected to 0.1 or 1.0 µg Cd2+/kg of body weight for 15 or 36 days under different conditions. The obtained data indicates the different functioning systems for the brain and the blood for MT metabolism under Cd effect. Our results indicate significant loss of metallothionein level in the brain and important increases in the amount of MT in serum proving that even minimal ingestion of toxic Cd is enough to trigger the release of MT protein in blood.

  3. CONCEPT OF DRUG INTERACTION

    OpenAIRE

    Singh Nidhi

    2012-01-01

    Drug interaction is an increasingly important cause of adverse reactions (ADR), and is the modification of the effect of one drug (object) by the prior or concomitant administration of another drug (precipitant drug). Drug interaction may either enhance or diminish the intended effect of one or both drugs. For example severe haemorrhage may occur if warfarin and salicylates (asprin) are combined. Precipitant drugs modify the object drug's absorption, distribution, metabolism, excretion or act...

  4. To the Issue of Application of L. Ron Hubbard Detoxication Method Under the Program of Semipalatinsk Region Population Rehabilitation

    International Nuclear Information System (INIS)

    Apusheva, B.K.; Nurumbetova, R.M.; Tuleubaev, B.A.

    1998-01-01

    The detoxification is one of the most acute problems of the population rehabilitation program of Semipalatinsk region suffered from the nuclear tests in 1949 - 1989. It is known that a Humanitarian Detoxification Service is success-fully functioning in Russia and facilitates the creation of improving centers for the removal of toxic chemical deposits, radiation decay products, and drugs out of the human organism. A method, which permits the successful removal of chemical deposits from the organism, consists of a number of procedures including the intake of a balanced amount of vitamins and minerals, physical exercises and sauna. It is based on the developments of an American scientist L. Ron Hubbard and analytical results of different biologists, physicians and pharmacologists. The effectiveness of the method was confirmed with the numerous clinical tests and examination of over 20,000 patients. The positive results were also obtained during the application of method to the people suffered from the Chernobyl accident. It is proposed to establish such detoxification centre in Kurchatov in order to perform similar investigations among the population of Semipalatinsk region affected by the nuclear testing. It will be created under the auspices of the Kazakh Detoxification Centre and the Pavlodar Centre of the Dianetika International Public Movement. The stable and successive functioning of the Centre is entirely dependent on the financing from the different funds and contract works. This paper proposes the ways of practical solution of man detoxification problem and the introduction of the method into the existing system of population rehabilitation

  5. 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.

  6. Design, Synthesis and Application of Fluorine-Labeled Taxoids as19F NMR Probes for the Metabolic Stability Assessment of Tumor-Targeted Drug Delivery Systems.

    Science.gov (United States)

    Seitz, Joshua D; Vineberg, Jacob G; Wei, Longfei; Khan, Jonathan F; Lichtenthal, Brendan; Lin, Chi-Feng; Ojima, Iwao

    2015-03-01

    Novel tumor-targeting drug conjugates, BLT-F 2 ( 1 ) and BLT-S-F 6 ( 2 ), bearing a fluorotaxoid as the warhead, a mechanism-based self-immolative disulfide linker, and biotin as the tumor-targeting module, were designed and synthesized as 19 F NMR probes. Fluorine atoms and CF 3 groups were strategically incorporated into the conjugates to investigate the mechanism of linker cleavage and factors that influence their plasma and metabolic stability by real-time monitoring with 19 F NMR. Time-resolved 19 F NMR study on probe 1 disclosed a stepwise mechanism for release of a fluorotaxoid, which might not have been detected by other analytical methods. Probe 2 was designed to bear two CF 3 groups in the taxoid moiety as "3-FAB" reporters for enhanced sensitivity and a polyethylene glycol oligomer insert to improve solubility. The clean analysis of the linker stability and reactivity of drug conjugates in blood plasma or cell culture media by HPLC and 1 H NMR is troublesome, due to the overlap of key signals/peaks with background arising from highly complex ingredients in biological systems. Accordingly, the use of 19 F NMR would provide a practical solution to this problem. In fact, our "3-FAB" probe 2 was proven to be highly useful to investigate the stability and reactivity of the self-immolative disulfide linker system in human blood plasma by 19 F NMR. It has also been revealed that the use of polysorbate 80 as excipient for the formulation of probe 2 dramatically increases the stability of the disulfide linker system. This finding further indicates that the tumor-targeting drug conjugates with polysorbate 80/EtOH/saline formulation for in vivo studies would have high stability in blood plasma, while the drug release in cancer cells proceeds smoothly.

  7. Non-steroidal anti-inflammatory drugs disturb the osmoregulatory, metabolic and cortisol responses associated with seawater exposure in rainbow trout.

    Science.gov (United States)

    Gravel, Amélie; Wilson, Jonathan M; Pedro, Dalila F N; Vijayan, Mathilakath M

    2009-05-01

    While detectable levels of non-steroidal anti-inflammatory drugs (NSAIDs) have been reported in various aquatic habitats, little is known about the mechanism of action of these pharmaceutical drugs on organisms. Recently we demonstrated that NSAIDs disrupt corticosteroidogenesis in rainbow trout (Oncorhynchus mykiss). As cortisol is a seawater adapting hormone, we hypothesized that exposure to NSAIDs will impair the hyposmoregulatory capacity of this species in seawater. Trout were exposed to either waterborne salicylate or ibuprofen in fresh water for four days and the salinity switched to 50% seawater for two days, followed by 100% seawater and sampled two days later. NSAIDs disturbed the seawater-induced elevation in plasma osmolality and concentrations of Cl(-) and K(+), but not Na(+) in rainbow trout. This was accompanied by enhanced gill glycolytic capacity and reduced liver glycogen content in seawater with NSAIDs, suggesting enhanced metabolic demand to fuel ion pumps. While salicylate did not affect gill Na(+)/K(+)-ATPase activity, ibuprofen inhibited the seawater-induced elevation in gill Na(+)/K(+)-ATPase activity. The drugs also further enhanced the seawater-induced elevation in plasma cortisol concentration; this response was greater with salicylate compared to ibuprofen. There were no changes in the transcript levels of key proteins involved in steroidogenesis with NSAIDs, whereas gill and brain GR protein expression expression was reduced with salicylate. Altogether, salicylate and ibuprofen exposures impaired the hyposmoregulatory capacity of rainbow trout in seawater, but the mode of action of the two drugs in bringing about these changes appears distinct in trout.

  8. Significant inhibitory impact of dibenzyl trisulfide and extracts of Petiveria alliacea on the activities of major drug-metabolizing enzymes in vitro: An assessment of the potential for medicinal plant-drug interactions.

    Science.gov (United States)

    Murray, J; Picking, D; Lamm, A; McKenzie, J; Hartley, S; Watson, C; Williams, L; Lowe, H; Delgoda, R

    2016-06-01

    Dibenzyl trisulfide (DTS) is the major active ingredient expressed in Petiveria alliacea L., a shrub widely used for a range of conditions, such as, arthritis, asthma and cancer. Given its use alone and concomitantly with prescription medicines, we undertook to investigate its impact on the activities of important drug metabolizing enzymes, the cytochromes P450 (CYP), a key family of enzymes involved in many adverse drug reactions. DTS and seven standardized extracts from the plant were assessed for their impact on the activities of CYPs 1A2, 2C19, 2C9, 2D6 and 3A4 on a fluorometric assay. DTS revealed significant impact against the activities of CYPs 1A2, 2C19 and 3A4 with IC50 values of 1.9, 4.0 and 3.2μM, respectively, which are equivalent to known standard inhibitors of these enzymes (furafylline, and tranylcypromine), and the most potent interaction with CYP1A2 displayed irreversible enzyme kinetics. The root extract, drawn with 96% ethanol (containing 2.4% DTS), displayed IC50 values of 5.6, 3.9 and 4.2μg/mL respectively, against the same isoforms, CYPs 1A2, 2C19 and 3A4. These investigations identify DTS as a valuable CYP inhibitor and P. alliacea as a candidate plant worthy of clinical trials to confirm the conclusions that extracts yielding high DTS may lead to clinically relevant drug interactions, whilst extracts yielding low levels of DTS, such as aqueous extracts, are unlikely to cause adverse herb-drug interactions. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. Cancer therapy leading to state of cancer metabolism depression for efficient operation of small dosage cytotoxic drugs

    OpenAIRE

    Ponizovskiy MR

    2015-01-01

    “Prolonged medical starvation” as the method of cancer therapy was borrowed from folk healers Omelchenko A and Breuss R. Author was convinced in efficiency of this method of cancer treatment via examination of cured patients and on own experience. The mechanism of this method of cancer therapy operates via Warburg effect targeting that promotes efficient cancer treatment with small cytotoxic drugs. Just it was described the mechanism of Warburg effect as well as mechanism transmutation of mit...

  10. Xenobiotic-metabolizing enzymes in plants and their role in uptake and biotransformation of veterinary drugs in the environment

    Czech Academy of Sciences Publication Activity Database

    Bártíková, H.; Skálová, L.; Stuchlíková, L.; Vokřál, I.; Vaněk, Tomáš; Podlipná, Radka

    2015-01-01

    Roč. 47, č. 3 (2015), s. 374-387 ISSN 0360-2532 R&D Projects: GA ČR(CZ) GA15-05325S; GA ČR(CZ) GA14-22593S Institutional support: RVO:61389030 Keywords : Pollutants * phytoremediation * drug phytotoxicity Subject RIV: CE - Biochemistry Impact factor: 4.526, year: 2015 http://www.tandfonline.com/doi/abs/10.3109/03602532.2015.1076437

  11. Studies on drug metabolism by fungi colonizing decomposing human cadavers. Part I: DNA sequence-based identification of fungi isolated from postmortem material.

    Science.gov (United States)

    Martínez-Ramírez, Jorge A; Strien, Juliane; Sanft, Juliane; Mall, Gita; Walther, Grit; Peters, Frank T

    2013-10-01

    Cadavers can be colonized by a wide variety of bacteria and fungi. Some of these microbes could change the concentration or the metabolic pattern of drugs present in postmortem samples. The purpose of this study was to identify fungi from human postmortem material and to further assess their potential role in the metabolism of drugs. Aliquots of 252 postmortem samples (heart blood, liver, kidney, and lung) taken from 105 moderately to severely decomposed bodies were streaked on Sabouraud agar for isolation of fungal species. One part of the samples was worked up immediately after autopsy (group I). The second part had previously been stored at -20 °C for at least 1 year (group II). Identification of the isolates was achieved morphologically by microscopy and molecularly by polymerase chain reaction amplification and sequencing of markers allowing species identification of the respective genera. Depending on the genus, different gene fragments were used: calmodulin for Aspergillus, β-tubulin for Penicillium, translation elongation factor 1α for Fusarium, and the internal transcribed spacer region of the ribosomal DNA for all remaining genera. A total of 156 fungal strains were isolated from 62% of the postmortem materials. By using these primers, 98% of the isolates could be identified to the species level. The most common genera were Candida (60.0%-six species), Penicillium (10.3%-two species), Rhodotorula (7.1%-one species), Mucor (6.4%-four species), Aspergillus (3.2%-four species), Trichosporon (3.2%-one species), and Geotrichum (3.2%-one species). Group I samples contained 53% more fungal species than stored samples suggesting some fungi did not survive the freezing process. The isolated fungi might be characteristic for decomposed bodies. The proposed methodology proved to be appropriate for the identification of fungi in this type of material.

  12. Studies on the metabolism and toxicological detection of the designer drug 4-methylthioamphetamine (4-MTA) in human urine using gas chromatography-mass spectrometry.

    Science.gov (United States)

    Ewald, Andreas H; Peters, Frank T; Weise, Magdalene; Maurer, Hans H

    2005-09-25

    4-Methylthioamphetamine (4-MTA) is a scheduled designer drug that has appeared on the illicit drug market and led to several non-fatal or even fatal poisonings. Only few data are available on its metabolism. The first aim of this study was to identify the 4-MTA metabolites in human urine and then to study whether the authors' STA procedure is suitable for screening for and identification of 4-MTA and/or its metabolites in urine. After enzymatic cleavage of conjugates, solid-phase extraction (SPE) and acetylation the following metabolites could be identified by full-scan gas chromatography-mass spectrometry (GC-MS): deamino-oxo 4-MTA, deamino-hydroxy 4-MTA, ring hydroxy and beta-hydroxy 4-MTA. 4-MTA sulfoxide could be identified as possible artifact. In urine samples after enzymatic hydrolysis, acidic extraction, and methylation, 4-methylthiobenzoic acid could be identified. The authors' systematical toxicological analysis (STA) procedure using full-scan GC-MS after acid hydrolysis, liquid-liquid extraction (LLE) and acetylation allowed detection of 4-MTA as target analyte plus all the above-mentioned metabolites with the exception of 4-methylthiobenzoic acid. The extraction efficiency of 4-MTA was approximately 70% and the limit of detection (LOD) was 30 ng/ml (S/N 3).

  13. Effects of volatile anaesthetics on heme metabolism in a murine genetic model of acute intermittent porphyria. A comparative study with other porphyrinogenic drugs.

    Science.gov (United States)

    Ruspini, Silvina Fernanda; Zuccoli, Johanna Romina; Lavandera, Jimena Verónica; Del Carmen Martínez, Marìa; Olivieri, Leda María; Gerez, Esther Noemí; Del Carmen Batlle, Alcira María; Buzaleh, Ana María

    2018-02-21

    Acute intermittent porphyria (AIP) is an inherited disease produced by a deficiency of Porphobilinogen deaminase (PBGD). The aim of this work was to evaluate the effects of Isoflurane and Sevoflurane on heme metabolism in a mouse genetic model of AIP to further support our previous proposal for avoiding their use in porphyric patients. A comparative study was performed administering the porphyrinogenic drugs allylisopropylacetamide (AIA), barbital and ethanol, and also between sex and mutation using AIP (PBG-D activity 70% reduced) and T1 (PBG-D activity 50% diminished) mice. The activities of 5-Aminolevulinic synthetase (ALA-S), PBG-D, Heme oxygenase (HO) and CYP2E1; the expression of ALA-S and the levels of 5-aminolevulinic acid (ALA) were measured in different tissues of mice treated with the drugs mentioned. Isoflurane increased liver, kidney and brain ALA-S activity of AIP females but only affected kidney AIP males. Sevoflurane induced ALA-S activity in kidney and brain of female AIP group. PBG-D activity was further reduced by Isoflurane in liver male T1; in AIP male mice activity remained in its low basal levels. Ethanol and barbital also caused biochemical alterations. Only AIA triggered neurological signs similar to those observed during human acute attacks in male AIP being the symptoms less pronounced in females although ALA-S induction was greater. Heme degradation was affected. Biochemical alterations caused by the porphyrinogenic drugs assayed were different in male and female mice and also between T1 and AIP being more affected the females of AIP group. This is the first study using volatile anaesthetics in an AIP genetic model confirming Isoflurane and Sevoflurane porphyrinogenicity. Copyright © 2018. Published by Elsevier B.V.

  14. Structural alert/reactive metabolite concept as applied in medicinal chemistry to mitigate the risk of idiosyncratic drug toxicity: a perspective based on the critical examination of trends in the top 200 drugs marketed in the United States.

    Science.gov (United States)

    Stepan, Antonia F; Walker, Daniel P; Bauman, Jonathan; Price, David A; Baillie, Thomas A; Kalgutkar, Amit S; Aleo, Michael D

    2011-09-19

    Because of a preconceived notion that eliminating reactive metabolite (RM) formation with new drug candidates could mitigate the risk of idiosyncratic drug toxicity, the potential for RM formation is routinely examined as part of lead optimization efforts in drug discovery. Likewise, avoidance of "structural alerts" is almost a norm in drug design. However, there is a growing concern that the perceived safety hazards associated with structural alerts and/or RM screening tools as standalone predictors of toxicity risks may be over exaggerated. In addition, the multifactorial nature of idiosyncratic toxicity is now well recognized based upon observations that mechanisms other than RM formation (e.g., mitochondrial toxicity and inhibition of bile salt export pump (BSEP)) also can account for certain target organ toxicities. Hence, fundamental questions arise such as: When is a molecule that contains a structural alert (RM positive or negative) a cause for concern? Could the molecule in its parent form exert toxicity? Can a low dose drug candidate truly mitigate metabolism-dependent and -independent idiosyncratic toxicity risks? In an effort to address these questions, we have retrospectively examined 68 drugs (recalled or associated with a black box warning due to idiosyncratic toxicity) and the top 200 drugs (prescription and sales) in the United States in 2009 for trends in physiochemical characteristics, daily doses, presence of structural alerts, evidence for RM formation as well as toxicity mechanism(s) potentially mediated by parent drugs. Collectively, our analysis revealed that a significant proportion (∼78-86%) of drugs associated with toxicity contained structural alerts and evidence indicating that RM formation as a causative factor for toxicity has been presented in 62-69% of these molecules. In several cases, mitochondrial toxicity and BSEP inhibition mediated by parent drugs were also noted as potential causative factors. Most drugs were administered

  15. [Drug-Drug Interactions with Consideration of Pharmacogenetics].

    Science.gov (United States)

    Ozawa, Shogo

    2018-01-01

     Elderly patients often suffer from a variety of diseases and therefore may be prescribed several kinds of drugs. Interactions between these drugs may cause problems in some patients. Guidelines for drug interactions were released on July 8, 2014 "Drug Interaction Guideline for Drug Development and Labeling Recommendations (Final Draft)". These guidelines include the theoretical basis for evaluating the mechanisms of drug interaction, the possible extent of drug interactions, and take into consideration special populations (e.g., infants, children, elderly patients, patients with hepatic or renal dysfunction, and subjects with minor deficient alleles for drug metabolizing enzymes and drug transporters). In this symposium article, I discuss this last special population: altered drug metabolism and drug interactions in subjects with minor alleles of genes encoding deficient drug metabolizing enzymes. I further discuss a drug label for eliglustat (Cerdelga) with instructions for patients with ultra-rapid, extensive, intermediate, and poor metabolizer phenotypes that arise from different CYP2D6 gene alleles.

  16. Dose-response effects of lycopene on selected drug-metabolizing and antioxidant enzymes in the rat

    DEFF Research Database (Denmark)

    Breinholt, V.; Lauridsen, S. T.; Daneshvar, B.

    2000-01-01

    detoxification enzymes provided evidence that lycopene was capable of inducing hepatic quinone reductase, approximately two-fold, at doses between 0.001 and 0.05 g/kg b.w, per day, whereas no effect was observed at the remaining doses tested. Glutathione transferase, using the two substrates, 2......,4-dichloronitrobenzene and 1-chloro-2,4-dinitrobenzene, was significantly induced at the 0.1 g/kg b.w. per day dose, whereas no effect was observed at the remaining lycopene doses. Analysis of the antioxidant status of thr blood compartment revealed that three out of four antioxidant enzymes were affected by lycopene...... to be affected by prior. lycopene exposure. The level of PhIP-DNA adducts in the liver or colon was likewise not affected by lycopene at any dose. Overall, the present study provides evidence that lycopene administered in the diet of young female rats exerts minor modifying effects toward antioxidant and drug...

  17. Novel Interactions between Gut Microbiome and Host Drug-Processing Genes Modify the Hepatic Metabolism of the Environmental Chemicals Polybrominated Diphenyl Ethers

    Energy Technology Data Exchange (ETDEWEB)

    Li, Cindy Yanfei; Lee, Soowan; Cade, Sara; Kuo, Li-Jung; Schultz, Irvin R.; Bhatt, Deepak K.; Prasad, Bhagwat; Bammler, Theo K.; Cui, Julia Yue

    2017-09-01

    The gut microbiome is a novel frontier in xenobiotic metabolism. Polybrominated diphenyl ethers (PBDEs), especially BDE-47 and BDE-99, are among the most abundant and persistent environmental contaminants that produce a variety of toxicities. Little is known about how the gut microbiome affects the hepatic metabolism of PBDEs and the PBDE-mediated regulation of drug-processing genes (DPGs) in vivo. The goal of this study was to determine the role of gut microbiome in modulating the hepatic biotransformation of PBDEs. Nine-week-old male C57BL/6J conventional (CV) or germ free (GF) mice were treated with vehicle, BDE-47 or BDE-99 (100 μmol/kg) for four days. Following BDE-47 treatment, GF mice had higher level of 5-OH-BDE-47 but lower levels of 4 other metabolites in liver than CV mice; whereas following BDE-99 treatment, GF mice had lower levels of 4 minor metabolites in liver than CV mice. RNA- Seq demonstrated that the hepatic expression of DPGs was regulated by both PBDEs and enterotypes. Under basal condition, the lack of gut microbiome up-regulated the Cyp2c subfamily but down-regulated the Cyp3a subfamily. Following PBDE exposure, certain DPGs were differentially regulated by PBDEs in a gut microbiome-dependent manner. Interestingly, the lack of gut microbiome augmented PBDE-mediated up- regulation of many DPGs, such as Cyp1a2 and Cyp3a11 in mouse liver, which was further confirmed by targeted metabolomics. The lack of gut microbiome also augmented the Cyp3a enzyme activity in liver. In conclusion, our study has unveiled a novel interaction between gut microbiome and the hepatic biotransformation of PBDEs.

  18. Progesterone receptor membrane component 1 inhibits the activity of drug-metabolizing cytochromes P450 and binds to cytochrome P450 reductase.

    Science.gov (United States)

    Szczesna-Skorupa, Elzbieta; Kemper, Byron

    2011-03-01

    Progesterone receptor membrane component 1 (PGRMC1) has been shown to interact with several cytochromes P450 (P450s) and to activate enzymatic activity of P450s involved in sterol biosynthesis. We analyzed the interactions of PGRMC1 with the drug-metabolizing P450s, CYP2C2, CYP2C8, and CYP3A4, in transfected cells. Based on coimmunoprecipitation assays, PGRMC1 bound efficiently to all three P450s, and binding to the catalytic cytoplasmic domain of CYP2C2 was much more efficient than to a chimera containing only the N-terminal transmembrane domain. Down-regulation of PGRMC1 expression levels in human embryonic kidney 293 and HepG2 cell lines stably expressing PGRMC1-specific small interfering RNA had no effect on the endoplasmic reticulum localization and expression levels of P450s, whereas enzymatic activities of CYP2C2, CYP2C8, and CYP3A4 were slightly higher in PGRMC1-deficient cells. Cotransfection of cells with P450s and PGRMC1 resulted in PGRMC1 concentration-dependent inhibition of the P450 activities, and this inhibition was partially reversed by increased expression of the P450 reductase (CPR). In contrast, CYP51 activity was decreased by down-regulation of PGRMC1 and expression of PGRMC1 in the PGRMC1-deficient cells increased CYP51 activity. In cells cotransfected with CPR and PGRMC1, strong binding of CPR to PGRMC1 was observed; however, in the presence of CYP2C2, interaction of PGRMC1 with CPR was significantly reduced, suggesting that CYP2C2 competes with CPR for binding to PGRMC1. These data show that in contrast to sterol synthesizing P450, PGRMC1 is not required for the activities of several drug-metabolizing P450s, and its overexpression inhibits those P450 activities. Furthermore, PGRMC1 binds to CPR, which may influence P450 activity.

  19. Concurrent subacute exposure to arsenic through drinking water and malathion via diet in male rats: effects on hepatic drug-metabolizing enzymes

    Energy Technology Data Exchange (ETDEWEB)

    Naraharisetti, Suresh Babu [Indian Veterinary Research Institute, Division of Pharmacology and Toxicology, Izatnagar, Uttar Pradesh (India); University of Washington, Department of Medicinal Chemistry, Seattle, WA (United States); Aggarwal, Manoj [Indian Veterinary Research Institute, Division of Pharmacology and Toxicology, Izatnagar, Uttar Pradesh (India); Institut fuer Arbeitsphysiologie an der Universitaet Dortmund, Dortmund (Germany); Sarkar, S.N.; Malik, J.K. [Indian Veterinary Research Institute, Division of Pharmacology and Toxicology, Izatnagar, Uttar Pradesh (India)

    2008-08-15

    Arsenic is a known global groundwater contaminant, while malathion is one of the most widely used pesticides in agriculture and public health practices in the world. Here, we investigated whether repeated exposure to arsenic at the groundwater contamination levels and to malathion at sublethal levels exerts adverse effects on the hepatic drug-metabolizing system in rats, and whether concurrent exposure is more hazardous than the single agent. Male Wistar rats were exposed daily to 4 or 40 ppm of arsenic via drinking water, 50 or 500 ppm of malathion-mixed feed and in a similar fashion co-exposed to 4 ppm of arsenic and 50 ppm of malathion or 40 ppm of arsenic and 500 ppm of malathion for 28 days. At term, toxicity was assessed by evaluating changes in body weight, liver weight, levels of cytochrome P{sub 450} (CYP), cytochrome b{sub 5} and microsomal and cytosolic proteins, and activities of aminopyrine-N-demethylase (ANDM), aniline-P-hydroxylase (APH), glutathione-S-transferase (GST) and uridine diphosphate glucuronosyltransferase (UGT) in liver. Arsenic and malathion alone did not alter body weight and liver weight, but these were significantly decreased in both the co-exposed groups. These treatments decreased the activities of ANDM and APH and the levels of liver microsomal and cytosolic proteins, increased GST activity and had no effect on UGT activity. The effects of exposure to low-dose and high-dose combinations on the activities of either phase I or phase II drug-metabolizing enzymes and protein content were mostly similar to that produced by the respective low and high dose of either arsenic or malathion, except APH activity. The effect of arsenic (40 ppm) on APH activity was partially, but significantly, inhibited by malathion (500 ppm). Results indicate that the body or liver weights and the biochemical parameters were differentially affected in male rats following concurrent subacute exposure to arsenic and malathion, with the co-exposure appearing

  20. Influence of various polymorphic variants of cytochrome P450 oxidoreductase (POR on drug metabolic activity of CYP3A4 and CYP2B6.

    Directory of Open Access Journals (Sweden)

    Xuan Chen

    Full Text Available Cytochrome P450 oxidoreductase (POR is known as the sole electron donor in the metabolism of drugs by cytochrome P450 (CYP enzymes in human. However, little is known about the effect of polymorphic variants of POR on drug metabolic activities of CYP3A4 and CYP2B6. In order to better understand the mechanism of the activity of CYPs affected by polymorphic variants of POR, six full-length mutants of POR (e.g., Y181D, A287P, K49N, A115V, S244C and G413S were designed and then co-expressed with CYP3A4 and CYP2B6 in the baculovirus-Sf9 insect cells to determine their kinetic parameters. Surprisingly, both mutants, Y181D and A287P in POR completely inhibited the CYP3A4 activity with testosterone, while the catalytic activity of CYP2B6 with bupropion was reduced to approximately ~70% of wild-type activity by Y181D and A287P mutations. In addition, the mutant K49N of POR increased the CLint (Vmax/Km of CYP3A4 up to more than 31% of wild-type, while it reduced the catalytic efficiency of CYP2B6 to 74% of wild-type. Moreover, CLint values of CYP3A4-POR (A115V, G413S were increased up to 36% and 65% of wild-type respectively. However, there were no appreciable effects observed by the remaining two mutants of POR (i.e., A115V and G413S on activities of CYP2B6. In conclusion, the extent to which the catalytic activities of CYP were altered did not only depend on the specific POR mutations but also on the isoforms of different CYP redox partners. Thereby, we proposed that the POR-mutant patients should be carefully monitored for the activity of CYP3A4 and CYP2B6 on the prescribed medication.

  1. Metabolism of s-triazine herbicides in tea and citrus plants

    International Nuclear Information System (INIS)

    Kakhniashvili, Kh.A.; Durmishidze, S.V.; Gigauri, M.Sh.

    1989-01-01

    The authors studied processes involved in assimilation, transport, and conversion of 14 C-atrazine and 14 C-simazine in plants of tea (Thea sinensis L.), lemon (Citrus limon Burm.), and orange (Citrus sinensis Osbeck). The main products of metabolism of the investigated herbicides in different organs of the indicated plants are isolated and identified. It is established that conjugates of hydroxytriazined with peptides and proteins accumulate in the plant cell. A new pathway of atrazine metabolism is clarified in the work, the indicated pathway involving two-component conjugates with peptides and glucose. The authors discuss the role played by oxidative conversions in detoxication of atrazine and simazine in the investigated plants, and identify the end products of oxidation

  2. Generalized Multifactor Dimensionality Reduction (GMDR) Analysis of Drug-Metabolizing Enzyme-Encoding Gene Polymorphisms may Predict Treatment Outcomes in Indian Breast Cancer Patients.

    Science.gov (United States)

    Agarwal, Gaurav; Tulsyan, Sonam; Lal, Punita; Mittal, Balraj

    2016-07-01

    Prediction of response and toxicity of chemotherapy can help personalize the treatment and choose effective yet non-toxic treatment regimen for a breast cancer patient. Interplay of variations in various drug-metabolizing enzyme (DME)-encoding genes results in variable response and toxicity of chemotherapeutic drugs. Generalized multi-analytical (GMDR) approach was used to determine the influence of the combination of variants of genes encoding phase 0 (SLC22A16); phase I (CYP450, NQO1); phase II (GSTs, MTHFR, UGT2B15); and phase III (ABCB1) DMEs along with confounding factors on the response and toxicity of chemotherapeutic drugs in breast cancer patients. In an Indian breast cancer patient cohort (n = 234), response to neo-adjuvant chemotherapy (n = 111) and grade 2-4 toxicity to chemotherapy were recorded. Patients were genotyped for 19 polymorphisms selected in four phases of DMEs by PCR or PCR-RFLP or Taqman allelic discrimination assay. Binary logistic regression and GMDR analysis was performed. Bonferroni test for multiple comparisons was applied, and p value was considered to be significant at T polymorphism, CT genotype was found to be significantly associated with response to NACT in uni-variate and multi-variate analysis (p = 0.018; p = 0.013). The TT genotype of NQO1 609C>T had a significant association with (absence of) grade 2-4 toxicity in uni-variate analysis (p = 0.021), but a non-significant correlation in multi-variate analysis. In GMDR analysis, interaction of CYP3A5*3, NQO1 609C>T, and ABCB1 1236C>T polymorphisms yielded the highest testing accuracy for response to NACT (CVT = 0.62). However, for grade 2-4 toxicity, CYP2C19*2 and ABCB1 3435C>T polymorphisms yielded the best interaction model (CVT = 0.57). This pharmacogenetic study suggests a role of higher order gene-gene interaction of DME-encoding genes, along with confounding factors, in determination of treatment outcomes and toxicity in breast cancer patients. This can be

  3. Assessment of serum lipid metabolism index and cytokine levels in patients with type 2 diabetes mellitus complicated by coronary heart disease after telmisartan combined with lipid-lowering drug treatment

    Directory of Open Access Journals (Sweden)

    Xin Wang

    2017-07-01

    Full Text Available Objective: To study the effect of telmisartan combined with lipid-lowering drug therapy on serum lipid metabolism index and cytokine levels in patients with type 2 diabetes mellitus complicated by coronary heart disease. Methods: A total of 106 patients with type 2 diabetes mellitus complicated by coronary heart disease who were treated in our hospital between September 2013 and October 2016 were collected and then divided into the control group (n=55 who received conventional treatment + lipid-lowering drug treatment and the observation group (n=51 who received conventional treatment + lipid-lowering drug + telmisartan treatment after the therapies were reviewed. Before and after treatment, serum levels of lipid metabolism indexes, inflammatory mediators and oxidative stress indexes were compared between two groups of patients. Results: Before treatment, the differences in serum levels of lipid metabolism indexes, inflammatory mediators and oxidative stress indexes were not statistically significant between two groups of patients. After treatment, serum TG and LDL-C levels in observation group were lower than those in control group while HDL-C level was higher than that in control group; serum inflammatory mediators IL-6, IL-8, HMGB1 and TNF-α levels were lower than those in control group; serum oxidative stress indexes MDA and ROS levels were lower than those in control group while GSH-Px level was higher than that in control group. Conclusion: Telmisartan combined with lipid-lowering drug therapy can effectively optimize the lipid metabolism and reduce the systemic inflammatory response and oxidative stress response in patients with type 2 diabetes mellitus complicated by coronary heart disease.

  4. Increasing throughput and information content for in vitro drug metabolism experiments using ultra-performance liquid chromatography coupled to a quadrupole time-of-flight mass spectrometer.

    Science.gov (United States)

    Castro-Perez, Jose; Plumb, Robert; Granger, Jennifer H; Beattie, Iain; Joncour, Karine; Wright, Andrew

    2005-01-01

    The field of drug metabolism has been revolutionized by liquid chromatography/mass spectrometry (LC/MS) applications with new technologies such as triple quadrupoles, ion traps and time-of-flight (ToF) instrumentation. Over the years, these developments have often relied on the improvements to the mass spectrometer hardware and software, which has allowed users to benefit from lower levels of detection and ease-of-use. One area in which the development pace has been slower is in high-performance liquid chromatography (HPLC). In the case of metabolite identification, where there are many challenges due to the complex nature of the biological matrices and the diversity of the metabolites produced, there is a need to obtain the most accurate data possible. Reactive or toxic metabolites need to be detected and identified as early as possible in the drug discovery process, in order to reduce the very costly attrition of compounds in late-phase development. High-resolution, exact mass measurement plays a very important role in metabolite identification because it allows the elimination of false positives and the determination of non-trivial metabolites in a much faster throughput environment than any other standard current methodology available to this field. By improving the chromatographic resolution, increased peak capacity can be achieved with a reduction in the number of co-eluting species leading to superior separations. The overall enhancement in the chromatographic resolution and peak capacity is transferred into a net reduction in ion suppression leading to an improvement in the MS sensitivity. To investigate this, a number of in vitro samples were analyzed using an ultra-performance liquid chromatography (UPLC) system, with columns packed with porous 1.7 mum particles, coupled to a hybrid quadrupole time-of-flight (ToF) mass spectrometer. This technique showed very clear examples for fundamental gains in sensitivity, chromatographic resolution and speed of

  5. Competing pathways in drug metabolism. I. Effect of input concentration on the conjugation of gentisamide in the once-through in situ perfused rat liver preparation

    International Nuclear Information System (INIS)

    Morris, M.E.; Yuen, V.; Tang, B.K.; Pang, K.S.

    1988-01-01

    Sulfation and glucuronidation are two parallel pathways for the metabolism of phenolic substrates. Gentisamide (GAM) was used as a model compound to examine the effects of parallel competing pathways on drug disappearance and metabolite formation in the once-through perfused rat liver preparation. GAM was found to form one glucuronide (GAM-5G) and two sulfate (GAM-2S and GAM-5S) conjugates. These GAM conjugates were biosynthesized in recirculating rat liver preparations, and were isolated by preparative high-performance liquid chromatography. Specific incorporation of 35S-sodium sulfate and [14C]glucose into GAM sulfate and glucuronide conjugates revealed corresponding elution patterns as labeled GAM metabolites. Their identities were characterized by enzymatic and acid hydrolyses and by NMR spectroscopy. Gentisamide-5-sulfate (GAM-5S) and gentisamide-5-glucuronide (GAM-5G) are major metabolites, and gentisamide-2-sulfate (GAM-2S) is a minor metabolite. Single-pass rat liver perfusions were used to examine the effect of stepwise increases/decreases of input GAM concentration (CIn) on the extraction ratio (E) of GAM and formation of metabolites. The E of GAM remained constant (about 0.89) at input concentrations from 0.9 to 120 microM and decreased at CIn greater than 120 microM. Metabolite patterns, however, changed with GAM CIn, even when E was constant at CIn up to 120 microM. GAM-5S was present as the major metabolite of GAM at all GAM CInS in most liver preparations but the proportions of GAM-5S and GAM-2S decreased at increasing CIn; the proportion of GAM-5G, a minor metabolite at low CIn, increased with increasing CIn. Biliary excretion rates at steady state accounted for 5.3 +/- 2.7% (mean +/- S.D.) of the input rate: GAM-5G was the predominant metabolite found

  6. Dietary diacetylene falcarindiol induces phase 2 drug-metabolizing enzymes and blocks carbon tetrachloride-induced hepatotoxicity in mice through suppression of lipid peroxidation.

    Science.gov (United States)

    Ohnuma, Tomokazu; Anan, Eisaburo; Hoashi, Rika; Takeda, Yuika; Nishiyama, Takahito; Ogura, Kenichiro; Hiratsuka, Akira

    2011-01-01

    Falcarindiol is a diacetylenic natural product containing unique carbon-carbon triple bonds. Mice were orally administrated falcarindiol (100 mg/kg), and drug-metabolizing and antioxidant enzymes were monitored in several tissues of mice. Treatment with falcarindiol was found to increase glutathione S-transferase (GST) and NAD(P)H: quinone oxidoreductase 1 activities in liver, small intestine, kidney, and lung. No changes were observed in cytochrome P450 (CYP) 1A known to activate procarcinogens. Western blot analysis revealed that various GST subunits including GSTA4, which plays an important role in the detoxification of alkenals produced from lipid peroxides, were induced in liver, small intestine, and kidney of falcarindiol-treated mice. Additionally, we investigated the protective effects of falcarindiol against hepatotoxicity induced by carbon tetrachloride (CCl(4)) and the mechanism of its hepatoprotective effect. Pretreatment with falcarindiol prior to the administration of CCl(4) significantly suppressed both an increase in serum alanine transaminase/aspartate transaminase (ALT/AST) activity and an increase in hepatic thiobarbituric acid reactive substance levels without affecting CCl(4)-mediated degradation of CYP2E1. Formation of hexanoyl-lysine and 4-hydroxy-2(E)-nonenal-histidine adducts, lipid peroxidation biomarkers, in homogenates from the liver of CCl(4)-treated mice was decreased in the group of mice pretreated with falcarindiol. These results suggest that the protective effects of falcarindiol against CCl(4) toxicity might, in part, be explained by anti-lipid peroxidation activity associated with the induction of the GSTs including GSTA4.

  7. The relationships of leptin, adiponectin levels and paraoxonase activity with metabolic and cardiovascular risk factors in females treated with psychiatric drugs

    Directory of Open Access Journals (Sweden)

    Aliye Ozenoglu

    2008-01-01

    Full Text Available OBJECTIVES: The aim of this study was to investigate serum leptin, adiponectin and paraoxonase1 levels in adult females receiving pharmacotherapy for various psychiatric disorders. METHODS: The study group consisted of 32 obese females (mean age 40.53 ± 11.00 years, mean body mass index 35.44 ± 5.33 kg/m² who were receiving treatment for psychiatric disorders, and the control group included 22 obese females (mean age 35.95 ± 9.16 years, mean body mass index 30.78 ± 3.33 kg/m² who were free of psychiatric disorders. Analyses were performed using a bioelectrical impedance device. Fasting blood samples were obtained for complete blood count and various biochemical tests, including determination of leptin, adiponectin and paraoxonase1 activity. RESULTS: Body mass index, waist and hip circumference, body fat percentage, fasting blood glucose, insulin, glycosylated hemoglobin, homeostasis model assesment of insulin resistance, alanine transaminase, aspartate tarnsaminase, and leptin levels were significantly higher in the study group than in controls. Although body weight was positively correlated with leptin levels in both groups, body weight was negatively correlated with adiponectin levels in the control group and positively correlated with adiponectin levels in the study group. In the study group, body mass index and hip circumference correlated positively with leptin levels, hip circumference correlated positively with adiponectin levels, and waist to hip ratio correlated positively with paraoxonase levels. In the control group, body mass index as well as waist and hip circumferences were positively correlated with leptin levels. Weight, body mass index, and hip circumference were also negatively correlated with the adiponectin/leptin ratio in the control group. CONCLUSION: This study indicates a higher risk for obesity-related disorders, particularly metabolic syndrome, diabetes and cardiovascular disease, in patients treated with

  8. s inhibition of drug metabolism

    African Journals Online (AJOL)

    accelerates toxic amyloid formation of human islet amyloid polypeptide: a possible link between bisphenol. A exposure and type 2 diabetes. PLoS One 2013;. 8(1):e54198. Bae S, Kim JH, Lim YH, Park HY, Hong YC. 5. Associations of bisphenol A exposure with heart rate variability and blood pressure. Hypertension 2012;.

  9. In vitro evaluation of major in vivo drug metabolic pathways using primary human hepatocytes and HepaRG cells in suspension and a dynamic three-dimensional bioreactor system.

    Science.gov (United States)

    Darnell, Malin; Ulvestad, Maria; Ellis, Ewa; Weidolf, Lars; Andersson, Tommy B

    2012-10-01

    Major human specific metabolites, not detected during in vivo and in vitro preclinical studies, may cause unexpected drug interactions and toxicity in human and delays in clinical programs. Thus, reliable preclinical tools for the detection of major human metabolites are of high importance. The aim of this study was to compare major drug metabolic pathways in HepaRG cells, a human hepatoma cell line, to fresh human hepatocytes, cryopreserved human hepatocytes, and human in vivo data. Furthermore, the maintenance of cytochrome P450 (P450) and UDP-glucuronosyltransferase (UGT) activities in a dynamic three-dimensional (3D) bioreactor were evaluated over time by using HepaRG cells and human hepatocytes. (14)C-diclofenac and a candidate from AstraZeneca's drug development program, (14)C-AZD6610, which are metabolized by P450 and UGT in vivo, were used as model substrates. The proportion of relevant biotransformation pathways of the investigated drug was clearly different in the various cell systems. The hydroxylation route was favored in primary human hepatocytes, whereas the glucuronidation route was favored in HepaRG cells. The human in vivo metabolite profile of AZD6610 was best represented by human hepatocytes, whereas all major diclofenac metabolites were detected in HepaRG cells. Moreover, the metabolite profiles in cryopreserved and fresh human hepatocytes were essentially the same. The liver bioreactor using both fresh human hepatocytes and HepaRG cells retained biotransformation capacity over 1 week. Thus, the incubation time can be increased from a few hours in suspension to several days in 3D cultures, which opens up for detection of metabolites from slowly metabolized drugs.

  10. Efeitos do alcoolismo e da desintoxicação alcoólica sobre o reparo e biomecânica óssea Effects of alcoholism and alcoholic detoxication on the repair and biomechanics of bone

    Directory of Open Access Journals (Sweden)

    Renato de Oliveira Horvath

    2011-01-01

    Full Text Available OBJETIVO: Avaliar os efeitos do consumo crônico de etanol e da desintoxicação alcoólica sobre a resistência mecânica do osso e neoformação óssea junto a implantes de hidroxiapatita densa (HAD realizados em ratos. MÉTODOS: Foram utilizados 15 ratos divididos em três grupos, sendo controle (CT, alcoolista crônico (AC e desintoxicado (DE. Após quatro semanas, foi realizada implantação de HAD na tíbia e produzida falha no osso parietal, em seguida o grupo AC continuaram a consumir etanol e o grupo DE iniciaram a desintoxicação. Ao completar 13 semanas os animais sofreram eutanásia, os ossos foram coletados para o processamento histomorfométrico e os fêmures encaminhados ao teste mecânico de resistência. RESULTADOS: Os animais do grupo AC apresentaram menores valores de neoformação óssea, de calcemia e resistência mecânica, quando comparado aos grupos CT e DE. Os animais dos grupos DE apresentaram valores superiores em todas as variáveis avaliadas em relação ao grupo AC. CONCLUSÃO: O consumo de etanol interferiu na osteogênese ao redor de implante de HAD, nos níveis de cálcio e na resistência mecânica óssea. A desintoxicação alcoólica se mostrou eficaz, pois aumentou à osteogênese e osseointegração da HAD, a calcemia e resistência mecânica óssea. Nivel de Evidência I, estudo terapeutico.OBJECTIVE: To evaluate the effects of chronic ethanol consumption and alcohol detoxication on the mechanical resistance of bone and bone neoformation around dense hydroxyapatite implants (DHA in rats. METHODS: Fifteen rats were separated into three groups: (1 control group (CT; (2 chronic alcoholic (CA, and (3 disintoxicated (DI. After four weeks, a DHA was implanted in the right tibia of the animals, and the CA group continued consuming ethanol, while the DI group started detoxication. The solid and liquid feeding of the animals was recorded, and a new alcohol dilution was effected every 48 hours. After 13 weeks, the

  11. Antineoplastic Drugs

    Science.gov (United States)

    Sadée, Wolfgang; El Sayed, Yousry Mahmoud

    The limited scope of therapeutic drug-level monitoring in cancer chemotherapy results from the often complex biochemical mechanisms that contribute to antineoplastic activity and obscure the relationships among drug serum levels and therapeutic benefits. Moreover, new agents for cancer chemotherapy are being introduced at a more rapid rate than for the treatment of other diseases, although the successful application of therapeutic drug-level monitoring may require several years of intensive study of the significance of serum drug levels. However, drug level monitoring can be of considerable value during phase I clinical trials of new antineoplastic agents in order to assess drug metabolism, bioavailability, and intersubject variability; these are important parameters in the interpretation of clinical studies, but have no immediate benefit to the patient. High performance liquid chromatography (HPLC) probably represents the most versatile and easily adaptable analytical technique for drug metabolite screening (1). HPLC may therefore now be the method of choice during phase I clinical trials of antineoplastic drugs. For example, within a single week we developed an HPLC assay—using a C18 reverse-phase column, UV detection, and direct serum injection after protein precipitation—for the new radiosensitizer, misonidazole (2).

  12. Beta-keto amphetamines: studies on the metabolism of the designer drug mephedrone and toxicological detection of mephedrone, butylone, and methylone in urine using gas chromatography-mass spectrometry.

    Science.gov (United States)

    Meyer, Markus R; Wilhelm, Jens; Peters, Frank T; Maurer, Hans H

    2010-06-01

    In recent years, a new class of designer drugs has appeared on the drugs of abuse market in many countries, namely, the so-called beta-keto (bk) designer drugs such as mephedrone (bk-4-methylmethamphetamine), butylone (bk-MBDB), and methylone (bk-MDMA). The aim of the present study was to identify the metabolites of mephedrone in rat and human urine using GC-MS techniques and to include mephedrone, butylone, and methylone within the authors' systematic toxicological analysis (STA) procedure. Six phase I metabolites of mephedrone were detected in rat urine and seven in human urine suggesting the following metabolic steps: N-demethylation to the primary amine, reduction of the keto moiety to the respective alcohol, and oxidation of the tolyl moiety to the corresponding alcohols and carboxylic acid. The STA procedure allowed the detection of mephedrone, butylone, methylone, and their metabolites in urine of rats treated with doses corresponding to those reported for abuse of amphetamines. Besides macro-based data evaluation, an automated evaluation using the automated mass spectral deconvolution and identification system was performed. Mephedrone and butylone could be detected also in human urine samples submitted for drug testing. Assuming similar kinetics in humans, the described STA procedure should be suitable for proof of an intake of the bk-designer drugs in human urine.

  13. Visualizing Drug Efficacy In Vivo

    Directory of Open Access Journals (Sweden)

    Weisheng Zhang

    2005-04-01

    Full Text Available Many enzymes are therapeutic targets for drug discovery, whereas other enzymes are important for understanding drug metabolism and pharmacokinetics during compound testing in animals. Testing of drug efficacy and metabolism in an animal model requires the measurement of disease endpoints as well as assays of enzyme activity in specific tissues at selected time points during treatment. This requires the removal of tissue and biochemical assays. Techniques to noninvasively assess drug effects on enzyme activity using imaging technology would facilitate understanding of drug efficacy, pharmacokinetics, and drug metabolism. Using a commercially available cytochrome P−450 3A substrate whose oxidized product is a luciferase substrate, we show for the first time that cytochrome P−450 enzyme activity can be measured in vivo in real time by bioluminescent imaging. This imaging approach could be applicable to study drug effects on therapeutic target enzymes, as well as drug metabolism enzymes.

  14. Evaluation of metabolism dependent inhibition of CYP2B6 mediated bupropion hydroxylation in human liver microsomes by monoamine oxidase inhibitors and prediction of potential as perpetrators of drug interaction.

    Science.gov (United States)

    Nirogi, Ramakrishna; Palacharla, Raghava Choudary; Mohammed, Abdul Rasheed; Manoharan, Arunkumar; Ponnamaneni, Ranjith Kumar; Bhyrapuneni, Gopinadh

    2015-03-25

    The objective of the study was to evaluate the metabolism dependent inhibition of CYP2B6 catalyzed bupropion hydroxylation in human liver microsomes by monoamine oxidase (MAO) inhibitors and to predict the drug-drug interaction potential of monoamine oxidase inhibitors as perpetrators of drug interaction. Human liver microsomal CYP2B6 activities were investigated using bupropion hydroxylation as probe substrate marker. The results from single point time dependent inhibition and shift assays suggest that clorgyline, pargyline, phenelzine, and selegiline were metabolism based inhibitors of CYP2B6. In IC50 shift assays, clorgyline, pargyline, phenelzine and selegiline are metabolism based inhibitors of CYP2B6 with fold shit of 3.0-, 3.7-, 2.9-, and 11.4-fold respectively. The inactivation of clorgyline was characterized by KI value of 2.5 ± 0.3 and k(inact) value of 0.045 ± 0.001 min(-1). Phenelzine inactivated CYP2B6 with KI and k(inact) values of 44.9 ± 6.9 μM and 0.085 ± 0.003 min(-1) respectively. Inactivation of selegiline was characterized with KI and k(inact) values of 22.0 ± 3.3 and 0.074 ± 0.002 min(-1) respectively. The inactivation caused by these inhibitors was not reversed by dialysis indicating irreversible inhibition. Based on the mechanistic static model, selegiline showed an increase in the area under the curve (AUC) of efavirenz and bupropion by 1.01-fold. Phenelzine predicted to cause an increase in the AUC of efavirenz and bupropion by 9.4- and 2.4-fold respectively considering unbound hepatic inlet concentrations of phenelzine. In conclusion, the results from this study demonstrated that MAO inhibitors can inactivate human liver microsomal CYP2B6. The likelihood of drug interaction when selegiline co-administered with CYP2B6 substrates is remote. Caution is required while co-administering phenelzine with substrates that are exclusively metabolized by CYP2B6 enzyme and substrates that have narrow therapeutic index. Copyright © 2015

  15. Clinical Pharmacokinetics of Systemically Administered Antileishmanial Drugs

    NARCIS (Netherlands)

    Kip, Anke E; Schellens, Jan H M; Beijnen, Jos H; Dorlo, Thomas P C

    This review describes the pharmacokinetic properties of the systemically administered antileishmanial drugs pentavalent antimony, paromomycin, pentamidine, miltefosine and amphotericin B (AMB), including their absorption, distribution, metabolism and excretion and potential drug-drug interactions.

  16. Drug transport proteins in the liver

    NARCIS (Netherlands)

    Faber, Klaas Nico; Muller, M.; Jansen, P.LM

    2003-01-01

    Together with drug metabolising enzymes, transmembrane transporters are important determinants of drug metabolism and drug clearance by the liver. Hepatic uptake of organic anions, cations, prostaglandins and bile salts is supported by dedicated transporter proteins in the basolateral (sinusoidal)

  17. Drug-drug interactions: new trends | Garba | Journal of ...

    African Journals Online (AJOL)

    The modification of the action of one drug by the other had been noticed for a long time. For example, in 19995, Williams (1) discovered that there was an enhanced metabolism of oestrogens caused by phenabarbital and rifampicin (all of which are now known to be inducers of drug metabolism). Chloroquine was found to ...

  18. The SMARTCyp cytochrome P450 metabolism prediction server

    DEFF Research Database (Denmark)

    Rydberg, Patrik; Gloriam, David Erik Immanuel; Olsen, Lars

    2010-01-01

    The SMARTCyp server is the first web application for site of metabolism prediction of cytochrome P450-mediated drug metabolism.......The SMARTCyp server is the first web application for site of metabolism prediction of cytochrome P450-mediated drug metabolism....

  19. Purine and pyrimidine metabolism in man V

    International Nuclear Information System (INIS)

    Nyhan, W.L.; Thompson, L.F.; Watts, R.W.E.

    1986-01-01

    This book comprises the proceedings of the Fifth International Symposium on Human Purine and Pyrimidine Metabolism. Its papers are organized under the following categories: adenosine receptors; purine receptors and the central nervous system; nucleoside and base transport; studies with antimetabolites; deoxynucleotide and nucleoside toxicity and metabolism; enzymes; purine and pyrimidine metabolism during lymphocyte differentiation; purine metabolism in skeletal muscle; purine nucleotide metabolism in the heart; purine and pyrimidine metabolism in primary cell cultures and in parasites; nucleoside kinases and drug activation; phosphoribosylpyrophosphate; S-adenosylmethionine metabolism; and the metabolic effects of interferon

  20. S-Adenosylmethionine metabolism and its relation to polyamine synthesis in rat liver. Effect of nutritional state, adrenal function, some drugs and partial hepatectomy

    Science.gov (United States)

    Eloranta, Terho O.; Raina, Aarne M.

    1977-01-01

    S-Adenosylmethionine metabolism and its relation to the synthesis and accumulation of polyamines was studied in rat liver under various nutritional conditions, in adrenalectomized or partially hepatectomized animals and after treatment with cortisol, thioacetamide or methylglyoxal bis(guanylhydrazone) {1,1′-[(methylethanediylidine)dinitrilo]diguanidine}. Starvation for 2 days only slightly affected S-adenosylmethionine metabolism. The ratio of spermidine/spermine decreased markedly, but the concentration of total polyamines did not change significantly. The activity of S-adenosylmethionine decarboxylase initially decreased and then increased during prolonged starvation. This increase was dependent on intact adrenals. Re-feeding of starved animals caused a rapid but transient stimulation of polyamine synthesis and also increased the concentrations of S-adenosylmethionine and S-adenosylhomocysteine. Similarly, cortisol treatment enhanced the synthesis of polyamines, S-adenosylmethionine and S-adenosylhomocysteine. Feeding with a methionine-deficient diet for 7–14 days profoundly increased the concentration of spermidine, whereas the concentrations of total polyamines and of S-adenosylmethionine showed no significant changes. The results show that nutritional state and adrenal function play a significant role in the regulation of hepatic metabolism of S-adenosylmethionine and polyamines. They further indicate that under a variety of physiological and experimental conditions the concentrations of S-adenosylmethionine and of total polyamines remain fairly constant and that changes in polyamine metabolism are not primarily connected with changes in the accumulation of S-adenosylmethionine or S-adenosylhomocysteine. PMID:597268

  1. Metabolic Heterogeneity Evidenced by MRS among Patient-Derived Glioblastoma Multiforme Stem-Like Cells Accounts for Cell Clustering and Different Responses to Drugs

    Directory of Open Access Journals (Sweden)

    Sveva Grande

    2018-01-01

    Full Text Available Clustering of patient-derived glioma stem-like cells (GSCs through unsupervised analysis of metabolites detected by magnetic resonance spectroscopy (MRS evidenced three subgroups, namely clusters 1a and 1b, with high intergroup similarity and neural fingerprints, and cluster 2, with a metabolism typical of commercial tumor lines. In addition, subclones generated by the same GSC line showed different metabolic phenotypes. Aerobic glycolysis prevailed in cluster 2 cells as demonstrated by higher lactate production compared to cluster 1 cells. Oligomycin, a mitochondrial ATPase inhibitor, induced high lactate extrusion only in cluster 1 cells, where it produced neutral lipid accumulation detected as mobile lipid signals by MRS and lipid droplets by confocal microscopy. These results indicate a relevant role of mitochondrial fatty acid oxidation for energy production in GSCs. On the other hand, further metabolic differences, likely accounting for different therapy responsiveness observed after etomoxir treatment, suggest that caution must be used in considering patient treatment with mitochondria FAO blockers. Metabolomics and metabolic profiling may contribute to discover new diagnostic or prognostic biomarkers to be used for personalized therapies.

  2. Strategies for the Assessment of Metabolic Profiles of Steroid Hormones in View of Diagnostics and Drug Monitoring: Analytical Problems and Challenges.

    Science.gov (United States)

    Plenis, Alina; Oledzka, Ilona; Kowalski, Piotr; Baczek, Tomasz

    2016-01-01

    During the last few years there has been a growing interest in research focused on the metabolism of steroid hormones despite that the study of metabolic hormone pathways is still a difficult and demanding task because of low steroid concentrations and a complexity of the analysed matrices. Thus, there has been an increasing interest in the development of new, more selective and sensitive methods for monitoring these compounds in biological samples. A lot of bibliographic databases for world research literature were structurally searched using selected review question and inclusion/exclusion criteria. Next, the reports of the highest quality were selected using standard tools (181) and they were described to evaluate the advantages and limitations of different approaches in the measurements of the steroids and their metabolites. The overview of the analytical challenges, development of methods used in the assessment of the metabolic pathways of steroid hormones, and the priorities for future research with a special consideration for liquid chromatography (LC) and capillary electrophoresis (CE) techniques have been presented. Moreover, many LC and CE applications in pharmacological and psychological studies as well as endocrinology and sports medicine, taking into account the recent progress in the area of the metabolic profiling of steroids, have been critically discussed. The latest reports show that LC systems coupled with mass spectrometry have the predominant position in the research of steroid profiles. Moreover, CE techniques are going to gain a prominent position in the diagnosis of hormone levels in the near future.

  3. Mycobacterium tuberculosis Metabolism

    Science.gov (United States)

    Warner, Digby F.

    2015-01-01

    Metabolism underpins the physiology and pathogenesis of Mycobacterium tuberculosis. However, although experimental mycobacteriology has provided key insights into the metabolic pathways that are essential for survival and pathogenesis, determining the metabolic status of bacilli during different stages of infection and in different cellular compartments remains challenging. Recent advances—in particular, the development of systems biology tools such as metabolomics—have enabled key insights into the biochemical state of M. tuberculosis in experimental models of infection. In addition, their use to elucidate mechanisms of action of new and existing antituberculosis drugs is critical for the development of improved interventions to counter tuberculosis. This review provides a broad summary of mycobacterial metabolism, highlighting the adaptation of M. tuberculosis as specialist human pathogen, and discusses recent insights into the strategies used by the host and infecting bacillus to influence the outcomes of the host–pathogen interaction through modulation of metabolic functions. PMID:25502746

  4. Metabolic Engineering VII Conference

    Energy Technology Data Exchange (ETDEWEB)

    Kevin Korpics

    2012-12-04

    The aims of this Metabolic Engineering conference are to provide a forum for academic and industrial researchers in the field; to bring together the different scientific disciplines that contribute to the design, analysis and optimization of metabolic pathways; and to explore the role of Metabolic Engineering in the areas of health and sustainability. Presentations, both written and oral, panel discussions, and workshops will focus on both applications and techniques used for pathway engineering. Various applications including bioenergy, industrial chemicals and materials, drug targets, health, agriculture, and nutrition will be discussed. Workshops focused on technology development for mathematical and experimental techniques important for metabolic engineering applications will be held for more in depth discussion. This 2008 meeting will celebrate our conference tradition of high quality and relevance to both industrial and academic participants, with topics ranging from the frontiers of fundamental science to the practical aspects of metabolic engineering.

  5. Metabolic Panel

    Science.gov (United States)

    A metabolic panel is a group of tests that measures different chemicals in the blood. These tests are usually done on ... and liver. There are two types: basic metabolic panel (BMP) and comprehensive metabolic panel (CMP). The BMP ...

  6. Efeitos do alcoolismo crônico e da desintoxicação alcóolica sobre a glândula submandibular de ratos: estudo morfométrico Effects of chronic alcoholism and alcoholic detoxication on rat submandibular glands: morphometric study

    Directory of Open Access Journals (Sweden)

    Simone Eloiza Sita Faustino

    2003-03-01

    Full Text Available Este estudo consiste de uma análise morfométrica de diversas estruturas parenquimatosas da glândula submandibular de ratos submetidos ao alcoolismo crônico experimental e de ratos recuperados após 30 dias de desintoxicação. Foram utilizados 3 grupos (5 animais por grupo: Controle, Alcoolizado e Desintoxicado. O fato do álcool atuar nos tecidos corporais, leva-nos a acreditar que possam ocorrer alterações na morfologia da glândula submandibular de ratos submetidos ao alcoolismo crônico. De fato, após os processos de alcoolização e desintoxicação há ocorrência de diferenças estatisticamente significantes quando confrontamos os 3 grupos entre si (dois a dois no que se refere à massa corpórea dos animais (g e da glândula submandibular (mg, ocorrendo, normalmente, uma redução tanto do grupo alcoolizado quanto do grupo desintoxicado em relação ao grupo controle e um significante aumento das massas corpórea e glandular do grupo desintoxicado em relação ao grupo alcoolizado. Quanto ao volume absoluto das diversas estruturas glandulares analisadas constatou-se diferenças estatisticamente significantes nos compartimentos acinar e do ducto granuloso, onde os grupos alcoolizado e desintoxicado apresentaram menor volume absoluto em relação ao grupo controle. Quanto aos outros parâmetros estereológicos estudados não houve diferenças estatisticamente significantes entre os grupos e entre as diversas estruturas glandulares analisadas.This work is a morphometric study of several parenquimatous structures of rats' submandibular gland which were submitted to experimental cronic alcoholism and others which were recovered after detoxication during 30 days. It was used 3 groups (5 rats in each group: Control, Alcoholic and Detoxicated. The fact of alcohol acts in body tissues, take us to believe that changes in the submandibular glands morphology of rats which were submitted to cronic alcoholism can happen. In fact, after

  7. The effect of non-steroidal anti-inflammatory drugs on the metabolism of 14C-arachidonic acid by human gingival tissue in vitro

    International Nuclear Information System (INIS)

    Elattar, T.M.; Lin, H.S.; Tira, D.E.

    1983-01-01

    We investigated the effect of non-steroidal anti-inflammatory drugs on prostaglandins (PGs) and 12-hydroxyeicosatetraenoic acid (12-HETE) formation by inflamed human gingival tissues. Gingival tissue homogenates were incubated with 14 C-arachidonic acid in the presence of indomethacin, piroxicam, or ibuprofen, and the organic solvent extracts were chromatographed on silica gel plates with standards for radiometric assay. There was a significant negative trend between the doses (10(-7)-10(-3) M) of each of indomethacin, piroxicam, and ibuprofen, and the amounts of PGF2 alpha, PGE2, PGD2, and 15-keto-PGE2 produced. All three drugs have a significant inhibitory effect on PGs and 12-HETE production at 10(-3) M when compared with the control. The rank order effectiveness of the drugs, at 10(-3) M, on PG inhibition was indomethacin greater than piroxicam greater than ibuprofen, and on 12-HETE inhibition was indomethacin greater than ibuprofen greater than piroxicam

  8. The effect of non-steroidal anti-inflammatory drugs on the metabolism of /sup 14/C-arachidonic acid by human gingival tissue in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Elattar, T.M.; Lin, H.S.; Tira, D.E.

    1983-09-01

    We investigated the effect of non-steroidal anti-inflammatory drugs on prostaglandins (PGs) and 12-hydroxyeicosatetraenoic acid (12-HETE) formation by inflamed human gingival tissues. Gingival tissue homogenates were incubated with /sup 14/C-arachidonic acid in the presence of indomethacin, piroxicam, or ibuprofen, and the organic solvent extracts were chromatographed on silica gel plates with standards for radiometric assay. There was a significant negative trend between the doses (10(-7)-10(-3) M) of each of indomethacin, piroxicam, and ibuprofen, and the amounts of PGF2 alpha, PGE2, PGD2, and 15-keto-PGE2 produced. All three drugs have a significant inhibitory effect on PGs and 12-HETE production at 10(-3) M when compared with the control. The rank order effectiveness of the drugs, at 10(-3) M, on PG inhibition was indomethacin greater than piroxicam greater than ibuprofen, and on 12-HETE inhibition was indomethacin greater than ibuprofen greater than piroxicam.

  9. Graviola: A Novel Promising Natural-Derived Drug That Inhibits Tumorigenicity and Metastasis of Pancreatic Cancer Cells In Vitro and In Vivo Through Altering Cell Metabolism

    Science.gov (United States)

    Torres, María P.; Rachagani, Satyanarayana; Purohit, Vinee; Pandey, Poomy; Joshi, Suhasini; Moore, Erik D.; Johansson, Sonny L.; Singh, Pankaj K.; Ganti, Apar K.; Batra, Surinder K.

    2012-01-01

    Pancreatic tumors are resistant to conventional chemotherapies. The present study was aimed at evaluating the potential of a novel plant-derived product as a therapeutic agent for pancreatic cancer (PC). The effects of an extract from the tropical tree Annona Muricata, commonly known as Graviola, was evaluated for cytotoxicity, cell metabolism, cancer-associated protein/gene expression, tumorigenicity, and metastatic properties of PC cells. Our experiments revealed that Graviola induced necrosis of PC cells by inhibiting cellular metabolism. The expression of molecules related to hypoxia and glycolysis in PC cells (i.e. HIF-1α, NF-κB, GLUT1, GLUT4, HKII, and LDHA) were downregulated in the presence of the extract. In vitro functional assays further confirmed the inhibition of tumorigenic properties of PC cells. Overall, the compounds that are naturally present in a Graviola extract inhibited multiple signaling pathways that regulate metabolism, cell cycle, survival, and metastatic properties in PC cells. Collectively, alterations in these parameters led to a decrease in tumorigenicity and metastasis of orthotopically implanted pancreatic tumors, indicating promising characteristics of the natural product against this lethal disease. PMID:22475682

  10. Graviola: a novel promising natural-derived drug that inhibits tumorigenicity and metastasis of pancreatic cancer cells in vitro and in vivo through altering cell metabolism.

    Science.gov (United States)

    Torres, María P; Rachagani, Satyanarayana; Purohit, Vinee; Pandey, Poomy; Joshi, Suhasini; Moore, Erik D; Johansson, Sonny L; Singh, Pankaj K; Ganti, Apar K; Batra, Surinder K

    2012-10-01

    Pancreatic tumors are resistant to conventional chemotherapies. The present study was aimed at evaluating the potential of a novel plant-derived product as a therapeutic agent for pancreatic cancer (PC). The effects of an extract from the tropical tree Annona Muricata, commonly known as Graviola, was evaluated for cytotoxicity, cell metabolism, cancer-associated protein/gene expression, tumorigenicity, and metastatic properties of PC cells. Our experiments revealed that Graviola induced necrosis of PC cells by inhibiting cellular metabolism. The expression of molecules related to hypoxia and glycolysis in PC cells (i.e. HIF-1α, NF-κB, GLUT1, GLUT4, HKII, and LDHA) were downregulated in the presence of the extract. In vitro functional assays further confirmed the inhibition of tumorigenic properties of PC cells. Overall, the compounds that are naturally present in a Graviola extract inhibited multiple signaling pathways that regulate metabolism, cell cycle, survival, and metastatic properties in PC cells. Collectively, alterations in these parameters led to a decrease in tumorigenicity and metastasis of orthotopically implanted pancreatic tumors, indicating promising characteristics of the natural product against this lethal disease. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  11. Cholestasis and regulation of genes related to drug metabolism and biliary transport in rat liver following treatment with cyclosporine A and sirolimus (Rapamycin)

    DEFF Research Database (Denmark)

    Bramow, S; Ott, P; Thomsen Nielsen, F

    2001-01-01

    Cyclosporine A and sirolimus are used alone or in combination as immunosuppressants in organ transplantation. To elucidate hepatic side effects, we examined hepatic mRNA of proteins involved in biliary and hepatocellular transport of drugs, formation of glutathione (GSH) and drug metabolising...... then analysed as were hepatic mRNA levels of canalicular transport proteins (Mrp2, Bsep, Mdr1b and Mdr2), sinusoidal transport proteins (Ntcp, Oatp1 and Oatp2), GSH related enzymes (gamma-glutamylcysteine synthetase light (GCSlc) and heavy (GCShc) chain subunits and glutathione-S-transferase) and CYPs (CYP3A9...

  12. Study on the Application of Chinese Patent Drug and Chinese Formula of Rabdosia Rubescens

    Science.gov (United States)

    Peng, Mengfan; Liu, Baosong; Mao, Mingsan

    2018-01-01

    Rabdosia rubescens contais many active ingredients such as terpenoids, flavonoids, polysaccharides and organic acids. Modern research has proved that Rabdosia rubescens has the effect of heat-clearing and detoxicating, antibacterial and anticancer, promoting blood circulation to arrest pain and anti-tumor. It is used in the treatment of sore throat, rheumatoid arthritis and various kinds of cancer. The clinical application of Rabdosia rubescens is restricted in the fat-soluble components, and the solubility of water solubility is ignored. The application of prescriptions, Chinese patent drug and food therapy of Rabdosia rubescens are less and fragmented. This paper inquires relevant literature, the application of Rabdosia rubescens in prescription, Chinese patent medicine and food therapy was reviewed, in order to make Rabdosiae rubescens play a greater role in the relevant area. On the basis of make the best use of everything, to promote the innovation and development of Chinese medicine and services to the people in our country.

  13. Drug Facts

    Medline Plus

    Full Text Available ... Why Is It So Hard to Quit Drugs? Effects of Drugs Drug Use and Other People Drug ... Unborn Children Drug Use and Your Health Other Effects on the Body Drug Use Hurts Brains Drug ...

  14. Induction of antioxidant and phase 2 drug-metabolizing enzymes by falcarindiol isolated from Notopterygium incisum extract, which activates the Nrf2/ARE pathway, leads to cytoprotection against oxidative and electrophilic stress.

    Science.gov (United States)

    Ohnuma, Tomokazu; Komatsu, Takao; Nakayama, Shinji; Nishiyama, Takahito; Ogura, Kenichiro; Hiratsuka, Akira

    2009-08-01

    In the present study, we isolated falcarindiol from Notopterygium incisum and investigated the effect of falcarindiol on the expression of antioxidant enzymes (AOEs), such as catalase, and phase 2 drug-metabolizing enzymes (DMEs), such as glutathione S-transferase and NAD(P)H:quinone oxidoreductase 1, in a cultured cell line from normal rat liver, Clone 9 cells. Exposure of Clone 9 cells to falcarindiol resulted in the significant induction of AOEs and phase 2 DMEs. Western blot analysis and transfection studies using a luciferase reporter construct demonstrated that the induction of AOEs and phase 2 DMEs by falcarindiol was caused through the Nrf2/ARE (nuclear factor-E2-related factor 2/antioxidant response element) pathway. Pretreatment of cells with falcarindiol accelerated the detoxification of a potentially toxic quinone (menadione) and mitigated menadione-induced cytotoxicity. We found that falcarindiol was a novel inducer of AOEs and phase 2 DMEs and falcarindiol might exhibit chemopreventive activity.

  15. [Drug promiscuity].

    Science.gov (United States)

    Guo, Zong-ru

    2011-04-01

    It is essential for a successful drug to possess two basic characteristics: satisfactory pharmacological action with sufficient potency and selectivity; good druggability with eligible physicochemical, pharmacokinetic and safety profiles, as well as structural novelty. Promiscuity is defined as the property of a drug to act with multiple molecular targets and exhibit distinct pharmacological effects. Promiscuous drugs are the basis of polypharmacology and the causes for side effects and unsuitable DMPK. Drug promiscuity originates from protein promiscuity. In order to accommodate, metabolize and excrete various endo- and exogenous substances, protein acquired the capability during evolution to adapt a wide range of structural diversity, and it is unnecessary to reserve a specific protein for every single ligand. The structures of target proteins are integration of conservativity and diversity. The former is represented by the relatively conservative domains for secondary structures folding, which leads to overlapping in ligand-binding and consequent cross-reactivity of ligands. Diversity, however, embodies the subtle difference in structures. Similar structural domain may demonstrate different functions due to alteration of amino acid sequences. The phenomenon of promiscuity may facilitate the "design in" of multi-target ligands for the treatment of complicated diseases, whereas it should be appropriately handled to improve druggability. Therefore, one of the primary goals in drug design is to scrutinize and manipulate the "merits and faults" of promiscuity. This review discusses the application of promiscuity in drug design for receptors, enzymes, ion channels and cytochrome P450. It also briefly describes the methods to predict ligand promiscuity based on either target or ligand structures.

  16. Tumor Metabolism of Malignant Gliomas

    Energy Technology Data Exchange (ETDEWEB)

    Ru, Peng; Williams, Terence M.; Chakravarti, Arnab; Guo, Deliang, E-mail: deliang.guo@osumc.edu [Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center & Arthur G James Cancer Hospital, Columbus, OH 43012 (United States)

    2013-11-08

    Constitutively activated oncogenic signaling via genetic mutations such as in the EGFR/PI3K/Akt and Ras/RAF/MEK pathways has been recognized as a major driver for tumorigenesis in most cancers. Recent insights into tumor metabolism have further revealed that oncogenic signaling pathways directly promote metabolic reprogramming to upregulate biosynthesis of lipids, carbohydrates, protein, DNA and RNA, leading to enhanced growth of human tumors. Therefore, targeting cell metabolism has become a novel direction for drug development in oncology. In malignant gliomas, metabolism pathways of glucose, glutamine and lipid are significantly reprogrammed. Moreover, molecular mechanisms causing these metabolic changes are just starting to be unraveled. In this review, we will summarize recent studies revealing critical gene alterations that lead to metabolic changes in malignant gliomas, and also discuss promising therapeutic strategies via targeting the key players in metabolic regulation.

  17. Text mining for drug-drug interaction.

    Science.gov (United States)

    Wu, Heng-Yi; Chiang, Chien-Wei; Li, Lang

    2014-01-01

    In order to understand the mechanisms of drug-drug interaction (DDI), the study of pharmacokinetics (PK), pharmacodynamics (PD), and pharmacogenetics (PG) data are significant. In recent years, drug PK parameters, drug interaction parameters, and PG data have been unevenly collected in different databases and published extensively in literature. Also the lack of an appropriate PK ontology and a well-annotated PK corpus, which provide the background knowledge and the criteria of determining DDI, respectively, lead to the difficulty of developing DDI text mining tools for PK data collection from the literature and data integration from multiple databases.To conquer the issues, we constructed a comprehensive pharmacokinetics ontology. It includes all aspects of in vitro pharmacokinetics experiments, in vivo pharmacokinetics studies, as well as drug metabolism and transportation enzymes. Using our pharmacokinetics ontology, a PK corpus was constructed to present four classes of pharmacokinetics abstracts: in vivo pharmacokinetics studies, in vivo pharmacogenetic studies, in vivo drug interaction studies, and in vitro drug interaction studies. A novel hierarchical three-level annotation scheme was proposed and implemented to tag key terms, drug interaction sentences, and drug interaction pairs. The utility of the pharmacokinetics ontology was demonstrated by annotating three pharmacokinetics studies; and the utility of the PK corpus was demonstrated by a drug interaction extraction text mining analysis.The pharmacokinetics ontology annotates both in vitro pharmacokinetics experiments and in vivo pharmacokinetics studies. The PK corpus is a highly valuable resource for the text mining of pharmacokinetics parameters and drug interactions.

  18. Gut Microbiota and Metabolic Disorders

    Directory of Open Access Journals (Sweden)

    Kyu Yeon Hur

    2015-06-01

    Full Text Available Gut microbiota plays critical physiological roles in the energy extraction and in the control of local or systemic immunity. Gut microbiota and its disturbance also appear to be involved in the pathogenesis of diverse diseases including metabolic disorders, gastrointestinal diseases, cancer, etc. In the metabolic point of view, gut microbiota can modulate lipid accumulation, lipopolysaccharide content and the production of short-chain fatty acids that affect food intake, inflammatory tone, or insulin signaling. Several strategies have been developed to change gut microbiota such as prebiotics, probiotics, certain antidiabetic drugs or fecal microbiota transplantation, which have diverse effects on body metabolism and on the development of metabolic disorders.

  19. Metabolic Syndrome

    Science.gov (United States)

    Metabolic syndrome is a group of conditions that put you at risk for heart disease and diabetes. These conditions ... agree on the definition or cause of metabolic syndrome. The cause might be insulin resistance. Insulin is ...

  20. The conduct of in vitro studies to address time-dependent inhibition of drug-metabolizing enzymes: a perspective of the pharmaceutical research and manufacturers of America.

    Science.gov (United States)

    Grimm, Scott W; Einolf, Heidi J; Hall, Steven D; He, Kan; Lim, Heng-Keang; Ling, Kah-Hiing John; Lu, Chuang; Nomeir, Amin A; Seibert, Eleanore; Skordos, Konstantine W; Tonn, George R; Van Horn, Robert; Wang, Regina W; Wong, Y Nancy; Yang, Tian J; Obach, R Scott

    2009-07-01

    Time-dependent inhibition (TDI) of cytochrome P450 (P450) enzymes caused by new molecular entities (NMEs) is of concern because such compounds can be responsible for clinically relevant drug-drug interactions (DDI). Although the biochemistry underlying mechanism-based inactivation (MBI) of P450 enzymes has been generally understood for several years, significant advances have been made only in the past few years regarding how in vitro time-dependent inhibition data can be used to understand and predict clinical DDI. In this article, a team of scientists from 16 pharmaceutical research organizations that are member companies of the Pharmaceutical Research and Manufacturers of America offer a discussion of the phenomenon of TDI with emphasis on the laboratory methods used in its measurement. Results of an anonymous survey regarding pharmaceutical industry practices and strategies around TDI are reported. Specific topics that still possess a high degree of uncertainty are raised, such as parameter estimates needed to make predictions of DDI magnitude from in vitro inactivation parameters. A description of follow-up mechanistic experiments that can be done to characterize TDI are described. A consensus recommendation regarding common practices to address TDI is included, the salient points of which include the use of a tiered approach wherein abbreviated assays are first used to determine whether NMEs demonstrate TDI or not, followed by more thorough inactivation studies for those that do to define the parameters needed for prediction of DDI.

  1. Drug Facts

    Medline Plus

    Full Text Available ... Facts Search form Search Menu Home Drugs That People Abuse Alcohol Facts Bath Salts Facts Cocaine (Coke, ... Drugs? Effects of Drugs Drug Use and Other People Drug Use and Families Drug Use and Kids ...

  2. Drug Facts

    Medline Plus

    Full Text Available ... Get Addicted to Drugs? Does Addiction Run in Families? Why Is It So Hard to Quit Drugs? ... Drug Use and Other People Drug Use and Families Drug Use and Kids Drug Use and Unborn ...

  3. Drug Facts

    Medline Plus

    Full Text Available ... People Drug Use and Families Drug Use and Kids Drug Use and Unborn Children Drug Use and ... Children and Teens Stay Drug-Free Talking to Kids About Drugs: What to Say if You Used ...

  4. Targeting metabolic disorders by natural products

    OpenAIRE

    Tabatabaei-Malazy, Ozra; Larijani, Bagher; Abdollahi, Mohammad

    2015-01-01

    The most prevalent metabolic disorders are diabetes mellitus, obesity, dyslipidemia, osteoporosis and metabolic syndrome, which are developed when normal metabolic processes are disturbed. The most common pathophysiologies of the above disorders are oxidative stress, Nrf2 pathways, epigenetic, and change in miRNA expression. There is a challenge in the prevention and treatment of metabolic disorders due to severe adverse effects of some synthetic drugs, their high cost, lack of safety and pov...

  5. Metabolic Reprogramming in Thyroid Carcinoma

    Directory of Open Access Journals (Sweden)

    Raquel Guimaraes Coelho

    2018-03-01

    Full Text Available Among all the adaptations of cancer cells, their ability to change metabolism from the oxidative to the glycolytic phenotype is a hallmark called the Warburg effect. Studies on tumor metabolism show that improved glycolysis and glutaminolysis are necessary to maintain rapid cell proliferation, tumor progression, and resistance to cell death. Thyroid neoplasms are common endocrine tumors that are more prevalent in women and elderly individuals. The incidence of thyroid cancer has increased in the Past decades, and recent findings describing the metabolic profiles of thyroid tumors have emerged. Currently, several drugs are in development or clinical trials that target the altered metabolic pathways of tumors are undergoing. We present a review of the metabolic reprogramming in cancerous thyroid tissues with a focus on the factors that promote enhanced glycolysis and the possible identification of promising metabolic targets in thyroid cancer.

  6. Metabolic Reprogramming in Thyroid Carcinoma

    Science.gov (United States)

    Coelho, Raquel Guimaraes; Fortunato, Rodrigo S.; Carvalho, Denise P.

    2018-01-01

    Among all the adaptations of cancer cells, their ability to change metabolism from the oxidative to the glycolytic phenotype is a hallmark called the Warburg effect. Studies on tumor metabolism show that improved glycolysis and glutaminolysis are necessary to maintain rapid cell proliferation, tumor progression, and resistance to cell death. Thyroid neoplasms are common endocrine tumors that are more prevalent in women and elderly individuals. The incidence of thyroid cancer has increased in the Past decades, and recent findings describing the metabolic profiles of thyroid tumors have emerged. Currently, several drugs are in development or clinical trials that target the altered metabolic pathways of tumors are undergoing. We present a review of the metabolic reprogramming in cancerous thyroid tissues with a focus on the factors that promote enhanced glycolysis and the possible identification of promising metabolic targets in thyroid cancer. PMID:29629339

  7. Short-term calorie restriction feminizes the mRNA profiles of drug metabolizing enzymes and transporters in livers of mice.

    Science.gov (United States)

    Fu, Zidong Donna; Klaassen, Curtis D

    2014-01-01

    Calorie restriction (CR) is one of the most effective anti-aging interventions in mammals. A modern theory suggests that aging results from a decline in detoxification capabilities and thus accumulation of damaged macromolecules. The present study aimed to determine how short-term CR alters mRNA profiles of genes that encode metabolism and detoxification machinery in the liver. Male C57BL/6 mice were fed CR (0, 15, 30, or 40%) diets for one month, followed by mRNA quantification of 98 xenobiotic processing genes (XPGs) in the liver, including 7 uptake transporters, 39 phase-I enzymes, 37 phase-II enzymes, 10 efflux transporters, and 5 transcription factors. In general, 15% CR did not alter mRNAs of most XPGs, whereas 30 and 40% CR altered over half of the XPGs (32 increased and 29 decreased). CR up-regulated some phase-I enzymes (fold increase), such as Cyp4a14 (12), Por (2.3), Nqo1 (1.4), Fmo2 (5.4), and Fmo3 (346), and numerous number of phase-II enzymes, such as Sult1a1 (1.2), Sult1d1 (2.0), Sult1e1 (33), Sult3a1 (2.2), Gsta4 (1.3), Gstm2 (1.3), Gstm3 (1.7), and Mgst3 (2.2). CR feminized the mRNA profiles of 32 XPGs in livers of male mice. For instance, CR decreased the male-predominantly expressed Oatp1a1 (97%) and increased the female-predominantly expressed Oatp1a4 (11). In conclusion, short-term CR alters the mRNA levels of over half of the 98 XPGs quantified in livers of male mice, and over half of these alterations appear to be due to feminization of the liver. Copyright © 2013 Elsevier Inc. All rights reserved.

  8. Soybean Toxin (SBTX) Impairs Fungal Growth by Interfering with Molecular Transport, Carbohydrate/Amino Acid Metabolism and Drug/Stress Responses

    Science.gov (United States)

    Morais, Janne K. S.; Bader, Oliver; Weig, Michael; Oliveira, Jose Tadeu A.; Arantes, Mariana R.; Gomes, Valdirene M.; Da Cunha, Maura; Oliveira, Hermogenes D.; Sousa, Daniele O. B.; Lourencao, Andre L.; Vasconcelos, Ilka M.

    2013-01-01

    Soybean toxin (SBTX) is an antifungal protein from soybeans with broad inhibitory activity against the growth and filamentation of many fungi, including human and plant pathogenic species such as Candida albicans, Candida parapsilosis, Aspergillus niger, Penicillium herquei, Cercospora sojina and Cercospora kikuchii. Understanding the mechanism by which SBTX acts on fungi and yeasts may contribute to the design of novel antifungal drugs and/or the development of transgenic plants resistant to pathogens. To this end, the polymorphic yeast C. albicans was chosen as a model organism and changes in the gene expression profile of strain SC5314 upon exposure to SBTX were examined. Genes that were differentially regulated in the presence of SBTX were involved in glucose transport and starvation-associated stress responses as well as in the control of both the induction and repression of C. albicans hyphal formation. Transmission electron microscopy showed that C. albicans cells exposed to SBTX displayed severe signs of starvation and were heavily granulated. Our data were indicative of C. albicans cell starvation despite sufficient nutrient availability in the medium; therefore, it can be speculated that SBTX blocks nutrient uptake systems. Because neither the starvation signal nor the alkaline response pathway lead to the induction of hyphae, we hypothesise that conflicting signals are transmitted to the complex regulatory network controlling morphogenesis, eventually preventing the filamentation signal from reaching a significant threshold. PMID:23894655

  9. The effect of the antipsoriatic drug metabolite etretin (Ro 10-1670) on UVB irradiation induced changes in the metabolism of arachidonic acid in human keratinocytes in culture

    International Nuclear Information System (INIS)

    Punnonen, Kari; Jansen, C.T.; Puustinen, Tapio

    1986-01-01

    [ 14 C]Arachidonic acid was avidly incorporated into human keratinocytes in culture and following exposure to UVB irradiation of 9 mJ/cm 2 (erythemally effective, EE) substantial amounts of 14 C-radiolabel were released from the cells. The release of radiolabel was accompanied by a decrease in the labelling of phosphatidylethanolamine whereas the labelling of triacylglycerols and cholesteryl esters was increased. Keratinocytes produced significant amounts of prostaglandin E 2 (PGE 2 ) and following UVB irradiation of 9 mJ/cm 2 (EE) the formation of prostaglandin E 2 was increased. Etretin (Ro 10-1670), the active metabolite of the antipsoriatic drug etretinate (Ro 10-9359), affected significantly neither the total release of radiolabel induced by UVB nor the formation of prostaglandin E 2 . However, in the presence of etretin the UVB irradiation induced transfer of [ 14 C]arachidonic acid into triacylglycerols and cholesteryl esters was not increased as much as in the corresponding experiments without etretin. On the basis of the present study it appears that etretin dose not interfere with the release of arachidonic acid in amounts which could be related to the therapeutic effects of the combination of retinoids with UVB irradiation (Re-UVB) in the treatment of psoriasis. (author)

  10. Use of liquid chromatography coupled to low- and high-resolution linear ion trap mass spectrometry for studying the metabolism of paynantheine, an alkaloid of the herbal drug Kratom in rat and human urine.

    Science.gov (United States)

    Philipp, Anika A; Wissenbach, Dirk K; Weber, Armin A; Zapp, Josef; Zoerntlein, Siegfried W; Kanogsunthornrat, Jidapha; Maurer, Hans H

    2010-04-01

    The Thai medicinal plant Mitragyna speciosa (Kratom in Thai) is misused as a herbal drug of abuse. During studies on the main Kratom alkaloid mitragynine (MG) in rats and humans, several dehydro analogs could be detected in urine of Kratom users, which were not found in rat urine after administration of pure MG. Questions arose as to whether these compounds are formed from MG only by humans or whether they are metabolites formed from the second abundant Kratom alkaloid paynantheine (PAY), the dehydro analog of MG. Therefore, the aim of the presented study was to identify the phase I and II metabolites of PAY in rat urine after administration of the pure alkaloid. This was first isolated from Kratom leaves. Liquid chromatography-linear ion trap mass spectrometry provided detailed structure information of the metabolites in the MS(n) mode particularly with high resolution. Besides PAY, the following phase I metabolites could be identified: 9-O-demethyl PAY, 16-carboxy PAY, 9-O-demethyl-16-carboxy PAY, 17-O-demethyl PAY, 17-O-demethyl-16,17-dihydro PAY, 9,17-O-bisdemethyl PAY, 9,17-O-bisdemethyl-16,17-dihydro PAY, 17-carboxy-16,17-dihydro PAY, and 9-O-demethyl-17-carboxy-16,17-dihydro PAY. These metabolites indicated that PAY was metabolized via the same pathways as MG. Several metabolites were excreted as glucuronides or sulfates. The metabolism studies in rats showed that PAY and its metabolites corresponded to the MG-related dehydro compounds detected in urine of the Kratom users. In conclusion, PAY and its metabolites may be further markers for a Kratom abuse in addition of MG and its metabolites.

  11. Differences in genotype and allele frequency distributions of polymorphic drug metabolizing enzymes CYP2C19 and CYP2D6 in mainland Chinese Mongolian, Hui and Han populations.

    Science.gov (United States)

    Yin, S-J; Ni, Y-B; Wang, S-M; Wang, X; Lou, Y-Q; Zhang, G-L

    2012-06-01

    Cytochrome P450 2C19 (CYP2C19) and CYP2D6 are important xenobiotic metabolic enzymes and both show considerable genetic variability between Orientals and Caucasians. There are known marked heterogeneity in susceptibility to various cancers and hypertension among Chinese Mongolian, Hui and Han ethnic groups, but the molecular mechanisms are unknown. Our objective was to investigate the patterns of distribution of CYP2C19 and CYP2D6 polymorphisms among healthy Chinese subjects to determine whether any observed inter-ethnic variability might be worth further investigation as possible contributors to the known differences in disease prevalence. Blood samples were collected from 454 unrelated Chinese healthy subjects (214 Han, 111 Hui, 129 Mongolian) for genotyping analysis. The single nucleotide polymorphisms (SNPs) CYP2C19*2 (681G>A in exon 5), CYP2C19*3 (636G>A in exon 4) and CYP2D6*10 (188C>T in exon 1) were determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Significantly higher frequencies of the CYP2C19 poor metabolic genotypes were observed in Chinese Han (18·7%), Chinese Hui (25·0%) and Chinese Mongolian (10·9%) subjects than has been reported for Caucasians (1·7-3·0%, P Hui (32·4%) and Han (29·7%) than in Chinese Mongolian (18·2%, P Hui ethnic groups than have been reported for Caucasians (11·1-16·3% and 0-0·2%, P Hui (40·6% and 30·7%) and Mongolian subjects (31·3% and 9·6%, both P Hui and Han populations. These differences may be important in explaining reported inter-ethnic differences in disease prevalence and response to drugs. © 2011 Blackwell Publishing Ltd.

  12. Short-term calorie restriction feminizes the mRNA profiles of drug metabolizing enzymes and transporters in livers of mice

    Energy Technology Data Exchange (ETDEWEB)

    Fu, Zidong Donna [Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160 (United States); Klaassen, Curtis D., E-mail: cklaasse@kumc.edu [Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160 (United States)

    2014-01-01

    Calorie restriction (CR) is one of the most effective anti-aging interventions in mammals. A modern theory suggests that aging results from a decline in detoxification capabilities and thus accumulation of damaged macromolecules. The present study aimed to determine how short-term CR alters mRNA profiles of genes that encode metabolism and detoxification machinery in the liver. Male C57BL/6 mice were fed CR (0, 15, 30, or 40%) diets for one month, followed by mRNA quantification of 98 xenobiotic processing genes (XPGs) in the liver, including 7 uptake transporters, 39 phase-I enzymes, 37 phase-II enzymes, 10 efflux transporters, and 5 transcription factors. In general, 15% CR did not alter mRNAs of most XPGs, whereas 30 and 40% CR altered over half of the XPGs (32 increased and 29 decreased). CR up-regulated some phase-I enzymes (fold increase), such as Cyp4a14 (12), Por (2.3), Nqo1 (1.4), Fmo2 (5.4), and Fmo3 (346), and numerous number of phase-II enzymes, such as Sult1a1 (1.2), Sult1d1 (2.0), Sult1e1 (33), Sult3a1 (2.2), Gsta4 (1.3), Gstm2 (1.3), Gstm3 (1.7), and Mgst3 (2.2). CR feminized the mRNA profiles of 32 XPGs in livers of male mice. For instance, CR decreased the male-predominantly expressed Oatp1a1 (97%) and increased the female-predominantly expressed Oatp1a4 (11). In conclusion, short-term CR alters the mRNA levels of over half of the 98 XPGs quantified in livers of male mice, and over half of these alterations appear to be due to feminization of the liver. - Highlights: • Utilized a graded CR model in male mice • The mRNA profiles of xenobiotic processing genes (XPGs) in liver were investigated. • CR up-regulates many phase-II enzymes. • CR tends to feminize the mRNA profiles of XPGs.

  13. Short-term calorie restriction feminizes the mRNA profiles of drug metabolizing enzymes and transporters in livers of mice

    International Nuclear Information System (INIS)

    Fu, Zidong Donna; Klaassen, Curtis D.

    2014-01-01

    Calorie restriction (CR) is one of the most effective anti-aging interventions in mammals. A modern theory suggests that aging results from a decline in detoxification capabilities and thus accumulation of damaged macromolecules. The present study aimed to determine how short-term CR alters mRNA profiles of genes that encode metabolism and detoxification machinery in the liver. Male C57BL/6 mice were fed CR (0, 15, 30, or 40%) diets for one month, followed by mRNA quantification of 98 xenobiotic processing genes (XPGs) in the liver, including 7 uptake transporters, 39 phase-I enzymes, 37 phase-II enzymes, 10 efflux transporters, and 5 transcription factors. In general, 15% CR did not alter mRNAs of most XPGs, whereas 30 and 40% CR altered over half of the XPGs (32 increased and 29 decreased). CR up-regulated some phase-I enzymes (fold increase), such as Cyp4a14 (12), Por (2.3), Nqo1 (1.4), Fmo2 (5.4), and Fmo3 (346), and numerous number of phase-II enzymes, such as Sult1a1 (1.2), Sult1d1 (2.0), Sult1e1 (33), Sult3a1 (2.2), Gsta4 (1.3), Gstm2 (1.3), Gstm3 (1.7), and Mgst3 (2.2). CR feminized the mRNA profiles of 32 XPGs in livers of male mice. For instance, CR decreased the male-predominantly expressed Oatp1a1 (97%) and increased the female-predominantly expressed Oatp1a4 (11). In conclusion, short-term CR alters the mRNA levels of over half of the 98 XPGs quantified in livers of male mice, and over half of these alterations appear to be due to feminization of the liver. - Highlights: • Utilized a graded CR model in male mice • The mRNA profiles of xenobiotic processing genes (XPGs) in liver were investigated. • CR up-regulates many phase-II enzymes. • CR tends to feminize the mRNA profiles of XPGs

  14. Relationship between genetic polymorphisms of drug-metabolizing enzymes (CYP1A1, CYP2E1, GSTM1, and NAT2), drinking habits, histological subtypes, and p53 gene point mutations in Japanese patients with gastric cancer.

    Science.gov (United States)

    Suzuki, Shioto; Muroishi, Youko; Nakanishi, Isao; Oda, Yoshio

    2004-01-01

    Genetic polymorphisms of drug-metabolizing enzymes have recently been shown to affect susceptibility to chemical carcinogenesis. However, the molecular mechanisms of individual susceptibility to gastric cancer have not been fully understood. Therefore, we studied the relationship between the genetic polymorphisms of drug-metabolizing enzymes, drinking habits, histological subtypes, and p53 gene point mutations in Japanese patients with gastric cancer. The genotypes of cytochromes P450 ( CYP) 1A1 and 2E1, glutathione S-transferase ( GST) M1, and N-acetyltransferase ( NAT) were investigated by polymerase chain reaction (PCR), allele-specific PCR, or restriction fragment length polymorphism (RFLP) following PCR in 146 Japanese patients with gastric cancer (67 intestinal-type and 79 diffuse-type carcinomas) and 177 autopsied controls. In addition, p53 gene point mutations of exons 5 through 9 in gastric cancer tissues were determined. The frequency of either being a habitual drinker or having a CYP2E1(*) 1A/(*) 1A genotype was significantly higher in patients with intestinal-type gastric cancer than in control subjects. The difference between the frequencies of habitual drinkers with the CYP2E1(*) 1A/(*) 1A genotype and non-drinkers with the CYP2E1(*) 5B allele was much more significant in the intestinal-type cancer versus the control group. Among intestinal-type cancer patients with the CYP2E1(*) 1A/(*) 1A genotype, p53 point mutations were significantly more frequent in the group of habitual drinkers than in that of non-drinkers. On the other hand, the combination of GSTM1 null and CYP2E1(*) 1A/(*) 1A genotypes increased the risk for diffuse-type gastric cancer, but had no influence on the frequency of p53 gene mutations. The present study suggests that individuals with both the CYP2E1(*) 1A/(*) 1A genotype and a history of habitual drinking have an increased risk of intestinal-type gastric cancer with a high frequency of p53 gene point mutations in the gastric

  15. Metabolism of phencyclidine

    International Nuclear Information System (INIS)

    Hoag, M.K.P.

    1987-01-01

    Phencyclidine (PCP) is a drug of abuse which may produce, in some users, a persistent schizophreniform psychosis. The possibility that long term effects of PCP are mediated by metabolic activation of the parent compound to reactive species is consistent with the demonstration of metabolism-dependent covalent binding of radiolabeled PCP in vivo and in vitro to macromolecules in rodent lung, liver, and kidney. Formation of the electrophilic iminium ion metabolite of PCP is believed to be critical for covalent binding since binding was inhibited by cyanide ion at concentrations which did not inhibit metabolism of PCP but did trap the iminium ion to form the corresponding alpha-aminonitrile. The present studies were designed to characterize further the biological fate of PCP by identifying possible macromolecular targets of the reactive metabolite(s)

  16. [Comparative experimental study of the influence of drugs that improve brain metabolism (angiogen, cytoflavin) on neuronal apoptosis and function of cerebral cortex during aging].

    Science.gov (United States)

    Bazhanova, E D; Anisimov, V N; Sukhanov, D S; Teplyĭ, D L

    2015-01-01

    The safety of cortical neurons and their functional activity is essential for organism at all stages of ontogenesis. However, aging changes leading to an increase in apoptosis level may cause considerable damage to cerebral cortex function, including sensorimotor. We have studied the role of exogenous neurometabolites (angiogen, cytoflavin) in apoptosis regulation and correction of age-related motor and behavioral disturbances. To study the regulation of neuronal morphofunctional activity, we used accelerate-senescent transgenic HER2 mice in comparison to wild type FBV mice. Functional changes in cerebral cortex were studied by the Suok test and open field test, the level of neuronal apoptosis was assessed by TUNEL method, the expression of apoptosis-modulating proteins was detected by immunohistochemistry and Western blotting. We have revealed differences in psycho-emotional and locomotor activity of these strains of mice. In addition, results of our study showed morphological differences: increase in the apoptosis level of cortical neurons in aged FBV type mice, but no changes in aged HER2 mice. The investigated drugs induce cell death of cortical neurons in transgenic mice of both ages and in young wild-type mice by p53-dependent pathway. Increased apoptosis in the cortex of old transgenic mice has important clinical implications, because reduced apoptosis during aging is one of the causes of cancer. The treatment of old wild-type animals reduces elevated neuronal apoptosis, which decreases risk of age neurodegeneration. Thus, revealed morphological changes in the cerebral cortex are the basis for involutional disabilities (including reduced locomotor activity and increased anxiety level). The use of angiogen and cytoflavin treatment improves functional activity of the cortex and protects normal structure of nervous tissue.

  17. Drug Addiction

    Science.gov (United States)

    ... attempt to stop taking the drug Recognizing unhealthy drug use in family members Sometimes it's difficult to ... sold to support drug use Recognizing signs of drug use or intoxication Signs and symptoms of drug ...

  18. Drug Allergy

    Science.gov (United States)

    ... Seizure Loss of consciousness Other conditions resulting from drug allergy Less common drug allergy reactions occur days ... reaction the first time you take the drug. Drugs commonly linked to allergies Although any drug can ...

  19. Promising toxicological biomarkers for the diagnosis of liver injury types: Bile acid metabolic profiles and oxidative stress marker as screening tools in drug development.

    Science.gov (United States)

    Masubuchi, Noriko; Nishiya, Takayoshi; Imaoka, Masako; Mizumaki, Kiyoko; Okazaki, Osamu

    2016-08-05

    optimization phase of drug discovery. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  20. Drug Facts

    Medline Plus

    Full Text Available ... some signs and symptoms of someone with a drug use problem? How Does Drug Use Become an Addiction? What Makes Someone More Likely ... So Hard to Quit Drugs? Effects of Drugs Drug Use and Other People Drug Use and Families Drug ...

  1. Robustness of metabolic networks

    Science.gov (United States)

    Jeong, Hawoong

    2009-03-01

    We investigated the robustness of cellular metabolism by simulating the system-level computational models, and also performed the corresponding experiments to validate our predictions. We address the cellular robustness from the ``metabolite''-framework by using the novel concept of ``flux-sum,'' which is the sum of all incoming or outgoing fluxes (they are the same under the pseudo-steady state assumption). By estimating the changes of the flux-sum under various genetic and environmental perturbations, we were able to clearly decipher the metabolic robustness; the flux-sum around an essential metabolite does not change much under various perturbations. We also identified the list of the metabolites essential to cell survival, and then ``acclimator'' metabolites that can control the cell growth were discovered. Furthermore, this concept of ``metabolite essentiality'' should be useful in developing new metabolic engineering strategies for improved production of various bioproducts and designing new drugs that can fight against multi-antibiotic resistant superbacteria by knocking-down the enzyme activities around an essential metabolite. Finally, we combined a regulatory network with the metabolic network to investigate its effect on dynamic properties of cellular metabolism.

  2. Nucleotide Metabolism

    DEFF Research Database (Denmark)

    Martinussen, Jan; Willemoës, M.; Kilstrup, Mogens

    2011-01-01

    Metabolic pathways are connected through their utilization of nucleotides as supplier of energy, allosteric effectors, and their role in activation of intermediates. Therefore, any attempt to exploit a given living organism in a biotechnological process will have an impact on nucleotide metabolism...

  3. Integration of Genome Scale Metabolic Networks and Gene Regulation of Metabolic Enzymes With Physiologically Based Pharmacokinetics

    Science.gov (United States)

    Maldonado, Elaina M.; Leoncikas, Vytautas; Fisher, Ciarán P.; Moore, J. Bernadette; Plant, Nick J.

    2017-01-01

    The scope of physiologically based pharmacokinetic (PBPK) modeling can be expanded by assimilation of the mechanistic models of intracellular processes from systems biology field. The genome scale metabolic networks (GSMNs) represent a whole set of metabolic enzymes expressed in human tissues. Dynamic models of the gene regulation of key drug metabolism enzymes are available. Here, we introduce GSMNs and review ongoing work on integration of PBPK, GSMNs, and metabolic gene regulation. We demonstrate example models. PMID:28782239

  4. Drug allergies

    Science.gov (United States)

    Allergic reaction - drug (medication); Drug hypersensitivity; Medication hypersensitivity ... A drug allergy involves an immune response in the body that produces an allergic reaction to a medicine. The ...

  5. Clinical update on metabolic syndrome

    Directory of Open Access Journals (Sweden)

    Juan Diego Hernández-Camacho

    2017-12-01

    Full Text Available Metabolic syndrome has been defined as a global issue since it affects a lot of people. Numerous factors are involved in metabolic syndrome development. It has been described that metabolic syndrome has negative consequences on health. Consequently, a lot of treatments have been proposed to palliate it such as drugs, surgery or life style changes where nutritional habits have shown to be an important point in its management. The current study reviews the literature existing about the actual epidemiology of metabolic syndrome, the components involucrate in its appearance and progression, the clinical consequences of metabolic syndrome and the nutritional strategies reported in its remission. A bibliographic search in PubMed and Medline was performed to identify eligible studies. Authors obtained that metabolic syndrome is present in population from developed and undeveloped areas in a huge scale. Environmental and genetic elements are involucrate in metabolic syndrome development. Metabolic syndrome exponentially increased risk of cardiovascular disease, some types of cancers, diabetes mellitus type 2, sleep disturbances, etc. Nutritional treatments play a crucial role in metabolic syndrome prevention, treatment and recovery.

  6. Xenobiotic Metabolism and Gut Microbiomes

    Science.gov (United States)

    Das, Anubhav; Srinivasan, Meenakshi; Ghosh, Tarini Shankar; Mande, Sharmila S.

    2016-01-01

    Humans are exposed to numerous xenobiotics, a majority of which are in the form of pharmaceuticals. Apart from human enzymes, recent studies have indicated the role of the gut bacterial community (microbiome) in metabolizing xenobiotics. However, little is known about the contribution of the plethora of gut microbiome in xenobiotic metabolism. The present study reports the results of analyses on xenobiotic metabolizing enzymes in various human gut microbiomes. A total of 397 available gut metagenomes from individuals of varying age groups from 8 nationalities were analyzed. Based on the diversities and abundances of the xenobiotic metabolizing enzymes, various bacterial taxa were classified into three groups, namely, least versatile, intermediately versatile and highly versatile xenobiotic metabolizers. Most interestingly, specific relationships were observed between the overall drug consumption profile and the abundance and diversity of the xenobiotic metabolizing repertoire in various geographies. The obtained differential abundance patterns of xenobiotic metabolizing enzymes and bacterial genera harboring them, suggest their links to pharmacokinetic variations among individuals. Additional analyses of a few well studied classes of drug modifying enzymes (DMEs) also indicate geographic as well as age specific trends. PMID:27695034

  7. Xenobiotic Metabolism and Gut Microbiomes.

    Directory of Open Access Journals (Sweden)

    Anubhav Das

    Full Text Available Humans are exposed to numerous xenobiotics, a majority of which are in the form of pharmaceuticals. Apart from human enzymes, recent studies have indicated the role of the gut bacterial community (microbiome in metabolizing xenobiotics. However, little is known about the contribution of the plethora of gut microbiome in xenobiotic metabolism. The present study reports the results of analyses on xenobiotic metabolizing enzymes in various human gut microbiomes. A total of 397 available gut metagenomes from individuals of varying age groups from 8 nationalities were analyzed. Based on the diversities and abundances of the xenobiotic metabolizing enzymes, various bacterial taxa were classified into three groups, namely, least versatile, intermediately versatile and highly versatile xenobiotic metabolizers. Most interestingly, specific relationships were observed between the overall drug consumption profile and the abundance and diversity of the xenobiotic metabolizing repertoire in various geographies. The obtained differential abundance patterns of xenobiotic metabolizing enzymes and bacterial genera harboring them, suggest their links to pharmacokinetic variations among individuals. Additional analyses of a few well studied classes of drug modifying enzymes (DMEs also indicate geographic as well as age specific trends.

  8. Drug Facts

    Medline Plus

    Full Text Available ... Drug Use and Kids Drug Use and Unborn Children Drug Use and Your Health Other Effects on ... Someone Find Treatment and Recovery Resources? Prevention Help Children and Teens Stay Drug-Free Talking to Kids ...

  9. Drug Facts

    Medline Plus

    Full Text Available ... Drug Use and Your Health Other Effects on the Body Drug Use Hurts Brains Drug Use and Mental Health Problems Often Happen Together The Link Between Drug Use and HIV/AIDS Treatment & ...

  10. Drug Facts

    Medline Plus

    Full Text Available ... Use and Unborn Children Drug Use and Your Health Other Effects on the Body Drug Use Hurts Brains Drug Use and Mental Health Problems Often Happen Together The Link Between Drug ...

  11. Drug Safety

    Science.gov (United States)

    ... over-the-counter drug. The FDA evaluates the safety of a drug by looking at Side effects ... clinical trials The FDA also monitors a drug's safety after approval. For you, drug safety means buying ...

  12. Drug Facts

    Medline Plus

    Full Text Available ... and symptoms of someone with a drug use problem? How Does Drug Use Become an Addiction? What ... Use Hurts Brains Drug Use and Mental Health Problems Often Happen Together The Link Between Drug Use ...

  13. Expression of Enzymes that Metabolize Medications

    Science.gov (United States)

    Wotring, Virginia E.; Peters, C. P.

    2012-01-01

    Most pharmaceuticals are metabolized by the liver. Clinically-used medication doses are given with normal liver function in mind. A drug overdose can result if the liver is damaged and removing pharmaceuticals from the circulation at a rate slower than normal. Alternatively, if liver function is elevated and removing drugs from the system more quickly than usual, it would be as if too little drug had been given for effective treatment. Because of the importance of the liver in drug metabolism we want to understand the effects of spaceflight on the enzymes of the liver.

  14. [HIV infection declines among intravenous drug addicts in Barcelona: 1987-1993].

    Science.gov (United States)

    Muga, R; Egea, J M; Tor, J; Rodríguez, R; Roca, J; Giménez, G; Foz, M

    1994-11-05

    The evolution of the prevalence of HIV infection in intravenous drug addicts who initiate hospital detoxication was analyzed. Six hundred fifty intravenous drug addicts (535 males, 115 females) were analyzed for HIV and surveyed in regard to demographic variables and the use of drugs over a period of 7 years (1987-1993): age, sex, year of initiation of intravenous drug addiction, length of the habit and year of admission. Most of the subjects were men (82%) with a mean age of 19.7 years at the time of initiation to the use of i.v. drugs and an age of 25.9 years on admission to the unit. The mean time of i.v. drug addiction at admission was 74 months. The characteristics of the patients according to the year of admission were homogeneous in regard to age, length of drug addiction and male/female ratio. More than 50% of the subjects had initiated the use of i.v. drugs during the first half of the last decade. The global prevalence of HIV infection was of 66.3% with no differences being observed between sexes. The frequency of infection was shown to have globally decreased from 1987 to 1993 (p = 0.06) although the rates of HIV infection in women did not significantly modify (p = 0.08) in contrast to that of men (p = 0.05). The epidemia of HIV infection in intravenous drug addicts may have entered into remission following a decade characterized by a spread in the use of heroin and great diffusion of the disease.

  15. Mucoadhesive Buccal Drug Delivery System

    OpenAIRE

    Pooja P.Thakkar; Meghana J.Chaudhari; Ami M.Soni; Dharti P.Pandya; Darshan A.Modi

    2012-01-01

    The buccal region of the oral cavity is an attractive target for administration of the drug of choice,particularly in overcoming deficiencies associated with the latter mode of administration. Problems suchas high first-pass metabolism and drug degradation in the gastrointestinal environment can becircumvented by administering the drug via the buccal route. Mucoadhesion can be defined as a state inwhich two components, of which one is of biological origin are held together for extended period...

  16. Drug-Path: a database for drug-induced pathways.

    Science.gov (United States)

    Zeng, Hui; Qiu, Chengxiang; Cui, Qinghua

    2015-01-01

    Some databases for drug-associated pathways have been built and are publicly available. However, the pathways curated in most of these databases are drug-action or drug-metabolism pathways. In recent years, high-throughput technologies such as microarray and RNA-sequencing have produced lots of drug-induced gene expression profiles. Interestingly, drug-induced gene expression profile frequently show distinct patterns, indicating that drugs normally induce the activation or repression of distinct pathways. Therefore, these pathways contribute to study the mechanisms of drugs and drug-repurposing. Here, we present Drug-Path, a database of drug-induced pathways, which was generated by KEGG pathway enrichment analysis for drug-induced upregulated genes and downregulated genes based on drug-induced gene expression datasets in Connectivity Map. Drug-Path provides user-friendly interfaces to retrieve, visualize and download the drug-induced pathway data in the database. In addition, the genes deregulated by a given drug are highlighted in the pathways. All data were organized using SQLite. The web site was implemented using Django, a Python web framework. Finally, we believe that this database will be useful for related researches. © The Author(s) 2015. Published by Oxford University Press.

  17. Metabolic Myopathies.

    Science.gov (United States)

    Tarnopolsky, Mark A

    2016-12-01

    Metabolic myopathies are genetic disorders that impair intermediary metabolism in skeletal muscle. Impairments in glycolysis/glycogenolysis (glycogen-storage disease), fatty acid transport and oxidation (fatty acid oxidation defects), and the mitochondrial respiratory chain (mitochondrial myopathies) represent the majority of known defects. The purpose of this review is to develop a diagnostic and treatment algorithm for the metabolic myopathies. The metabolic myopathies can present in the neonatal and infant period as part of more systemic involvement with hypotonia, hypoglycemia, and encephalopathy; however, most cases present in childhood or in adulthood with exercise intolerance (often with rhabdomyolysis) and weakness. The glycogen-storage diseases present during brief bouts of high-intensity exercise, whereas fatty acid oxidation defects and mitochondrial myopathies present during a long-duration/low-intensity endurance-type activity or during fasting or another metabolically stressful event (eg, surgery, fever). The clinical examination is often normal between acute events, and evaluation involves exercise testing, blood testing (creatine kinase, acylcarnitine profile, lactate, amino acids), urine organic acids (ketones, dicarboxylic acids, 3-methylglutaconic acid), muscle biopsy (histology, ultrastructure, enzyme testing), MRI/spectroscopy, and targeted or untargeted genetic testing. Accurate and early identification of metabolic myopathies can lead to therapeutic interventions with lifestyle and nutritional modification, cofactor treatment, and rapid treatment of rhabdomyolysis.

  18. Animal metabolism

    International Nuclear Information System (INIS)

    Walburg, H.E.

    1977-01-01

    Studies on placental transport included the following: clearance of tritiated water as a baseline measurement for transport of materials across perfused placentas; transport of organic and inorganic mercury across the perfused placenta of the guinea pig in late gestation; and transport of cadmium across the perfused placenta of the guinea pig in late gestation. Studies on cadmium absorption and metabolism included the following: intestinal absorption and retention of cadmium in neonatal rats; uptake and distribution of an oral dose of cadmium in postweanling male and female, iron-deficient and normal rats; postnatal viability and growth in rat pups after oral cadmium administration during gestation; and the effect of calcium and phosphorus on the absorption and toxicity of cadmium. Studies on gastrointestinal absorption and mineral metabolism included: uptake and distribution of orally administered plutonium complex compounds in male mice; gastrointestinal absorption of 144 Ce in the newborn mouse, rat, and pig; and gastrointestinal absorption of 95 Nb by rats of different ages. Studies on iodine metabolism included the following: influence of thyroid status and thiocyanate on iodine metabolism in the bovine; effects of simulated fallout radiation on iodine metabolism in dairy cattle; and effects of feeding iodine binding agents on iodine metabolism in the calf

  19. Cariporide and other new and powerful NHE1 inhibitors as potentially selective anticancer drugs--an integral molecular/biochemical/metabolic/clinical approach after one hundred years of cancer research.

    Science.gov (United States)

    Harguindey, Salvador; Arranz, Jose Luis; Polo Orozco, Julian David; Rauch, Cyril; Fais, Stefano; Cardone, Rosa Angela; Reshkin, Stephan J

    2013-11-06

    In recent years an increasing number of publications have emphasized the growing importance of hydrogen ion dynamics in modern cancer research, from etiopathogenesis and treatment. A proton [H+]-related mechanism underlying the initiation and progression of the neoplastic process has been recently described by different research groups as a new paradigm in which all cancer cells and tissues, regardless of their origin and genetic background, have a pivotal energetic and homeostatic disturbance of their metabolism that is completely different from all normal tissues: an aberrant regulation of hydrogen ion dynamics leading to a reversal of the pH gradient in cancer cells and tissues (↑pHi/↓pHe, or "proton reversal"). Tumor cells survive their hostile microenvironment due to membrane-bound proton pumps and transporters, and their main defensive strategy is to never allow internal acidification because that could lead to their death through apoptosis. In this context, one of the primary and best studied regulators of both pHi and pHe in tumors is the Na+/H+ exchanger isoform 1 (NHE1). An elevated NHE1 activity can be correlated with both an increase in cell pH and a decrease in the extracellular pH of tumors, and such proton reversal is associated with the origin, local growth, activation and further progression of the metastatic process. Consequently, NHE1 pharmaceutical inhibition by new and potent NHE1 inhibitors represents a potential and highly selective target in anticancer therapy. Cariporide, being one of the better studied specific and powerful NHE1 inhibitors, has proven to be well tolerated by humans in the cardiological context, however some side-effects, mainly related to drug accumulation and cerebrovascular complications were reported. Thus, cariporide could become a new, slightly toxic and effective anticancer agent in different human malignancies.

  20. Drug-Drug/Drug-Excipient Compatibility Studies on Curcumin using Non-Thermal Methods

    OpenAIRE

    Moorthi Chidambaram; Kathiresan Krishnasamy

    2014-01-01

    Purpose: Curcumin is a hydrophobic polyphenol isolated from dried rhizome of turmeric. Clinical usefulness of curcumin in the treatment of cancer is limited due to poor aqueous solubility, hydrolytic degradation, metabolism, and poor oral bioavailability. To overcome these limitations, we proposed to fabricate curcumin-piperine, curcumin-quercetin and curcumin-silibinin loaded polymeric nanoformulation. However, unfavourable combinations of drug-drug and drug-excipient may result in interacti...

  1. Molecular interactions between NAFLD and xenobiotic metabolism

    Directory of Open Access Journals (Sweden)

    Adviti eNaik

    2013-01-01

    Full Text Available Non-alcoholic fatty liver disease (NAFLD, the hepatic manifestation of the metabolic syndrome, is a complex multifactorial disease characterised by metabolic deregulations that include accumulation of lipids in the liver, lipotoxicity and insulin resistance. The progression of NAFLD to NASH and cirrhosis, and ultimately to carcinomas, is governed by interplay of pro-inflammatory pathways, oxidative stress, as well as fibrogenic and apoptotic cues. As the liver is the major organ of biotransformation, deregulations in hepatic signalling pathways have effects on both, xenobiotic and endobiotic metabolism. Several major nuclear receptors involved in the transcription and regulation of phase I and II drug metabolizing enzymes and transporters also have endobiotic ligands including several lipids. Hence, hepatic lipid accumulation in steatosis and NAFLD, which leads to deregulated activation patterns of nuclear receptors, may result in altered drug metabolism capacity in NAFLD patients. On the other hand, genetic and association studies have indicated that a malfunction in drug metabolism can affect the prevalence and severity of NAFLD. This review focuses on the complex interplay between NAFLD pathogenesis and drug metabolism. A better understanding of these relationships is a prerequisite for developing improved drug dosing algorithms for the pharmacotherapy of patients with different stages of NAFLD.

  2. Adaptations in the energy metabolism of parasites

    NARCIS (Netherlands)

    van Grinsven, K.W.A.|info:eu-repo/dai/nl/304833436

    2009-01-01

    For this thesis fundamental research was performed on the metabolic adaptations found in parasites. Studying the adaptations in parasite metabolisms leads to a better understanding of parasite bioenergetics and can also result in the identification of new anti-parasitic drug targets. We focussed on

  3. Drug-drug interation prediction between ketoconazole and anti-liver ...

    African Journals Online (AJOL)

    Aims: To predict the metabolic behavior and metabolism-based drug-drug interaction of gomisin G. Methods: ... Results: Gomisin G can be well docked into the activity site of CYP3A4, and distance between gomisin G the heme active site was 2.75 Å. To .... Fang ZZ, Krausz KW, Li F, Cheng J, Tanaka N, Gon- zalez FJ.

  4. What is Metabolic Syndrome?

    Science.gov (United States)

    ... Research Home / Metabolic Syndrome Metabolic Syndrome What Is Metabolic syndrome is the name for a group of risk ... three metabolic risk factors to be diagnosed with metabolic syndrome. A large waistline. This also is called abdominal ...

  5. [Metabolic myopathies].

    Science.gov (United States)

    Papazian, Óscar; Rivas-Chacón, Rafael

    2013-09-06

    To review the metabolic myopathies manifested only by crisis of myalgias, cramps and rigidity of the muscles with decreased voluntary contractions and normal inter crisis neurologic examination in children and adolescents. These metabolic myopathies are autosomic recessive inherited enzymatic deficiencies of the carbohydrates and lipids metabolisms. The end result is a reduction of intra muscle adenosine triphosphate, mainly through mitochondrial oxidative phosphorylation, with decrease of available energy for muscle contraction. The one secondary to carbohydrates intra muscle metabolism disorders are triggered by high intensity brief (fatty acids metabolism disorders are triggered by low intensity prolonged (> 10 min) exercises. The conditions in the first group in order of decreasing frequency are the deficiencies of myophosforilase (GSD V), muscle phosphofructokinase (GSD VII), phosphoglycerate mutase 1 (GSD X) and beta enolase (GSD XIII). The conditions in the second group in order of decreasing frequency are the deficiencies of carnitine palmitoyl transferase II and very long chain acyl CoA dehydrogenase. The differential characteristics of patients in each group and within each group will allow to make the initial presumptive clinical diagnosis in the majority and then to order only the necessary tests to achieve the final diagnosis. Treatment during the crisis includes hydration, glucose and alkalinization of urine if myoglobin in blood and urine are elevated. Prevention includes avoiding exercise which may induce the crisis and fasting. The prognosis is good with the exception of rare cases of acute renal failure due to hipermyoglobinemia because of severe rabdomyolisis.

  6. Bioadhesive polymeric platforms for transmucosal drug delivery ...

    African Journals Online (AJOL)

    Of the various routes of drug delivery, the oral route is often preferred by the patient. However, peroral administration of drugs has disadvantages such as hepatic first-pass metabolism and enzymatic degradation within the gastrointestinal tract which constitutes a hindrance to oral administration of certain classes of drugs, ...

  7. Drug Facts

    Medline Plus

    Full Text Available ... Drug Use Hurts Brains Drug Use and Mental Health Problems Often Happen Together The Link Between Drug Use and HIV/AIDS Treatment & Recovery Why Does a Person Need Treatment? Does Drug Treatment Work? What ... Institute on Drug Abuse (NIDA) is part of the National Institutes of Health (NIH) , the principal biomedical and behavioral research agency ...

  8. Drug disposition and drug-drug interaction data in 2013 FDA new drug applications: a systematic review.

    Science.gov (United States)

    Yu, Jingjing; Ritchie, Tasha K; Mulgaonkar, Aditi; Ragueneau-Majlessi, Isabelle

    2014-12-01

    The aim of the present work was to perform a systematic review of drug metabolism, transport, pharmacokinetics, and DDI data available in the NDAs approved by the FDA in 2013, using the University of Washington Drug Interaction Database, and to highlight significant findings. Among 27 NMEs approved, 22 (81%) were well characterized with regard to drug metabolism, transport, or organ impairment, in accordance with the FDA drug interaction guidance (2012) and were fully analyzed in this review. In vitro, a majority of the NMEs were found to be substrates or inhibitors/inducers of at least one drug metabolizing enzyme or transporter. However, in vivo, only half (n = 11) showed clinically relevant drug interactions, with most related to the NMEs as victim drugs and CYP3A being the most affected enzyme. As perpetrators, the overall effects for NMEs were much less pronounced, compared with when they served as victims. In addition, the pharmacokinetic evaluation in patients with hepatic or renal impairment provided useful information for further understanding of the drugs' disposition. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

  9. Mucoadhesive drug delivery systems

    Directory of Open Access Journals (Sweden)

    Rahamatullah Shaikh

    2011-01-01

    Full Text Available Mucoadhesion is commonly defined as the adhesion between two materials, at least one of which is a mucosal surface. Over the past few decades, mucosal drug delivery has received a great deal of attention. Mucoadhesive dosage forms may be designed to enable prolonged retention at the site of application, providing a controlled rate of drug release for improved therapeutic outcome. Application of dosage forms to mucosal surfaces may be of benefit to drug molecules not amenable to the oral route, such as those that undergo acid degradation or extensive first-pass metabolism. The mucoadhesive ability of a dosage form is dependent upon a variety of factors, including the nature of the mucosal tissue and the physicochemical properties of the polymeric formulation. This review article aims to provide an overview of the various aspects of mucoadhesion, mucoadhesive materials, factors affecting mucoadhesion, evaluating methods, and finally various mucoadhesive drug delivery systems (buccal, nasal, ocular, gastro, vaginal, and rectal.

  10. Metabolism of 1,2-dibromoethane in the human fetal liver.

    Science.gov (United States)

    Kulkarni, A P; Edwards, J; Richards, I S

    1992-01-01

    1. Toxicity of 1,2-dibromoethane requires bioactivation via glutathione S-transferase. Since this enzyme is undetectable in the fetus of several laboratory animal species during early gestation, in vitro studies were carried out with human fetal liver to assess potential fetotoxicity. 2. Glutathione S-transferase occurs abundantly in the human fetal liver cytosol and its titer is equal to or exceeds that found in adult human liver when estimated using 1-chloro-2,4-nitrobenzene as the second substrate. 3. Human fetal liver cytosolic glutathione S-transferase metabolized 1,2-dibromoethane with a high efficiency (mean +/- SD specific activity of 3.10 +/- 0.83 nmol/min/mg protein). This reaction was enzymatic in nature and the rate of conjugation was proportional to the concentration of reduced glutathione, 1,2-dibromoethane and the enzyme present in the reaction medium. 4. A significant bioactivation with a possibility of only limited detoxication via cytochrome P-450-dependent oxidation suggests that human fetus may be at greater risk from 1,2-dibromoethane toxicity than adult.

  11. Bone metabolism in healthy ambulatory control premonopausal ...

    African Journals Online (AJOL)

    Long-term anti-epileptic drug use significantly affects biochemical parameters of bone metabolism. These effects on bone biochemistry markers were not reflected in lumbar spine BMD in this study. The mean duration of treatment for epilepsy was eight years (±6.3). Majority of the patients were on enzyme inducing drugs ...

  12. Transporters and drug-drug interactions: important determinants of drug disposition and effects.

    Science.gov (United States)

    König, Jörg; Müller, Fabian; Fromm, Martin F

    2013-07-01

    Uptake and efflux transporters determine plasma and tissue concentrations of a broad variety of drugs. They are localized in organs such as small intestine, liver, and kidney, which are critical for drug absorption and elimination. Moreover, they can be found in important blood-tissue barriers such as the blood-brain barrier. Inhibition or induction of drug transporters by coadministered drugs can alter pharmacokinetics and pharmacodynamics of the victim drugs. This review will summarize in particular clinically observed drug-drug interactions attributable to inhibition or induction of intestinal export transporters [P-glycoprotein (P-gp), breast cancer resistance protein (BCRP)], to inhibition of hepatic uptake transporters [organic anion transporting polypeptides (OATPs)], or to inhibition of transporter-mediated [organic anion transporters (OATs), organic cation transporter 2 (OCT2), multidrug and toxin extrusion proteins (MATEs), P-gp] renal secretion of xenobiotics. Available data on the impact of nutrition on transport processes as well as genotype-dependent, transporter-mediated drug-drug interactions will be discussed. We will also present and discuss data on the variable extent to which information on the impact of transporters on drug disposition is included in summaries of product characteristics of selected countries (SPCs). Further work is required regarding a better understanding of the role of the drug metabolism-drug transport interplay for drug-drug interactions and on the extrapolation of in vitro findings to the in vivo (human) situation.