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Sample records for renal drug transporters

  1. Multiple Drug Transporters Are Involved in Renal Secretion of Entecavir.

    Science.gov (United States)

    Yang, Xi; Ma, Zhiyuan; Zhou, Sisi; Weng, Yayun; Lei, Hongmei; Zeng, Su; Li, Liping; Jiang, Huidi

    2016-10-01

    Entecavir (ETV) is a first-line antiviral agent for the treatment of chronic hepatitis B virus infection. Renal excretion is the major elimination path of ETV, in which tubular secretion plays the key role. However, the secretion mechanism has not been clarified. We speculated that renal transporters mediated the secretion of ETV. Therefore, the aim of our study was to elucidate which transporters contribute to the renal disposition of ETV. Our results revealed that ETV (50 μM) remarkably reduced the accumulation of probe substrates in MDCK cells stably expressing human multidrug and toxin efflux extrusion proteins (hMATE1/2-K), organic cation transporter 2 (hOCT2), and carnitine/organic cation transporters (hOCTNs) and increased the substrate accumulation in cells transfected with multidrug resistance-associated protein 2 (hMRP2) or multidrug resistance protein 1 (hMDR1). Moreover, ETV was proved to be a substrate of the above-described transporters. In transwell studies, the transport of ETV in MDCK-hOCT2-hMATE1 showed a distinct directionality from BL (hOCT2) to AP (hMATE1), and the cellular accumulation of ETV in cells expressing hMATE1 was dramatically lower than that of the mock-treated cells. The accumulation of ETV in mouse primary renal tubular cells was obviously affected by inhibitors of organic anion transporter 1/3 (Oat1/3), Oct2, Octn1/2, and Mrp2. Therefore, the renal uptake of ETV is likely mediated by OAT1/3 and OCT2 while the efflux is mediated by MATEs, MDR1, and MRP2, and OCTN1/2 may participate in both renal secretion and reabsorption. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  2. Quantitative Prediction of Human Renal Clearance and Drug-Drug Interactions of Organic Anion Transporter Substrates Using In Vitro Transport Data: A Relative Activity Factor Approach.

    Science.gov (United States)

    Mathialagan, Sumathy; Piotrowski, Mary A; Tess, David A; Feng, Bo; Litchfield, John; Varma, Manthena V

    2017-04-01

    Organic anion transporters (OATs) are important in the renal secretion, and thus, the clearance, of many drugs; and their functional change can result in pharmacokinetic variability. In this study, we applied transport rates measured in vitro using OAT-transfected human embryonic kidney cells to predict human renal secretory and total renal clearance of 31 diverse drugs. Selective substrates to OAT1 (tenofovir), OAT2 (acyclovir and ganciclovir), and OAT3 (benzylpenicillin, oseltamivir acid) were used to obtain relative activity factors (RAFs) for these individual transporters by relating in vitro transport clearance (after physiologic scaling) to in vivo secretory clearance. Using the estimated RAFs (0.64, 7.3, and 4.1, respectively, for OAT1, OAT2, and OAT3, respectively) and the in vitro active clearances, renal secretory clearance and total renal clearance were predicted with average fold errors (AFEs) of 1.89 and 1.40, respectively. The results show that OAT3-mediated transport play a predominant role in renal secretion for 22 of the 31 drugs evaluated. This mechanistic static approach was further applied to quantitatively predict renal drug-drug interactions (AFE ∼1.6) of the substrate drugs with probenecid, a clinical probe OAT inhibitor. In conclusion, the proposed in vitro-in vivo extrapolation approach is the first comprehensive attempt toward mechanistic modeling of renal secretory clearance based on routinely employed in vitro cell models.

  3. Drug-induced renal injury

    African Journals Online (AJOL)

    Drugs can cause acute renal failure by causing pre-renal, intrinsic or post-renal toxicity. Pre-renal ... incidence of drug dose adjustment in renal impairment in the SAMJ. ... Fever, haemolytic anaemia, thrombocytopenia, renal impairment and.

  4. Down-regulation of intestinal drug transporters in chronic renal failure in rats.

    Science.gov (United States)

    Naud, Judith; Michaud, Josée; Boisvert, Caroline; Desbiens, Karine; Leblond, Francois A; Mitchell, Andrew; Jones, Christine; Bonnardeaux, Alain; Pichette, Vincent

    2007-03-01

    Chronic renal failure (CRF) is associated with an increased bioavailability of drugs by a poorly understood mechanism. One hypothesis is a reduction in the elimination of drugs by the intestine, i.e., drug elimination mediated by protein membrane transporters such as P-glycoprotein (Pgp) and multidrug-resistance-related protein (MRP) 2. The present study aimed to investigate the repercussions of CRF on intestinal transporters involved in drug absorption [organic anion-transportingpolypeptide (Oatp)] and those implicated in drug extrusion (Pgp and MRP2). Pgp, MRP2, MRP3, Oatp2, and Oatp3 protein expression and Pgp, MRP2, and Oatp3 mRNA expression were assessed in the intestine of CRF (induced by five-sixth nephrectomy) and control rats. Pgp and MRP2 activities were measured using the everted gut technique. Rat enterocytes and Caco-2 cells were incubated with sera from control and CRF rats to characterize the mechanism of transporters' down-regulation. Protein expression of Pgp, MRP2, and MRP3 were reduced by more than 40% (p CRF rats, whereas Oatp2 and Oatp3 expression remained unchanged. There was no difference in the mRNA levels assessed by real-time polymerase chain reaction. Pgp and MRP2 activities were decreased by 30 and 25%, respectively, in CRF rats compared with control (p CRF in rats is associated with a decrease in intestinal Pgp and MRP2 protein expression and function secondarily to serum uremic factors. This reduction could explain the increased bioavailability of drugs in CRF.

  5. Effect of hypouricaemic and hyperuricaemic drugs on the renal urate efflux transporter, multidrug resistance protein 4.

    NARCIS (Netherlands)

    El-Sheikh, A.A.K.; Heuvel, J.J.M.W. van den; Koenderink, J.B.; Russel, F.G.M.

    2008-01-01

    BACKGROUND AND PURPOSE: The xanthine oxidase inhibitors allopurinol and oxypurinol are used to treat hyperuricaemia, whereas loop and thiazide diuretics can cause iatrogenic hyperuricaemia. Some uricosuric drugs and salicylate have a bimodal action on urate renal excretion. The mechanisms of action

  6. [Renal toxicity of antiviral drugs].

    Science.gov (United States)

    Frasca', Giovanni M; Balestra, Emilio; Tavio, Marcello; Morroni, Manrico; Manarini, Gloria; Brigante, Fabiana

    2012-01-01

    Highly effective and powerful antiviral drugs have been introduced into clinical practice in recent years which are associated with an increased incidence of nephrotoxicity. The need of combining several drugs, the fragility of the patients treated, and the high susceptibility of the kidney are all factors contributing to renal injury. Many pathogenetic mechanisms are involved in the nephrotoxicity of antiviral drugs, including drug interaction with transport proteins in the tubular cell; direct cytotoxicity due to a high intracellular drug concentration; mitochondrial injury; and intrarenal obstruction or stone formation due to the low solubility of drugs at a normal urinary pH. As a result, various clinical pictures may be observed in patients treated with antiviral drugs, ranging from tubular dysfunction (Fanconi syndrome, renal tubular acidosis, nephrogenic diabetes insipidus) to acute renal failure (induced by tubular necrosis or crystal nephropathy) and kidney stones. Careful attention should be paid to prevent renal toxicity by evaluating the glomerular filtration rate before therapy and adjusting the drug dosage accordingly, avoiding the combination with other nephrotoxic drugs, and monitoring renal parameters on a regular basis while treating patients.

  7. Altered Renal Expression of Relevant Clinical Drug Transporters in Different Models of Acute Uremia in Rats. Role of Urea Levels

    Directory of Open Access Journals (Sweden)

    Anabel Brandoni

    2015-06-01

    Full Text Available Background/Aims: Organic anion transporter 1 (Oat1 and 3 (Oat3 are organic anion transporters that play critical roles in the body disposition of numerous clinically important drugs. We investigated the effects of acute uremia on the renal expression of Oat1 and Oat3 in three in vivo experimental models of acute kidney injury (AKI: induced by ischemia, by ureteral obstruction and by the administration of HgCl2. We also evaluated the influence of urea in the expression of these transporters in proximal tubular cells suspensions. Methods: Membranes were isolated from kidneys of each experimental group and from cell suspensions incubated with different urea concentrations. Oat1 and Oat3 expressions were performed by immunoblotting. Results: A good correlation between uremia and the renal protein expression of Oat1 and Oat3 was observed in vivo. Moreover, the incubation of isolated proximal tubular cells with different concentrations of urea decreases protein expression of Oat1 and Oat3 in plasma membranes in a dose-dependent manner. Conclusion: The more severe the renal failure, the more important is the decrease in protein expression of the transporters in renal membranes where they are functional. The in vitro study demonstrates that urea accounts, at least in part, for the decreased expression of Oat1 and Oat3 in proximal tubule plasma membranes.

  8. Assessment of Amino Acid/Drug Transporters for Renal Transport of [18F]Fluciclovine (anti-[18F]FACBC in Vitro

    Directory of Open Access Journals (Sweden)

    Masahiro Ono

    2016-10-01

    Full Text Available [18F]Fluciclovine (trans-1-amino-3-[18F]fluorocyclobutanecarboxylic acid; anti-[18F]FACBC, a positron emission tomography tracer used for the diagnosis of recurrent prostate cancer, is transported via amino acid transporters (AATs with high affinity (Km: 97–230 μM. However, the mechanism underlying urinary excretion is unknown. In this study, we investigated the involvement of AATs and drug transporters in renal [18F]fluciclovine reuptake. [14C]Fluciclovine (trans-1-amino-3-fluoro[1-14C]cyclobutanecarboxylic acid was used because of its long half-life. The involvement of AATs in [14C]fluciclovine transport was measured by apical-to-basal transport using an LLC-PK1 monolayer as model for renal proximal tubules. The contribution of drug transporters herein was assessed using vesicles/cells expressing the drug transporters P-glycoprotein (P-gp, breast cancer resistance protein (BCRP, multidrug resistance-associated protein 4 (MRP4, organic anion transporter 1 (OAT1, organic anion transporter 3 (OAT3 , organic cation transporter 2 (OCT2, organic anion transporting polypeptide 1B1 (OATP1B1, and organic anion transporting polypeptide 1B3 (OATP1B3. The apical-to-basal transport of [14C]fluciclovine was attenuated by l-threonine, the substrate for system alanine-serine-cysteine (ASC AATs. [14C]Fluciclovine uptake by drug transporter-expressing vesicles/cells was not significantly different from that of control vesicles/cells. Fluciclovine inhibited P-gp, MRP4, OAT1, OCT2, and OATP1B1 (IC50 > 2.95 mM. Therefore, system ASC AATs may be partly involved in the renal reuptake of [18F]fluciclovine. Further, given that [18F]fluciclovine is recognized as an inhibitor with millimolar affinity for the tested drug transporters, slow urinary excretion of [18F]fluciclovine may be mediated by system ASC AATs, but not by drug transporters.

  9. Flozins, inhibitors of type 2 renal sodium-glucose co-transporter – not only antihyperglycemic drugs

    OpenAIRE

    Mizerski Grzegorz; Kicinski Pawel; Jaroszynski Andrzej

    2015-01-01

    The kidneys play a crucial role in the regulation of the carbohydrate metabolism. In normal physiological conditions, the glucose that filters through the renal glomeruli is subsequently nearly totally reabsorbed in the proximal renal tubules. Two transporters are engaged in this process: sodium-glucose co-transporter type 1 (SGLT1), and sodium-glucose co-transporter type type 2 (SGLT2) - this being located in the luminal membrane of the renal tubular epithelial cells. It was found that the a...

  10. Flozins, inhibitors of type 2 renal sodium-glucose co-transporter – not only antihyperglycemic drugs

    Directory of Open Access Journals (Sweden)

    Mizerski Grzegorz

    2015-09-01

    Full Text Available The kidneys play a crucial role in the regulation of the carbohydrate metabolism. In normal physiological conditions, the glucose that filters through the renal glomeruli is subsequently nearly totally reabsorbed in the proximal renal tubules. Two transporters are engaged in this process: sodium-glucose co-transporter type 1 (SGLT1, and sodium-glucose co-transporter type type 2 (SGLT2 - this being located in the luminal membrane of the renal tubular epithelial cells. It was found that the administration of dapagliflozin, a selective SGLT2 inhibitor, in patients with type 2 diabetes, is associated with the reduction of HbA1c concentration by 0.45-1.11%. Additional benefits from the treatment with dapagliflozin are the reduction of arterial blood pressure and a permanent reduction of body weight. This outcome is related to the effect of osmotic diuresis and to the considerable loss of the glucose load by way of urine excretion. Dapagliflozin may be successfully applied in type 2 diabetes monotherapy, as well as in combined therapy (including insulin, where it is equally effective as other oral anti-diabetic drugs. Of note: serious adverse effects of dapagliflozin administration are rarely observed. What is more, episodes of severe hypoglycaemia related with the treatment occur only sporadically, most often in the course of diabetes polytherapy. The most frequent effects of the SGLT2 inhibitors are inseparably associated with the mechanism of their action (the glucuretic effect, and cover urogenital infections with a mild clinical course. At present, clinical trials are being continued of the administration of several subsequent drugs from this group, the most advanced of these being the use of canagliflozin and empagliflozin.

  11. Entecavir interacts with influx transporters hOAT1, hCNT2, hCNT3, but not with hOCT2: the potential for renal transporter-mediated cytotoxicity and drug-drug interactions

    Directory of Open Access Journals (Sweden)

    František eTrejtnar

    2016-01-01

    Full Text Available Entecavir (ETV is one of the most potent agents for the treatment of the hepatitis B viral infection. The drug is principally eliminated by the kidney. The goal of this study was to investigate the potential of ETV to interact in vitro with the renal SLC transporters hOAT1, hOCT2, hCNT2 and hCNT3. Potential drug-drug interactions of ETV at the renal transporters with antiviral drugs known to be excreted by the kidney (adefovir, tenofovir, cidofovir as well as transporter-dependent cytotoxicity were also examined. Interactions with the selected transporters along with cytotoxicity were studied in several transiently-transfected cellular models using specific substrates and inhibitors. ETV was found to be both a substrate and inhibitor of hOAT1 (IC50 = 175.3 µM, hCNT2 (IC50 = 241.9 µM and hCNT3 (IC50 = 278.4 µM transporters, although it interacted with the transporters with relatively low affinities. ETV inhibited the cellular uptake of adefovir, tenofovir and cidofovir by hOAT1; however, effective inhibition was shown at ETV concentrations exceeding therapeutic levels. In comparison with adefovir, tenofovir and cidofovir, ETV displayed no transporter-mediated cytotoxicity in cells transfected with hOAT1, hCNT2, and hCNT3. No significant interaction of ETV with hOCT2 was detected. The study demonstrates interactions of ETV with several human renal transporters. For the first time, an interaction of ETV with the hCNTs was proved. We show that the potency of ETV to cause nephrotoxicity and/or clinically significant drug-drug interactions related to the tested transporters is considerably lower than that of adefovir, tenofovir and cidofovir.

  12. Drug-induced renal disease.

    Science.gov (United States)

    Curtis, J R

    1979-11-01

    The clinical manifestations of drug-induced renal disease may include all the manifestations attributed to natural or spontaneous renal diseases such as acute renal failure, chronic renal failure, acute nephritic syndrome, renal colic, haematuria, selective tubular defects, obstructive nephropathy, etc. It is therefore vital in any patient with renal disease whatever the clinical manifestations might be, to obtain a meticulous drug and toxin inventory. Withdrawal of the offending drug may result in amelioration or cure of the renal disorder although in the case of severe renal failure it may be necessary to utilise haemodialysis or peritoneal dialysis to tide the patient over the period of acute renal failure. Analgesic nephropathy is an important cause of terminal chronic renal failure and it is therefore vital to make the diagnosis as early as possible. The pathogenesis of some drug-induced renal disorders appears to be immunologically mediated. There are many other pathogenetic mechanisms involved in drug-induced renal disorders and some drugs may under appropriate circumstances be responsible for a variety of different nephrotoxic effects. For example, the sulphonamides have been incriminated in examples of crystalluria, acute interstitial nephritis, acute tubular necrosis, generalised hypersensitivity reactions, polyarteritis nodosa and drug-induced lupus erythematosus.

  13. Drug Transporter Genetic Variants Are Not Associated with TDF-Related Renal Dysfunction in Patients with HIV-1 Infection: A Pharmacogenetic Study.

    Directory of Open Access Journals (Sweden)

    Takeshi Nishijima

    Full Text Available To investigate whether single nucleotide polymorphisms (SNP of drug transporter proteins for TDF is a risk factor for TDF-related renal function decrement.This study investigated the association between 3 SNPs (ABCC2-24, 1249, and ABCB1 2677, which are shown to be associated with TDF-induced tubulopathy, and clinically important renal outcomes (>10ml/min/1.73m2 decrement in eGFR relative to baseline, >25% decrement in eGFR, and eGFR 10ml/min/1.73m2 and those without such decrement (ABCC2: -24, p = 0.53, 1249, p = 0.68; ABCB1: 2677, p = 0.74, nor between those without and with the other two renal outcomes (>25% decrement: ABCC2: -24, p = 0.83, 1249, p = 0.97, ABCB1: 2677, p = 0.40; eGFR <60ml/min/1.73m2: ABCC2: -24, p = 0.51, 1249, p = 0.81, ABCB1: 2677, p = 0.94. Logistic regression analysis showed that the risk genotype of the three SNPs were not associated with any of the three renal outcomes, respectively. Logistic regression model that applied either dominant, recessive, or additive model yielded the same results.SNPs of the drug transporters for TDF are not associated with clinically important renal outcomes in patients who initiated TDF-containing ART.

  14. Renal transepithelial transport of nucleosides.

    Science.gov (United States)

    Nelson, J A; Vidale, E; Enigbokan, M

    1988-01-01

    Previous work from this and other laboratories has suggested that the mammalian kidney has unique mechanisms for handling purine nucleosides. For example, in humans and in mice, adenosine undergoes net renal reabsorption whereas deoxyadenosine is secreted [Kuttesch and Nelson: Cancer Chemother. Pharmacol. 8, 221 (1982)]. The relationships between these renal transport systems and classical renal organic cation and anion, carbohydrate, and cell membrane nucleoside transport carriers are not established. To investigate possible relationships between such carriers, we have tested effects of selected classical transport inhibitors on the renal clearances of adenosine, deoxyadenosine, 5'-deoxy-5-fluorouridine (5'-dFUR), and 5-fluorouracil in mice. The secretion of deoxyadenosine and 5'-dFUR, but not the reabsorption of adenosine or 5-fluorouracil, was prevented by the classical nucleoside transport inhibitors, dipyridamole and nitrobenzylthioinosine. Cimetidine, an inhibitor of the organic cation secretory system, also inhibited the secretion of 5'-dFUR, although it did not inhibit deoxyadenosine secretion in earlier studies [Nelson et al.: Biochem. Pharmacol. 32, 2323 (1983)]. The specific inhibitor of glucose renal reabsorption, phloridzin, failed to inhibit the reabsorption of adenosine or the secretion of deoxyadenosine. Failure of the nucleoside transport inhibitors and phloridzin to prevent adenosine reabsorption suggests that adenosine reabsorption may occur via a unique process. On the other hand, inhibition of the net secretion of deoxyadenosine and 5'-dFUR by dipyridamole and nitrobenzylthioinosine implies a role for the carrier that is sensitive to these compounds in the renal secretion (active transport) of these nucleosides.

  15. Drugs in pregnancy. Renal disease.

    Science.gov (United States)

    Marsh, J E; Maclean, D; Pattison, J M

    2001-12-01

    The management of pregnant women with renal impairment presents a major challenge to obstetricians, nephrologists, and ultimately paediatricians. As renal failure progresses there is an increase in both maternal and fetal complications. Often these women have intercurrent medical conditions and, prior to conception, are receiving a broad range of prescribed medications. A successful obstetric outcome relies upon careful pre-pregnancy counselling and planning, obsessive monitoring during pregnancy, and close liaison between different specialist teams. Experience is mounting in the management of pregnant transplant recipients, but the introduction of newer immunosuppressive agents which have great promise in prolonging graft survival present new problems for those recipients of a kidney transplant who are planning to conceive. We review drug prescription for pregnant patients with renal impairment, end-stage renal failure, or a kidney transplant.

  16. The anti-epileptic drug substance vigabatrin inhibits taurine transport in intestinal and renal cell culture models

    DEFF Research Database (Denmark)

    Plum, Jakob Munk; Nøhr, Martha Kampp; Hansen, Steen H

    2014-01-01

    , such evidence does not preclude the involvement of other transporters. The aim of the present study was, therefore, to investigate if vigabatrin interacts with taurine transport. The uptake of taurine was measured in intestinal human Caco-2 and canine MDCK cell monolayers in the absence or presence of amino...... acids such as GABA and vigabatrin. Vigabatrin inhibits the uptake of taurine in Caco-2 and MDCK cells to 34±3 and 53±2%, respectively, at a concentration of 30mM. In Caco-2 cells the uptake of vigabatrin under neutral pH conditions is concentration-dependent and saturable with a Km-value of 27mM (log......Km is 1.43±0.09). In conclusion, the present study shows that vigabatrin was able to inhibit the uptake of taurine in intestinal and renal cell culture models. Furthermore, uptake of vigabatrin in Caco-2 cells under neutral pH conditions was concentration-dependent and saturable and suggesting...

  17. Maternal drugs and neonatal renal failure

    Directory of Open Access Journals (Sweden)

    M Sahay

    2014-01-01

    Full Text Available Maternal use of drugs during pregnancy may cause irreversible renal failure in the newborn. This report highlights the adverse effect of telmisartan during the last trimester of pregnancy. The neonate presented with oliguric renal failure and the renal histology showed proximal tubular dysgenesis.

  18. Drugs Approved for Kidney (Renal Cell) Cancer

    Science.gov (United States)

    ... 2015 2014 2013 2012 Media Resources Media Contacts Multicultural Media ... This page lists cancer drugs approved by the Food and Drug Administration (FDA) for kidney (renal cell) cancer. The list ...

  19. Drug Dosing During Continuous Renal Replacement Therapies

    OpenAIRE

    Thompson, A. Jill

    2008-01-01

    Continuous renal replacement therapies (CRRT) are used to manage fluid overload and/or renal failure. The continuous nature of the fluid and solute removal has less impact on hemodynamic variables in critically ill patients, making CRRT preferred over intermittent hemodialysis for some patients in the intensive care arena. The impact of CRRT on drug removal is variable depending on the CRRT modality, the ultrafiltrate and dialysate flow rates, the filter, and the patient's residual renal func...

  20. Drug dosing during continuous renal replacement therapies

    National Research Council Canada - National Science Library

    Thompson, A Jill

    2008-01-01

    ... in the intensive care arena. The impact of CRRT on drug removal is variable depending on the CRRT modality, the ultrafiltrate and dialysate flow rates, the filter, and the patient's residual renal function...

  1. Drug dosing during continuous renal replacement therapies.

    Science.gov (United States)

    Thompson, A Jill

    2008-04-01

    Continuous renal replacement therapies (CRRT) are used to manage fluid overload and/or renal failure. The continuous nature of the fluid and solute removal has less impact on hemodynamic variables in critically ill patients, making CRRT preferred over intermittent hemodialysis for some patients in the intensive care arena. The impact of CRRT on drug removal is variable depending on the CRRT modality, the ultrafiltrate and dialysate flow rates, the filter, and the patient's residual renal function; all of these may change from patient to patient or even in the same patient depending on the clinical status. However, CRRT modalities are generally more efficient than intermittent hemodialysis at drug removal, in some cases approximating or even exceeding normal renal function, resulting in a significant risk of subtherapeutic dosing if conventional hemodialysis dosing recommendations are followed. This annotated bibliography provides a summary of publications analyzing drug removal during CRRT, including CRRT settings and drug clearance values found in each study. Caution is warranted as findings from one study may not be generalizable to all patients due to the many factors that influence drug removal. Serum drug concentrations should be monitored when available, and patient clinical status is exceedingly important for following expected and unexpected responses to drug therapies. Reviews on general drug dosing calculations in CRRT are available elsewhere.

  2. Drugs of abuse and renal disease.

    Science.gov (United States)

    Bakir, A A; Dunea, G

    1996-03-01

    The complications of drug abuse encompass a spectrum of glomerular, interstitial, and vascular diseases. They comprise the heroin-associated nephropathy seen in African-American intravenous drug addicts, which, however, has given way in the 1990s to HIV-associated nephropathy. Infections with methicillin-resistant Staphylococcus aureus may cause acute glomerulonephritis by releasing bacterial superantigens. Hepatitis C has supplanted hepatitis B and may give rise to membranoproliferative glomerulonephritis and cryoglobulinemia. Addicts who inject drugs subcutaneously ('skin popping') may develop amyloidosis. Cocaine causes rhabdomyolysis, severe hypertension, occasionally renal failure in the absence of rhabdomyolysis, and may hasten progression to uremia in patients with underlying renal insufficiency. 'Ecstasy', an amphetamine-like recreational drug, has caused acute renal failure, electrolyte disturbances, and malignant hypertension. In Belgium and some other European countries, women taking Chinese herbs in a slimming regimen have developed a severe and irreversible interstitial fibrosis that is assuming epidemic proportions.

  3. Renal amyloidosis in a drug abuser.

    Science.gov (United States)

    Tan, A U; Cohen, A H; Levine, B S

    1995-03-01

    Drug abusers, particularly those who inject drugs s.c. ("skin popping"), may develop amyloidosis. Chronic infections are thought to play a pathogenetic role in this setting. A patient is presented who had a history of "skin popping" cocaine and heroin and developed nephrotic syndrome, with an elevated serum creatinine and a creatinine clearance of 61 mL/min. Renal biopsy demonstrated amyloidosis. Treatment with colchicine was initiated, and proteinuria decreased to near normal levels after 12 months. Concomitant with the decrease in proteinuria, creatinine clearance improved, although a repeat renal biopsy failed to show any significant improvement in amyloid burden. These observations suggest that colchicine may be a useful treatment in reversing the proteinuria of renal amyloidosis associated with drug abuse. Furthermore, clinical improvement may occur before any demonstrable regression in the amyloidosis.

  4. Discontinued drug in 2007: renal, endocrine and metabolic drugs.

    Science.gov (United States)

    Colca, Jerry R

    2008-11-01

    This perspective is the first part of an annual series of papers discussing drugs dropped from clinical development in the previous year. Specifically, this paper focuses on the 14 renal, endocrine and metabolic drugs discontinued in 2007. The candidates covered in this summary were being developed for treatment of diabetes, obesity, reproductive and urogenital health issues, and growth hormone deficiency. Information for this perspective was derived from a search of the Pharmaprojects database for drugs discontinued after reaching Phase I - III clinical trials.

  5. Regulation of renal peripheral benzodiazepine receptors by anion transport inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Basile, A.S.; Lueddens, W.M.; Skolnick, P.

    1988-01-01

    The in vitro and in vivo regulation of (/sup 3/H)Ro 5-4864 binding to peripheral benzodiazepine receptors (PBR) by ion transport/exchange inhibitors was studied in the kidney. The potencies of 9-anthroic acid, furosemide, bumetanide, hydrochlorothiazide and SITS as inhibitors of (/sup 3/H)Ro 5-4864 binding to renal membranes were consistent with their actions as anion transport inhibitors (Ki approx. = 30 - 130 ..mu..M). In contrast, spironolactone, amiloride, acetazolamide, and ouabain were less potent (Ki=100-1000 ..mu..M). Administration of furosemide to rats for five days resulted in a profound diuresis accompanied by a significant increase in PBR density (43%) that was apparent by the fifth day of treatment. Administration of hydrochlorothiazide or Ro 5-4864 for five days also caused diuresis and increased renal PBR density. Both the diuresis and increased density of PBR produced by Ro 5-4864 were blocked by coadministration of PK 11195, which alone had no effect on either PBR density or urine volume. The equilibrium binding constants of (/sup 3/H)Ro 5-4864 to cardiac membranes were unaffected by administration of any of these drugs. These findings suggest that renal PBR may be selectively modulated in vivo and in vitro by administration of ion transport/exchange inhibitors. 36 references, 4 tables.

  6. Novel antiretroviral drugs and renal function monitoring of HIV patients.

    Science.gov (United States)

    Maggi, Paolo; Montinaro, Vincenzo; Mussini, Cristina; Di Biagio, Antonio; Bellagamba, Rita; Bonfanti, Paolo; Calza, Leonardo; Cherubini, Chiara; Corsi, Paola; Gargiulo, Miriam; Montella, Francesco; Rusconi, Stefano

    2014-01-01

    Chronic kidney disease is a major comorbidity in patients affected by HIV infection. In addition, the introduction of new antiretroviral agents that interact with creatinine transporters is raising some concerns. In this review we analyze the currently available data about three new antiretroviral drugs and one new pharmacokinetic enhancer. Three of them (rilpivirine, cobicistat, dolutegravir) have shown some interactions with renal function, while tenofovir alafenamide fumarate reduces the plasmatic concentration of the parent drug. The future use of tenofovir alafenamide seems to be encouraging in order to reduce the renal interaction of tenofovir. Rilpivirine, cobicistat, and dolutegravir reduce the tubular secretion of creatinine, inducing a decrease of estimated glomerular filtration rate according to creatinine. Rilpivirine and dolutegravir block the uptake of creatinine from the blood, inhibiting organic cation transporter 2, and cobicistat interacts with the efflux inhibiting multidrug and toxin extrusion protein 1. This effect can then be considered a "reset" of the estimated glomerular filtration rate according to creatinine. However, clinicians should carefully monitor renal function in order to identify possible alterations suggestive of a true renal functional impairment. Owing to the interference of these drugs with creatinine secretion, an alternative way of estimation of glomerular filtration rate would be desirable. However, at the moment, other methods of direct glomerular filtration rate measurement have a high impact on the patient, are not readily available, or are not reliable in HIV patients. Consequently, use of classic formulas to estimate glomerular filtration rate is still recommended. Also, tubular function needs to be carefully monitored with simple tests such as proteinuria, phosphatemia, urinary excretion of phosphate, normoglycemic glycosuria, and excretion of uric acid.

  7. Drug dosing during continuous renal replacement therapy.

    Science.gov (United States)

    Churchwell, Mariann D; Mueller, Bruce A

    2009-01-01

    Continuous renal replacement therapy (CRRT) has given clinicians an important option in the care of critically ill patients. The slow and continuous dialysate and ultrafiltrate flow rates that are employed with CRRT can yield drug clearances similar to an analogous glomerular filtration rate of the native kidneys. Advantages such as superior volume control, excellent metabolic control, and hemodynamic tolerance by critically ill patients are well documented, but an understanding of drug dosing for CRRT is still a bit of a mystery. Although some pharmaceutical companies have dedicated postmarket research in this direction, many pharmaceutical companies have chosen not to pursue this information as it is not mandated and represents a relatively small part of their market. This lack of valuable information has created many challenges in the care of the critically ill patient as intermittent hemodialysis drug dosing recommendations cannot be extrapolated to CRRT. This drug dosing review will highlight factors that clinicians should consider when determining a pharmacotherapy regimen for a patient receiving CRRT.

  8. Expression and function of renal and hepatic organic anion transporters in extrahepatic cholestasis

    Science.gov (United States)

    Brandoni, Anabel; Hazelhoff, María Herminia; Bulacio, Romina Paula; Torres, Adriana Mónica

    2012-01-01

    Obstructive jaundice occurs in patients suffering from cholelithiasis and from neoplasms affecting the pancreas and the common bile duct. The absorption, distribution and elimination of drugs are impaired during this pathology. Prolonged cholestasis may alter both liver and kidney function. Lactam antibiotics, diuretics, non-steroidal anti-inflammatory drugs, several antiviral drugs as well as endogenous compounds are classified as organic anions. The hepatic and renal organic anion transport pathways play a key role in the pharmacokinetics of these compounds. It has been demonstrated that acute extrahepatic cholestasis is associated with increased renal elimination of organic anions. The present work describes the molecular mechanisms involved in the regulation of the expression and function of the renal and hepatic organic anion transporters in extrahepatic cholestasis, such as multidrug resistance-associated protein 2, organic anion transporting polypeptide 1, organic anion transporter 3, bilitranslocase, bromosulfophthalein/bilirubin binding protein, organic anion transporter 1 and sodium dependent bile salt transporter. The modulation in the expression of renal organic anion transporters constitutes a compensatory mechanism to overcome the hepatic dysfunction in the elimination of organic anions. PMID:23197884

  9. Expression and function of renal and hepatic organic anion transporters in extrahepatic cholestasis

    Institute of Scientific and Technical Information of China (English)

    Anabel Brandoni; María Herminia Hazelhoff; Romina Paula Bulacio; Adriana Mónica Torres

    2012-01-01

    Obstructive jaundice occurs in patients suffering from cholelithiasis and from neoplasms affecting the pancreas and the common bile duct.The absorption,distribution and elimination of drugs are impaired during this pathology.Prolonged cholestasis may alter both liver and kidney function.Lactam antibiotics,diuretics,non-steroidal anti-inflammatory drugs,several antiviral drugs as well as endogenous compounds are classified as organic anions.The hepatic and renal organic anion transport pathways play a key role in the pharmacokinetics of these compounds.It has been demonstrated that acute extrahepatic cholestasis is associated with increased renal elimination of organic anions.The present work describes the molecular mechanisms involved in the regulation of the expression and function of the renal and hepatic organic anion transporters in extrahepatic cholestasis,such as multidrug resistanceassociated protein 2,organic anion transporting polypeptide 1,organic anion transporter 3,bilitranslocase,bromosulfophthalein/bilirubin binding protein,organic anion transporter 1 and sodium dependent bile salt transporter.The modulation in the expression of renal organic anion transporters constitutes a compensatory mechanism to overcome the hepatic dysfunction in the elimination of organic anions.

  10. Renal and hepatic transporter expression in type 2 diabetic rats.

    Science.gov (United States)

    Nowicki, Michael T; Aleksunes, Lauren M; Sawant, Sharmilee P; Dnyanmote, Ankur V; Mehendale, Harihara M; Manautou, José E

    2008-01-01

    Membrane transporters are critical for the uptake as well as elimination of chemicals and by-products of metabolism from the liver and kidneys. Since these proteins are important determinants of chemical disposition, changes in their expression in different disease states can modulate drug pharmacokinetics. The present study investigated alterations in the renal and hepatic expression of organic anion and cation transporters (Oats/Octs), multidrug resistance-associated proteins (Mrps), breast cancer resistance protein (Bcrp), P-glycoprotein (Pgp), and hepatic Na(+)-taurocholate cotransporting polypeptide (Ntcp) in type 2 diabetic rats. For this purpose, type 2 diabetes was induced by feeding male Sprague-Dawley rats a high fat diet followed by a single dose of streptozotocin (45 mg/kg, i.p., in 0.01 M citrate buffer pH 4.3) on day 14. Controls received normal diet and vehicle. Kidney and liver samples were collected on day 24 for generation of crude plasma membrane fractions and Western blot analysis of Oat, Oct, Mrp, Bcrp, Pgp, and Ntcp proteins. With regards to renal uptake transporters, type 2 diabetes increased levels of Oat2 (2.3-fold) and decreased levels of Oct2 to 50% of control kidneys. Conversely, efflux transporters Mrp2, Mrp4, and Bcrp were increased 5.4-fold, 2-fold, and 1.6-fold, respectively in type 2 diabetic kidneys with no change in levels of Mrp1, Mrp5, or Pgp. Studies of hepatic transporters in type 2 diabetic rats reveal that the protein level of Mrp5 was reduced to 4% of control livers with no change in levels of Bcrp, Mrp1, Mrp2, Mrp4, Ntcp, or Pgp. The changes reported in this study may have implications in type 2 diabetic patients.

  11. Drug-eluting stents in renal artery stenosis

    Energy Technology Data Exchange (ETDEWEB)

    Zaehringer, M. [Marienhospital Stuttgart, Department of Radiology, Stuttgart (Germany); Pattynama, P.M.T. [Erasmus MC-University Medical Center Rotterdam, Rotterdam (Netherlands); Talen, A. [genae associates nv, Antwerp (Belgium); Sapoval, M. [Hopital Europeen Georges Pompidou, Service de Radiologie Cardio-Vasculaire, Paris (France); Inserm U 780 epidemiologie Cardio Vasculaire, Paris (France)

    2008-04-15

    Because of higher acute and long-term success rates compared with balloon angioplasty alone, percutaneous stent implantation has become an accepted therapy for the treatment of atherosclerotic renal artery stenosis. Restenosis rates after successful renal stent placement vary from 6 up to 40%, depending on the definition of restenosis, the diameter of the treated vessel segment and comorbidities. The safety and efficacy of drug-eluting stents for the treatment of renal-artery stenosis is poorly defined. The recently published GREAT study is the only prospective study, comparing bare-metal and sirolimus-coated low profile stent systems in renal artery stenosis, showing a relative risk reduction of angiographic binary in-stent restenosis by 50%. This is an opinion paper on indications, current treatment options and restenosis rates following renal artery stenting and the potential use of drug-eluting stents for this indication. (orig.)

  12. Renal amino acid transport systems and essential hypertension.

    Science.gov (United States)

    Pinto, Vanda; Pinho, Maria João; Soares-da-Silva, Patrício

    2013-08-01

    Several clinical and animal studies suggest that "blood pressure goes with the kidney," that is, a normotensive recipient of a kidney genetically programmed for hypertension will develop hypertension. Intrarenal dopamine plays an important role in the pathogenesis of hypertension by regulating epithelial sodium transport. The candidate transport systems for L-DOPA, the source for dopamine, include the sodium-dependent systems B(0), B(0,+), and y(+)L, and the sodium-independent systems L (LAT1 and LAT2) and b(0,+). Renal LAT2 is overexpressed in the prehypertensive spontaneously hypertensive rat (SHR), which might contribute to enhanced L-DOPA uptake in the proximal tubule and increased dopamine production, as an attempt to overcome the defect in D1 receptor function. On the other hand, it has been recently reported that impaired arginine transport contributes to low renal nitric oxide bioavailability observed in the SHR renal medulla. Here we review the importance of renal amino acid transporters in the kidney and highlight pathophysiological changes in the expression and regulation of these transporters in essential hypertension. The study of the regulation of renal amino acid transporters may help to define the underlying mechanisms predisposing individuals to an increased risk for development of hypertension.

  13. Transvascular lipoprotein transport in patients with chronic renal disease

    DEFF Research Database (Denmark)

    Jensen, Trine Krogsgaard; Nordestgaard, Børge Grønne; Feldt-Rasmussen, Bo

    2004-01-01

    BACKGROUND: While increased plasma cholesterol is a well-established cardiovascular risk factor in the general population, this is not so among patients with chronic renal disease. We hypothesized that the transvascular lipoprotein transport, in addition to the lipoprotein concentration in plasma......: Transvascular LDL transport may be increased in diabetic patients with chronic renal disease, suggesting that lipoprotein flux into the arterial wall is increased. A similar mechanism does not operate in nondiabetic patients with chronic renal disease.......BACKGROUND: While increased plasma cholesterol is a well-established cardiovascular risk factor in the general population, this is not so among patients with chronic renal disease. We hypothesized that the transvascular lipoprotein transport, in addition to the lipoprotein concentration in plasma......, determines the degree of atherosclerosis among patients with chronic renal disease. METHODS: We used an in vivo method for measurement of transvascular transport of low-density lipoprotein (LDL) in 21 patients with chronic renal disease and in 42 healthy control patients. Autologous 131-iodinated LDL...

  14. Drug transporters in breast cancer

    DEFF Research Database (Denmark)

    Kümler, Iben; Stenvang, Jan; Moreira, José

    2015-01-01

    Despite the advances that have taken place in the past decade, including the development of novel molecular targeted agents, cytotoxic chemotherapy remains the mainstay of cancer treatment. In breast cancer, anthracyclines and taxanes are the two main chemotherapeutic options used on a routine...... basis. Although effective, their usefulness is limited by the inevitable development of resistance, a lack of response to drug-induced cancer cell death. A large body of research has resulted in the characterization of a plethora of mechanisms involved in resistance; ATP-binding cassette transporter...

  15. Recent advances in understanding hepatic drug transport

    Science.gov (United States)

    Stieger, Bruno; Hagenbuch, Bruno

    2016-01-01

    Cells need to strictly control their internal milieu, a function which is performed by the plasma membrane. Selective passage of molecules across the plasma membrane is controlled by transport proteins. As the liver is the central organ for drug metabolism, hepatocytes are equipped with numerous drug transporters expressed at the plasma membrane. Drug disposition includes absorption, distribution, metabolism, and elimination of a drug and hence multiple passages of drugs and their metabolites across membranes. Consequently, understanding the exact mechanisms of drug transporters is essential both in drug development and in drug therapy. While many drug transporters are expressed in hepatocytes, and some of them are well characterized, several transporters have only recently been identified as new drug transporters. Novel powerful tools to deorphanize (drug) transporters are being applied and show promising results. Although a large set of tools are available for studying transport in vitro and in isolated cells, tools for studying transport in living organisms, including humans, are evolving now and rely predominantly on imaging techniques, e.g. positron emission tomography. Imaging is an area which, certainly in the near future, will provide important insights into "transporters at work" in vivo. PMID:27781095

  16. 75 FR 1395 - Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting

    Science.gov (United States)

    2010-01-11

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee; Notice of... to the public. ] Name of Committee: Cardiovascular and Renal Drugs Advisory Committee....

  17. 76 FR 39404 - Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting

    Science.gov (United States)

    2011-07-06

    ... HUMAN SERVICES Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee; Notice of... to the public. Name of Committee: Cardiovascular and Renal Drugs Advisory Committee. General Function... application (NDA) 202439, rivaroxaban tablets, submitted by Johnson & Johnson Pharmaceutical Research...

  18. Delineation on Therapeutic Significance of Transporters as Molecular Targets of Drugs

    Institute of Scientific and Technical Information of China (English)

    KANAI Yoshikat; HE Xin; LIU Chang-xiao

    2011-01-01

    Transporters are membrane proteins mediating permeation of organic and inorganic solutes through the plasma membrane and membranes of intracellular organella.They play essential roles in the epithelial absorption and cellular uptake of nutrients as well as absorption,distribution,metabolism,and excretion of drugs.Because transporters contribute to determining the distribution of compounds in the body in concert with metabolic/synthetic enzymes,the drugs that affect the functions of transporters are expected to alter the distribution of compounds in the body and to ameliorate disrupted homeostasis.In this context,drugs targeting transporters have been used clinically.Such drugs include antidepressants targeting monoamine transporters,diuretics targeting inorganic ion transporters of renal tubules,and uricosuric agents targeting renal urate transporters.Now new transporter-targeting drugs designed based on post-genome drug development strategy have been in the process of clinical trials or basic/clinical researches.For example,the inhibitors of renal Na/glucose cotransporter SGLT2 have been proved for their efficacy in the treatment of diabetes mellitus.The cancer L-type amino acid transporter 1(LAT1)has been considered as a target of cancer diagnosis and therapeutics.The transporter-targeting drugs are expected to provide new rationale in the therapeutics of various diseases.

  19. Water transport by the renal Na(+)-dicarboxylate cotransporter

    DEFF Research Database (Denmark)

    Meinild, A K; Loo, D D; Pajor, A M;

    2000-01-01

    This study investigated the ability of the renal Na(+)-dicarboxylate cotransporter, NaDC-1, to transport water. Rabbit NaDC-1 was expressed in Xenopus laevis oocytes, cotransporter activity was measured as the inward current generated by substrate (citrate or succinate), and water transport...... was monitored by the changes in oocyte volume. In the absence of substrates, oocytes expressing NaDC-1 showed an increase in osmotic water permeability, which was directly correlated with the expression level of NaDC-1. When NaDC-1 was transporting substrates, there was a concomitant increase in oocyte volume....... This solute-coupled influx of water took place in the absence of, and even against, osmotic gradients. There was a strict stoichiometric relationship between Na(+), substrate, and water transport of 3 Na(+), 1 dicarboxylate, and 176 water molecules/transport cycle. These results indicate that the renal Na...

  20. Water transport by the renal Na(+)-dicarboxylate cotransporter

    DEFF Research Database (Denmark)

    Meinild, A K; Loo, D D; Pajor, A M

    2000-01-01

    was monitored by the changes in oocyte volume. In the absence of substrates, oocytes expressing NaDC-1 showed an increase in osmotic water permeability, which was directly correlated with the expression level of NaDC-1. When NaDC-1 was transporting substrates, there was a concomitant increase in oocyte volume....... This solute-coupled influx of water took place in the absence of, and even against, osmotic gradients. There was a strict stoichiometric relationship between Na(+), substrate, and water transport of 3 Na(+), 1 dicarboxylate, and 176 water molecules/transport cycle. These results indicate that the renal Na......This study investigated the ability of the renal Na(+)-dicarboxylate cotransporter, NaDC-1, to transport water. Rabbit NaDC-1 was expressed in Xenopus laevis oocytes, cotransporter activity was measured as the inward current generated by substrate (citrate or succinate), and water transport...

  1. Renal toxicity of the anticancer drug fostriecin

    NARCIS (Netherlands)

    de Vries, EGE; Meijer, S; Mulder, NH; de Jong, Paul; de Jong, Robert

    Purpose: Fostriecin is an inhibitor of topoisomerase II catalytic activity. In a phase I trial we observed renal toxicity, documented as a rise in serum creatinine, which was reversible and non-dose-limiting. The purpose of this study was a detailed analysis of this toxicity. Methods: A total of 20

  2. Drug administration in patients with renal insufficiency. Minimising renal and extrarenal toxicity.

    Science.gov (United States)

    Matzke, G R; Frye, R F

    1997-03-01

    Renal insufficiency has been associated with an increased risk of adverse effects with many classes of medications. The risk of some, but not all, adverse effects has been linked to the patient's degree of residual renal function. This may be the result of inappropriate individualisation of those agents that are primarily eliminated by the kidney, or an alteration in the pharmacodynamic response as a result of renal insufficiency. The pathophysiological mechanism responsible for alterations in drug disposition, especially metabolism and renal excretion, is the accumulation of uraemic toxins that may modulate cytochrome P450 enzyme activity and decrease glomerular filtration as well as tubular secretion. The general principles to enhance the safety of drug therapy in patients with renal insufficiency include knowledge of the potential toxicities and interactions of the therapeutic agent, consideration of possible alternatives therapies and individualisation of drug therapy based on patient level of renal function. Although optimisation of the desired therapeutic outcomes are of paramount importance, additional pharmacotherapeutic issues for patients with reduced renal function are the prevention or minimisation of future acute or chronic nephrotoxic insults, as well as the severity and occurrence of adverse effects on other organ systems. Risk factors for the development of nephrotoxicity for selected high-risk therapies (e.g. aminoglycosides, nonsteroidal anti-inflammatory drugs, ACE inhibitors and radiographic contrast media) are quite similar and include pre-existing renal insufficiency, concomitant administration of other nephrotoxins, volume depletion and concomitant hepatic disease or congestive heart failure. Investigations of prophylactic approaches to enhance the safety of these agents in patients with renal insufficiency have yielded inconsistent outcomes. Hydration with saline prior to drug exposure has given the most consistent benefit, while sodium

  3. Luminal nucleotides are tonic inhibitors of renal tubular transport

    DEFF Research Database (Denmark)

    Leipziger, Jens Georg

    2011-01-01

    PURPOSE OF REVIEW: Extracellular ATP is an essential local signaling molecule in all organ systems. In the kidney, purinergic signaling is involved in an array of functions and this review highlights those of relevance for renal tubular transport. RECENT FINDINGS: Purinergic receptors are expressed...... in all renal tubular segments and their stimulation generally leads to transport inhibition. Recent evidence has identified the tubular lumen as a restricted space for purinergic signaling. The concentrations of ATP in the luminal fluids are sufficiently high to inflict a tonic inhibition of renal...... tubular absorption via P2 receptors. The apical P2Y2 receptor plays a crucial role in this process. ATP is released continuously into the tubular lumen. The release is augmented in response to an increase of tubular flow and after stimulation of G-protein-coupled receptors. The primary cilium appears...

  4. [Compatibility of Banxia Houpo decoction on hepatic CYP450 and renal organicion transporters in mice].

    Science.gov (United States)

    Wang, Fumeng; Lu, Yan; Kong, Lingdong

    2011-01-01

    By analyzing the related indicators [hepatic CYP450 subtype and renal organic anion and cation transporters (OATs and OCTs)], the present study investigated the effects of formula Banxia Houpo decoction principal drug pinellia, assistant drug magnolia, their compatibility and the principle of the whole decoction on the metabolism ability in the liver and the transport change in the kidney of mice. Biochemical and molecular (RT-PCR and western blotting) results indicated that pinellia increased activity and expression of hepatic Cyp2e1 and Cyp3a11 in mice, respectively. Pinellia and magnolia increased expression of renal OAT1, OAT3, OCT1 and OCT2 in mice, respectively. The compatibility of pinellia and magnolia, as well as Banxia Houpo decoction synergistically restrained the activated effect of pinellia on hepatic Cyp2e1, therefore avoiding liver peroxidation and reducing toxicity potential. The compatibility of this drug pair and Banxia Houpo decoction not only reduced activity and expression of hepatic Cyp3a11 to control drug metabolism speed, but also balanced the expression of renal OAT1/3 and OCT1/2 to enhance drug efficacy. The effect of compatibility of Banxia Houpo decoction was better than that of pinellia and magnolia pair, and the normal dosage was better than the high dosage. The present study proved the advantage of the compatibility of pinellia combined with magnolia and the principle of Banxia Houpo decoction, which related to hepatic CYP450 and renal organic ion transporters, and guided the clinical use of Banxia Houpo decoction to exert its toxicity reduction and efficacy enhancement.

  5. FARMACOFISIOLOGÍA RENAL

    Directory of Open Access Journals (Sweden)

    Musso CG

    2014-03-01

    Full Text Available Renal physiology plays a key role in the pharmacokinetics of many drugs. Knowledge of the particularities of each nephron function (filtration, secretion, reabsorption and excretion and each of renal tubular transport mechanisms (simple diffusion, facilitated diffusion, facilitated transport, active transport, endocytosis and pinocytosis is fundamental to achieve better management of drug prescriptions.

  6. Drug metabolism in chronic renal failure.

    Science.gov (United States)

    Pichette, Vincent; Leblond, François A

    2003-04-01

    Pharmacokinetic studies conducted in patients with CRF demonstrate that the nonrenal clearance of multiple drugs is reduced. Although the mechanism by which this occurs is unclear, several studies have shown that CRF affects the metabolism of drugs by inhibiting key enzymatic systems in the liver, intestine and kidney. The down-regulation of selected isoforms of the hepatic cytochrome P450 (CYP450) has been reported secondary to a decrease in gene expression. This is associated with major reductions in metabolism of drugs mediated by CYP450. The main hypothesis to explain the decrease in liver CYP450 activity in CRF appears to be the accumulation of circulating factors which can modulate CYP450 activity. Liver phase II metabolic reactions are also reduced in CRF. On the other hand, intestinal drug disposition is affected in CRF. Increased bioavailability of several drugs has been reported in CRF, reflecting decrease in either intestinal first-pass metabolism or extrusion of drugs (mediated by P-glycoprotein). Indeed, intestinal CYP450 is also down-regulated secondary to reduced gene expression, whereas, decreased intestinal P-glycoprotein activity has been described. Finally, although the kidneys play a major role in the excretion of drugs, it has the capacity to metabolize endogenous and exogenous compounds. CRF will lead to a decrease in the ability of the kidney to metabolize drugs, but the repercussions on the systemic clearance of drugs is still poorly defined, except for selected xenobiotics. In conclusion, reduced drug metabolism should be taken into account when evaluating the pharmacokinetics of drugs in patients with CRF.

  7. Deregulated Renal Calcium and Phosphate Transport during Experimental Kidney Failure.

    Science.gov (United States)

    Pulskens, Wilco P; Verkaik, Melissa; Sheedfar, Fareeba; van Loon, Ellen P; van de Sluis, Bart; Vervloet, Mark G; Hoenderop, Joost G; Bindels, René J

    2015-01-01

    Impaired mineral homeostasis and inflammation are hallmarks of chronic kidney disease (CKD), yet the underlying mechanisms of electrolyte regulation during CKD are still unclear. Here, we applied two different murine models, partial nephrectomy and adenine-enriched dietary intervention, to induce kidney failure and to investigate the subsequent impact on systemic and local renal factors involved in Ca(2+) and Pi regulation. Our results demonstrated that both experimental models induce features of CKD, as reflected by uremia, and elevated renal neutrophil gelatinase-associated lipocalin (NGAL) expression. In our model kidney failure was associated with polyuria, hypercalcemia and elevated urinary Ca(2+) excretion. In accordance, CKD augmented systemic PTH and affected the FGF23-αklotho-vitamin-D axis by elevating circulatory FGF23 levels and reducing renal αklotho expression. Interestingly, renal FGF23 expression was also induced by inflammatory stimuli directly. Renal expression of Cyp27b1, but not Cyp24a1, and blood levels of 1,25-dihydroxy vitamin D3 were significantly elevated in both models. Furthermore, kidney failure was characterized by enhanced renal expression of the transient receptor potential cation channel subfamily V member 5 (TRPV5), calbindin-D28k, and sodium-dependent Pi transporter type 2b (NaPi2b), whereas the renal expression of sodium-dependent Pi transporter type 2a (NaPi2a) and type 3 (PIT2) were reduced. Together, our data indicates two different models of experimental kidney failure comparably associate with disturbed FGF23-αklotho-vitamin-D signalling and a deregulated electrolyte homeostasis. Moreover, this study identifies local tubular, possibly inflammation- or PTH- and/or FGF23-associated, adaptive mechanisms, impacting on Ca(2+)/Pi homeostasis, hence enabling new opportunities to target electrolyte disturbances that emerge as a consequence of CKD development.

  8. Deregulated Renal Calcium and Phosphate Transport during Experimental Kidney Failure.

    Directory of Open Access Journals (Sweden)

    Wilco P Pulskens

    Full Text Available Impaired mineral homeostasis and inflammation are hallmarks of chronic kidney disease (CKD, yet the underlying mechanisms of electrolyte regulation during CKD are still unclear. Here, we applied two different murine models, partial nephrectomy and adenine-enriched dietary intervention, to induce kidney failure and to investigate the subsequent impact on systemic and local renal factors involved in Ca(2+ and Pi regulation. Our results demonstrated that both experimental models induce features of CKD, as reflected by uremia, and elevated renal neutrophil gelatinase-associated lipocalin (NGAL expression. In our model kidney failure was associated with polyuria, hypercalcemia and elevated urinary Ca(2+ excretion. In accordance, CKD augmented systemic PTH and affected the FGF23-αklotho-vitamin-D axis by elevating circulatory FGF23 levels and reducing renal αklotho expression. Interestingly, renal FGF23 expression was also induced by inflammatory stimuli directly. Renal expression of Cyp27b1, but not Cyp24a1, and blood levels of 1,25-dihydroxy vitamin D3 were significantly elevated in both models. Furthermore, kidney failure was characterized by enhanced renal expression of the transient receptor potential cation channel subfamily V member 5 (TRPV5, calbindin-D28k, and sodium-dependent Pi transporter type 2b (NaPi2b, whereas the renal expression of sodium-dependent Pi transporter type 2a (NaPi2a and type 3 (PIT2 were reduced. Together, our data indicates two different models of experimental kidney failure comparably associate with disturbed FGF23-αklotho-vitamin-D signalling and a deregulated electrolyte homeostasis. Moreover, this study identifies local tubular, possibly inflammation- or PTH- and/or FGF23-associated, adaptive mechanisms, impacting on Ca(2+/Pi homeostasis, hence enabling new opportunities to target electrolyte disturbances that emerge as a consequence of CKD development.

  9. Membrane transporters and new drug development

    Institute of Scientific and Technical Information of China (English)

    EndoH

    2002-01-01

    Molecular biology has made it possible to identify membrane transporter molecules that transport hydrophilic endogenous and exogenous compounds across cellular membranes.Ther are two possibilities on transporters relevant to new drug development,drug targets and pharmacokinetics.Human genome database predicts that more than 10% of common diseases may be tightly related with membrane transporter dysfunction.Thus,membrane transporters would be possible molecular targets for new drug development.As an example,I will talk on our discovery of L-type amino acid transporter 1(LAT1) being oncofetal and upregulated in cancers for their rapid growth and metastasis.We provide evidence that inhibition of LAT1 functions may become novel types of anticancer tools.As another example in human pharmacokinetics,application of stable expressing cell lines of human drug transporters will be proposed including organic anion and cation transporters which are distributed in various organs including the liver and kidney.These transporters are multispecific in their substrate recognition,and better molecules to anticipate drug-drug interactions in human bodies before new drug candidates are given in clinical trials.This in vitro technique may contribute to decide suitable compounds in particular by high throughout screening strategy.

  10. Role of Transport and Kinetics in Growth of Renal Stones

    Science.gov (United States)

    Kassemi, Mohammad; Iskovitz, Ilana

    2012-01-01

    Renal stone disease is not only a concern on earth but could conceivably pose as a serious risk to the astronauts health and safety in Space. In this paper, a combined transport-kinetics model for growth of calcium oxalate crystals is presented. The model is used to parametrically investigate the growth of renal calculi in urine with a focus on the coupled effects of transport and surface reaction on the ionic concentrations at the surface of the crystal and their impact on the resulting growth rates. It is shown that under nominal conditions of low solution supersaturation and low Damkohler number that typically exist on Earth, the surface concentrations of calcium and oxalate approach their bulk solution values in the urine and the growth rate is most likely limited by the surface reaction kinetics. But for higher solution supersaturations and larger Damkohler numbers that may be prevalent in the microgravity environment of Space, the calcium and oxalate surface concentrations tend to shift more towards their equilibrium or saturation values and thus the growth process may be limited by the transport through the medium. Furthermore, parametric numerical studies suggest that changes to the renal biochemistry of astronauts due in space may promote development of renal calculi during long duration space expeditions.

  11. Intrarenal purinergic signaling in the control of renal tubular transport

    DEFF Research Database (Denmark)

    Prætorius, Helle; Leipziger, Jens Georg

    2010-01-01

    Renal tubular epithelial cells receive hormonal input that regulates volume and electrolyte homeostasis. In addition, numerous intrarenal, local signaling agonists have appeared on the stage of renal physiology. One such system is that of intrarenal purinergic signaling. This system involves all...... the elements necessary for agonist-mediated intercellular communication. ATP is released from epithelial cells, which activates P2 receptors in the apical and basolateral membrane and thereby modulates tubular transport. Termination of the signal is conducted via the breakdown of ATP to adenosine. Recent far......-reaching advances indicate that ATP is often used as a local transmitter for classical sensory transduction. This transmission apparently also applies to sensory functions in the kidney. Locally released ATP is involved in sensing of renal tubular flow or in detecting the distal tubular load of NaCl at the macula...

  12. Interaction of immunosuppressive drugs with human organic anion transporter (OAT) 1 and OAT3, and multidrug resistance-associated protein (MRP) 2 and MRP4

    NARCIS (Netherlands)

    El-Sheikh, A.A.K.; Greupink, R.; Wortelboer, H.M.; Heuvel, J.J.M.W. van den; Schreurs, M.; Koenderink, J.B.; Masereeuw, R.; Russel, F.G.M.

    2013-01-01

    Renal proximal tubule transporters can play a key role in excretion, pharmacokinetic interactions, and toxicity of immunosuppressant drugs. Basolateral organic anion transporters (OATs) and apical multidrug resistance-associated proteins (MRPs) contribute to the active tubular uptake and urinary eff

  13. Drug Transport and Pharmacokinetics for Chemical Engineers

    Science.gov (United States)

    Simon, Laurent; Kanneganti, Kumud; Kim, Kwang Seok

    2010-01-01

    Experiments in continuous-stirred vessels were proposed to introduce methods in pharmacokinetics and drug transport to chemical engineering students. The activities can be incorporated into the curriculum to illustrate fundamentals learned in the classroom. An appreciation for the role of pharmacokinetics in drug discovery will also be gained…

  14. Integrating biomarkers to predict renal and cardiovascular drug efficacy: PRE score applications from drug registration to personalized medicine

    OpenAIRE

    Schievink, Bauke

    2016-01-01

    The prevalence of chronic kidney disease is increasing worldwide, and forecasts for 2030 indicate that the number of patients requiring renal replacement therapies will more than double. The increase in requirement of renal replacement therapies and the availability of only few proven effective therapies highlight the need to develop new drugs and intervention strategies. In the current drug development and registration process a single renal risk marker is selected and a drug is targeted tow...

  15. Transporter protein and drug resistance of Trypanosoma.

    Science.gov (United States)

    Medina, Noraine P; Mingala, Claro N

    2016-01-01

    Trypanosoma infection is one of the most important infections in livestock and humans. One of the main problems of its therapeutic control and treatment is the resurgence of drug resistance. One of the most studied causes of such resistance is the function of its adenosine transporter gene. A trypanosomal gene TbAT1 from Trypanosoma brucei has been cloned in yeast to demonstrate its function in the transport of adenosine and trypanocidal agents. Drug resistant trypanosomes showed a defective TbAT1 variant; furthermore, deletion of the gene and set point mutations in the transporter gene has been demonstrated from isolates from relapse patients. The molecular understanding of the mechanism of action trypanocidal agents and function of transporter gene can lead to control of drug resistance of Trypanosomes.

  16. Drug Transporters in the Intestine

    DEFF Research Database (Denmark)

    Steffansen, Bente

    2016-01-01

    The enterocyte monolayer in the intestinal membrane impacts on the bioavailability (BA) of many orally administered active pharmaceutical ingredients (APIs). The monolayer expresses a multitude of membrane transporters belonging to the solute carrier (SLC) and ATP-binding cassette (ABC) families ...

  17. P-glycoprotein- and mrp2-mediated octreotide transport in renal proximal tubule

    Science.gov (United States)

    Gutmann, Heike; Miller, David S; Droulle, Agathe; Drewe, Jürgen; Fahr, Alfred; Fricker, Gert

    2000-01-01

    Transepithelial transport of a fluorescent derivative of octreotide (NBD-octreotide) was studied in freshly isolated, functionally intact renal proximal tubules from killifish (Fundulus heteroclitus). Drug accumulation in the tubular lumen was visualized by means of confocal microscopy and was measured by image analysis. Secretion of NBD-octreotide into the tubular lumen was demonstrated and exhibited the all characteristics of specific and energy-dependent transport. Steady state luminal fluorescence averaged about five times cellular fluorescence and was reduced to cellular levels when metabolism was inhibited by NaCN. NBD-octreotide secretion was inhibited in a concentration-dependent manner by unlabelled octreotide, verapamil and leukotriene C4 (LTC4). Conversely, unlabelled octreotide reduced in a concentration dependent manner the p-glycoprotein (Pgp)-mediated secretion of a fluorescent cyclosporin A derivative (NBDL-CS) and the mrp2-mediated secretion of fluorescein methotrexate (FL-MTX). This inhibition was not due to impaired metabolism or toxicity since octreotide had no influence on the active transport of fluorescein (FL), a substrate for the classical renal organic anion transport system. The data are consistent with octreotide being transported across the brush border membrane of proximal kidney tubules by both Pgp and mrp2. PMID:10694230

  18. Renal targeting of a non-steroidal antiinflammatory drug : effects on renal prostaglandin synthesis in the rat

    NARCIS (Netherlands)

    Haas, M; Moolenaar, F; Meijer, DKF; de Jong, PE; de Zeeuw, D

    1998-01-01

    1, Renal specific targeting of the non-steroidal anti-inflammatory drug naproxen was obtained by coupling to the low-molecular-mass protein lysozyme. A previous study showed that conjugation to lysozyme resulted in a 70-fold increase of naproxen accumulation in the kidney with a subsequent renal rel

  19. Renal targeting of a non-steroidal antiinflammatory drug : effects on renal prostaglandin synthesis in the rat

    NARCIS (Netherlands)

    Haas, M; Moolenaar, F; Meijer, DKF; de Jong, PE; de Zeeuw, D

    1998-01-01

    1, Renal specific targeting of the non-steroidal anti-inflammatory drug naproxen was obtained by coupling to the low-molecular-mass protein lysozyme. A previous study showed that conjugation to lysozyme resulted in a 70-fold increase of naproxen accumulation in the kidney with a subsequent renal

  20. Drug-related acute renal failure in hospitalised patients.

    Science.gov (United States)

    Iavecchia, Lujan; Cereza García, Gloria; Sabaté Gallego, Mònica; Vidal Guitart, Xavier; Ramos Terrades, Natalia; de la Torre, Judith; Segarra Medrano, Alfons; Agustí Escasany, Antònia

    2015-01-01

    The information available on the incidence and the characteristics of patients with acute renal failure (ARF) related to drugs is scarce. To estimate the incidence of drug-related ARF in hospitalised patients and to compare their characteristics with those of patients with ARF due to other causes. We selected a prospective cohort of patients with ARF during hospital admission (July 2010-July 2011). Information on patients' demographics, medical antecedents, ARF risk factors, ARF severity according to the RIFLE classification and hospital drug administration was collected. We analysed the relationship of drugs with the ARF episodes using Spanish Pharmacovigilance System methods and algorithm. A total of 194 cases had an episode of hospital-acquired ARF. The median age of patients was 72 years [IQR 20]; 60% were men. The ARF incidence during hospitalization was 9.6 per 1,000 admissions. According to the RIFLE classification, a risk of kidney damage or kidney injury was present in 77.8% of cases. In 105 (54.1%) cases, ARF was drug-related; the drugs most frequently involved were diuretics, agents acting on the renin-angiotensin system, immunosuppressants, β-blocking agents, calcium channel blockers, contrast media and non-steroid anti-inflammatory drugs. Patients with drug-related ARF had more multi-morbidity, fewer ARF risk factors and lower mortality. Half of ARF episodes during hospitalisation were drug related. Patients with drug-related ARF had higher cardiovascular morbidity than those with ARF related to other causes, but they had a lower frequency of ARF risk factors and mortality. Copyright © 2015 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.

  1. 77 FR 21982 - Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting

    Science.gov (United States)

    2012-04-12

    ... HUMAN SERVICES Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee; Notice of... to the public. Name of Committee: Cardiovascular and Renal Drugs Advisory Committee. General Function... patients with acute coronary syndrome (ACS) [ST elevation myocardial infarction (STEMI), non-ST...

  2. 78 FR 76307 - Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting

    Science.gov (United States)

    2013-12-17

    ... HUMAN SERVICES Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee; Notice of... to the public. Name of Committee: Cardiovascular and Renal Drugs Advisory Committee. General Function... atherothrombotic events in patients with a history of myocardial infarction (MI). The applicant also proposes...

  3. 78 FR 76308 - Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting

    Science.gov (United States)

    2013-12-17

    ... HUMAN SERVICES Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee; Notice of... to the public. Name of Committee: Cardiovascular and Renal Drugs Advisory Committee. General Function... coronary syndrome [ST elevation myocardial infarction, non-ST elevation myocardial infarction, or...

  4. 77 FR 43600 - Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting

    Science.gov (United States)

    2012-07-25

    ... HUMAN SERVICES Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee; Notice of... to the public. Name of Committee: Cardiovascular and Renal Drugs Advisory Committee. General Function... West- Ward Pharmaceutical Corp., to increase blood pressure in acute hypotensive states, such as...

  5. 78 FR 36787 - Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting

    Science.gov (United States)

    2013-06-19

    ... HUMAN SERVICES Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee; Notice of... to the public. Name of Committee: Cardiovascular and Renal Drugs Advisory Committee. General Function... Pharmaceutical Company, Ltd., for the proposed indication of slowing kidney disease in adults at risk of...

  6. Role of drug transporters and drug accumulation in the temporal acquisition of drug resistance

    Directory of Open Access Journals (Sweden)

    Veitch Zachary

    2008-11-01

    Full Text Available Abstract Background Anthracyclines and taxanes are commonly used in the treatment of breast cancer. However, tumor resistance to these drugs often develops, possibly due to overexpression of drug transporters. It remains unclear whether drug resistance in vitro occurs at clinically relevant doses of chemotherapy drugs and whether both the onset and magnitude of drug resistance can be temporally and causally correlated with the enhanced expression and activity of specific drug transporters. To address these issues, MCF-7 cells were selected for survival in increasing concentrations of doxorubicin (MCF-7DOX-2, epirubicin (MCF-7EPI, paclitaxel (MCF-7TAX-2, or docetaxel (MCF-7TXT. During selection cells were assessed for drug sensitivity, drug uptake, and the expression of various drug transporters. Results In all cases, resistance was only achieved when selection reached a specific threshold dose, which was well within the clinical range. A reduction in drug uptake was temporally correlated with the acquisition of drug resistance for all cell lines, but further increases in drug resistance at doses above threshold were unrelated to changes in cellular drug uptake. Elevated expression of one or more drug transporters was seen at or above the threshold dose, but the identity, number, and temporal pattern of drug transporter induction varied with the drug used as selection agent. The pan drug transporter inhibitor cyclosporin A was able to partially or completely restore drug accumulation in the drug-resistant cell lines, but had only partial to no effect on drug sensitivity. The inability of cyclosporin A to restore drug sensitivity suggests the presence of additional mechanisms of drug resistance. Conclusion This study indicates that drug resistance is achieved in breast tumour cells only upon exposure to concentrations of drug at or above a specific selection dose. While changes in drug accumulation and the expression of drug transporters does

  7. Drug dosing during intermittent hemodialysis and continuous renal replacement therapy : special considerations in pediatric patients.

    Science.gov (United States)

    Veltri, Michael A; Neu, Alicia M; Fivush, Barbara A; Parekh, Rulan S; Furth, Susan L

    2004-01-01

    Chronic renal failure is, fortunately, an unusual occurrence in children; however, many children with various underlying illnesses develop acute renal failure, and transiently require renal replacement therapy - peritoneal dialysis, intermittent hemodialysis (IHD), or continuous renal replacement therapy (CRRT). As children with acute and chronic renal failure often have multiple comorbid conditions requiring drug therapy, generalists, intensivists, nephrologists, and pharmacists need to be aware of the issues surrounding the management of drug therapy in pediatric patients undergoing renal replacement therapy. This article summarizes the pharmacokinetics and dosing of many drugs commonly prescribed for pediatric patients, and focuses on the management of drug therapy in pediatric patients undergoing IHD and CRRT in the intensive care unit setting. Peritoneal dialysis is not considered in this review. Finally, a summary table with recommended initial dosages for drugs commonly encountered in pediatric patients requiring IHD or CRRT is presented.

  8. Role of N-glycosylation in renal betaine transport.

    Science.gov (United States)

    Schweikhard, Eva S; Burckhardt, Birgitta C; Joos, Friedericke; Fenollar-Ferrer, Cristina; Forrest, Lucy R; Kempson, Stephen A; Ziegler, Christine

    2015-09-01

    The osmolyte and folding chaperone betaine is transported by the renal Na(+)-coupled GABA (γ-aminobutyric acid) symporter BGT-1 (betaine/GABA transporter 1), a member of the SLC6 (solute carrier 6) family. Under hypertonic conditions, the transcription, translation and plasma membrane (PM) insertion of BGT-1 in kidney cells are significantly increased, resulting in elevated betaine and GABA transport. Re-establishing isotonicity involves PM depletion of BGT-1. The molecular mechanism of the regulated PM insertion of BGT-1 during changes in osmotic stress is unknown. In the present study, we reveal a link between regulated PM insertion and N-glycosylation. Based on homology modelling, we identified two sites (Asn(171) and Asn(183)) in the extracellular loop 2 (EL2) of BGT-1, which were investigated with respect to trafficking, insertion and transport by immunogold-labelling, electron microscopy (EM), mutagenesis and two-electrode voltage clamp measurements in Xenopus laevis oocytes and uptake of radiolabelled substrate into MDCK (Madin-Darby canine kidney) and HEK293 (human embryonic kidney) cells. Trafficking and PM insertion of BGT-1 was clearly promoted by N-glycosylation in both oocytes and MDCK cells. Moreover, association with N-glycans at Asn(171) and Asn(183) contributed equally to protein activity and substrate affinity. Substitution of Asn(171) and Asn(183) by aspartate individually caused no loss of BGT-1 activity, whereas the double mutant was inactive, suggesting that N-glycosylation of at least one of the sites is required for function. Substitution by alanine or valine at either site caused a dramatic loss in transport activity. Furthermore, in MDCK cells PM insertion of N183D was no longer regulated by osmotic stress, highlighting the impact of N-glycosylation in regulation of this SLC6 transporter.

  9. Drug transport in HEMA conjunctival inserts containing precipitated drug particles.

    Science.gov (United States)

    Gupta, Chhavi; Chauhan, Anuj

    2010-07-01

    This paper focuses on exploring the mechanism of cyclosporine A transport in hydroxyethyl methacrylate (HEMA) rods to develop conjunctival inserts for extended ocular delivery. Cylindrical conjunctival HEMA inserts were prepared by thermal polymerization in presence of drug at high loadings to create rods containing particles of drug dispersed in the matrix. The drug release rates were measured to explore the effect of length, drug loading, crosslinking, and mixing in the release medium. Also microstructure of the inserts was characterized by SEM imaging. The inserts release the drug for a period of about a month at therapeutic rates. The rates of drug release are zero order and independent of drug loading and crosslinking for certain period of time. These effects were shown to arise due to a mass-transfer boundary layer in the fluid and a mathematical model was developed by coupling mass transfer in the insert with that in the boundary layer in the surrounding fluid. The model with diffusivity in the insert and boundary layer thickness as parameters fits the experimental data and explains all trends in release kinetics. The fitted diffusivity is about twice that obtained by direct measurements, which agreed well with the value obtained by using the Brinkman's equation but only after accounting for drug binding to the polymer.

  10. Role of organic cation transporter OCT2 and multidrug and toxin extrusion proteins MATE1 and MATE2-K for transport and drug interactions of the antiviral lamivudine.

    Science.gov (United States)

    Müller, Fabian; König, Jörg; Hoier, Eva; Mandery, Kathrin; Fromm, Martin F

    2013-09-15

    The antiviral lamivudine is cleared predominantly by the kidney with a relevant contribution of renal tubular secretion. It is not clear which drug transporters mediate lamivudine renal secretion. Our aim was to investigate lamivudine as substrate of the renal drug transporters organic cation transporter 2 (OCT2) and multidrug and toxin extrusion proteins MATE1 and MATE2-K. Uptake experiments were performed in OCT2, MATE1, or MATE2-K single-transfected human embryonic kidney 293 (HEK) cells. Transcellular transport experiments were performed in OCT2 and/or MATE1 single- or double-transfected Madin-Darby canine kidney II (MDCK) cells grown on transwell filters. Lamivudine uptake was significantly increased in HEK-OCT2, HEK-MATE1, and HEK-MATE2-K cells compared to control cells. In transcellular experiments, OCT2 located in the basolateral membrane had no effect on transcellular lamivudine transport. MATE1 located in the apical membrane decreased intracellular concentrations and increased transcellular transport of lamivudine from the basal to the apical compartment. MATE1- or MATE2-K-mediated transport was increased by an oppositely directed pH gradient. Several simultaneously administered drugs inhibited OCT2- or MATE2-K-mediated lamivudine uptake. The strongest inhibitors were carvedilol for OCT2 and trimethoprim for MATE2-K (inhibition by 96.3 and 83.7% at 15 μM, respectively, ptransport in OCT2-MATE1 double-transfected cells was inhibited by trimethoprim with an IC₅₀ value of 6.9 μM. Lamivudine is a substrate of renal drug transporters OCT2, MATE1, and MATE2-K. Concomitant administration of drugs that inhibit these transporters could decrease renal clearance of lamivudine.

  11. Renal failure caused by chemicals, foods, plants, animal venoms, and misuse of drugs. An overview.

    Science.gov (United States)

    Abuelo, J G

    1990-03-01

    Nephrotoxicity caused by contrast media and drugs is a frequent cause of renal failure in medical practice. However, there are only sporadic cases of renal failure caused by chemicals, foods, plants, animal venoms, and misused or illegal drugs, and standard medical textbooks are limited in the coverage given to the subject. This review provides a referenced compilation of these lesser-known nephrotoxins and gives an overview of renal failure caused by substances other than properly used medications.

  12. Drug-induced renal function impairment : a population-based survey

    NARCIS (Netherlands)

    Monster, TBM; de Jong, PE; de Jong-van den Berg, LTW

    2003-01-01

    Purpose The knowledge that drugs can affect renal function is mainly based on experimental studies or case reports. Thus, it has only been investigated in selected populations. Here we describe drug groups associated with altered renal function in the general population. Methods To study this, we us

  13. Renal aquaporins and sodium transporters with special focus on urinary tract obstruction

    DEFF Research Database (Denmark)

    Frøkiaer, Jørgen; Li, Chunling; Shi, Yimin

    2003-01-01

    seven aquaporins are expressed at distinct sites in the kidney and 4 members of this family (AQP1-4) have been demonstrated to play pivotal roles in the physiology and pathophysiology for renal regulation of body water balance. Osmotic equilibration via renal aquaporins is maintained by active transport...... of NaCl. The major sodium transporters and channels in the individual renal tubule segments have been identified and the regulation of these transporters and channels are fundamental for renal sodium reabsorption and for establishing the driving force. In this mini-review the role of renal aquaporins...... and sodium transporters and channels is briefly described and their key role for the impaired urinary concentrating capacity in response to urinary tract obstruction is reviewed. Thus this review updates previous detailed reviews (1-5)....

  14. Physiologically-based pharmacokinetic modeling of renally excreted antiretroviral drugs in pregnant women.

    Science.gov (United States)

    De Sousa Mendes, Maïlys; Hirt, Deborah; Urien, Saik; Valade, Elodie; Bouazza, Naïm; Foissac, Frantz; Blanche, Stephane; Treluyer, Jean-Marc; Benaboud, Sihem

    2015-11-01

    Physiological changes during pregnancy can affect drug disposition. Anticipating these changes will help to maximize drug efficacy and safety in pregnant women. Our objective was to determine if physiologically-based pharmacokinetics (PBPK) can accurately predict changes in the disposition of renally excreted antiretroviral drugs during pregnancy. Whole body PBPK models were developed for three renally excreted antiretroviral drugs, tenofovir (TFV), emtricitabine (FTC) and lamivudine (3TC). To assess the impact of pregnancy on PK, time-varying pregnancy-related physiological parameters available within the p-PBPK Simcyp software package were used. Renal clearance during pregnancy followed glomerular filtration changes with or without alterations in secretion. PK profiles were simulated and compared with observed data, i.e. area under the curves (AUC), peak plasma concentrations (Cmax ) and oral clearances (CL/F). PBPK models successfully predicted TFV, FTC and 3TC disposition for non-pregnant and pregnant populations. Both renal secretion and filtration changed during pregnancy. Changes in renal clearance secretion were related to changes in renal plasma flow. The maximum clearance increases were approximately 30% (TFV 33%, FTC 31%, 3TC 29%). Pregnancy PBPK models are useful tools to quantify a priori the drug exposure changes during pregnancy for renally excreted drugs. These models can be applied to evaluate alternative dosing regimens to optimize drug therapy during pregnancy. © 2015 The British Pharmacological Society.

  15. Nephron-Specific Deletion of Circadian Clock Gene Bmal1 Alters the Plasma and Renal Metabolome and Impairs Drug Disposition.

    Science.gov (United States)

    Nikolaeva, Svetlana; Ansermet, Camille; Centeno, Gabriel; Pradervand, Sylvain; Bize, Vincent; Mordasini, David; Henry, Hugues; Koesters, Robert; Maillard, Marc; Bonny, Olivier; Tokonami, Natsuko; Firsov, Dmitri

    2016-10-01

    The circadian clock controls a wide variety of metabolic and homeostatic processes in a number of tissues, including the kidney. However, the role of the renal circadian clocks remains largely unknown. To address this question, we performed a combined functional, transcriptomic, and metabolomic analysis in mice with inducible conditional knockout (cKO) of BMAL1, which is critically involved in the circadian clock system, in renal tubular cells (Bmal1(lox/lox)/Pax8-rtTA/LC1 mice). Induction of cKO in adult mice did not produce obvious abnormalities in renal sodium, potassium, or water handling. Deep sequencing of the renal transcriptome revealed significant changes in the expression of genes related to metabolic pathways and organic anion transport in cKO mice compared with control littermates. Furthermore, kidneys from cKO mice exhibited a significant decrease in the NAD(+)-to-NADH ratio, which reflects the oxidative phosphorylation-to-glycolysis ratio and/or the status of mitochondrial function. Metabolome profiling showed significant changes in plasma levels of amino acids, biogenic amines, acylcarnitines, and lipids. In-depth analysis of two selected pathways revealed a significant increase in plasma urea level correlating with increased renal Arginase II activity, hyperargininemia, and increased kidney arginine content as well as a significant increase in plasma creatinine concentration and a reduced capacity of the kidney to secrete anionic drugs (furosemide) paralleled by an approximate 80% decrease in the expression level of organic anion transporter 3 (SLC22a8). Collectively, these results indicate that the renal circadian clocks control a variety of metabolic/homeostatic processes at the intrarenal and systemic levels and are involved in drug disposition. Copyright © 2016 by the American Society of Nephrology.

  16. Testosterone increases urinary calcium excretion and inhibits expression of renal calcium transport proteins.

    NARCIS (Netherlands)

    Hsu, Y.J.; Dimke, H.; Schoeber, J.P.H.; Hsu, S.C.; Lin, S.H.; Chu, P.; Hoenderop, J.G.J.; Bindels, R.J.M.

    2010-01-01

    Although gender differences in the renal handling of calcium have been reported, the overall contribution of androgens to these differences remains uncertain. We determined here whether testosterone affects active renal calcium reabsorption by regulating calcium transport proteins. Male mice had hig

  17. Novel molecular pathways in renal Mg2+ transport: a guided tour along the nephron

    DEFF Research Database (Denmark)

    San-Cristobal, Pedro; Dimke, Henrik Anthony; Hoenderop, Joost Gj;

    2010-01-01

    This review highlights recent advances in renal magnesium (Mg) handling. The understanding of the molecular processes of epithelial Mg transport has expanded considerably due to the identification of novel genes involved in hypomagnesemic disorders....

  18. Impact on creatinine renal clearance by the interplay of multiple renal transporters: a case study with INCB039110.

    Science.gov (United States)

    Zhang, Yan; Warren, Mark S; Zhang, Xuexiang; Diamond, Sharon; Williams, Bill; Punwani, Naresh; Huang, Jane; Huang, Yong; Yeleswaram, Swamy

    2015-04-01

    Serum creatinine is commonly used as a marker of renal function, but increases in serum creatinine might not represent changes in glomerular filtration rate (GFR). INCB039110 (2-(3-(4-(7H-pyrrolo[2,3-day]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile) is an inhibitor of the Janus kinases (JAKs) with selectivity for JAK1. In a phase 1 study, a modest and reversible increase in serum creatinine was observed after treatment with INCB039110. However, a dedicated renal function study with INCB039110, assessed by iohexol plasma clearance, conducted in healthy volunteers indicated no change in GFR. In vitro studies were therefore conducted to investigate the interaction of INCB039110 with five transporters that are likely involved in the renal clearance of creatinine. Cell systems expressing individual or multiple transporters were used, including a novel quintuple-transporter model OAT2/OCT2/OCT3/MATE1/MATE2-K. INCB039110 potently inhibited OCT2-mediated uptake of creatinine as well as MATE1-/MATE2-K-mediated efflux of creatinine. Given the interactions of INCB039110 with multiple transporters affecting creatinine uptake and efflux, an integrated system expressing all five transporters was sought; in that system, INCB039110 caused a dose-dependent decrease in transcellular transport of creatinine with weaker net inhibition compared with the effects on individual transporters. In summary, a molecular mechanism for the increase in serum creatinine by INCB039110 has been established. These studies also underline the limitations of using serum creatinine as a marker of renal function.

  19. Intrarenal purinergic signaling in the control of renal tubular transport

    DEFF Research Database (Denmark)

    Prætorius, Helle; Leipziger, Jens Georg

    2010-01-01

    Renal tubular epithelial cells receive hormonal input that regulates volume and electrolyte homeostasis. In addition, numerous intrarenal, local signaling agonists have appeared on the stage of renal physiology. One such system is that of intrarenal purinergic signaling. This system involves all ...

  20. Dose adjustment guidelines for medications in patients with renal impairment: how consistent are drug information sources?

    Science.gov (United States)

    Khanal, A; Castelino, R L; Peterson, G M; Jose, M D

    2014-01-01

    It is known that patients with renal disease are often administered inappropriate dosages of drugs. A lack of quantitative data in the available drug information sources and inconsistency in dosing information may augment the problem of dosing error. To determine the concordance among five drug information sources regarding the dosing recommendations provided for drugs considered problematic in patients with renal impairment and to determine the consistency among the sources regarding the definition of renal impairment and categorisation of chronic kidney disease. Five standard drug information sources were reviewed for 61 drugs recommended to be used with caution in renal impairment. Information on recommendations for dosage adjustment in renal impairment was extracted and analysed. Further, the definition and classification of renal impairment were recorded. The recommendation for each drug was coded into six different categories and the intersource reliability was calculated. Only slight agreement was observed among the sources (Fleiss Kappa: 0.3). Qualitative data were not well defined, and there was a lack of consistency in quantitative values. Some drugs marked as contraindicated in one source were not mentioned as such in others. Also, drugs considered as not requiring dosage adjustment in one source had explicit recommendations in other sources. The definition and classification of renal impairment differed among the five information sources. There should be an evidence-based approach to drug dosage adjustment in order to bring uniformity to the recommendations. Regular updating of the content of the drug information sources is also important. © 2013 The Authors; Internal Medicine Journal © 2013 Royal Australasian College of Physicians.

  1. Safety and efficacy of coronary drug eluting stent for atherosclerotic stenosis of the small renal artery

    Institute of Scientific and Technical Information of China (English)

    LI Chun-jie; WU Zheng; YAN Hong-bing; WANG Jian; ZHAO Han-jun

    2009-01-01

    @@ Small diameter renal artery refers to the renal artery with the cross-section diameter less than 5 mm, the incidence of which is approximately 8%.1 Small diameter renal artery is common in patients with congenital multi-branch renal arteries, diabetes and multi-coronary artery lesions. Renal artery bare-mental stent (BMS) implantation is the standard treatment for ostial renal artery stenosis.2,3 However, the restenosis rate4-6 is too high and becomes one of the relative contraindications for small diameter renal artery stent implantation. Clinical trials (e.g. RAVEL,7,8 SIRIUS9 and TAXUS-IV10) have proved that drug eluting stent (DES), compared with BMS, can reduce the restenosis rate after the percutanous coronary intervention (PCI). And Huda et al11 claimed that DES had the better results than BMS in the treatment of obstructive superficial femoral artery disease. However,there are few studies involved restenosis after the renal artery intervention. We hypothesized that coronary DES applied in renal artery stenosis might inhibit intimal proliferation effectively as in coronary artery disease;therefore we evaluated the results of 25 patients with atherosclerotic renal artery stenosis treated using coronary DES to assess the safety and efficacy of coronary DES in patients with small renal artery stenotic lesions.

  2. Renal xenobiotic transporters are differentially expressed in mice following cisplatin treatment.

    Science.gov (United States)

    Aleksunes, Lauren M; Augustine, Lisa M; Scheffer, George L; Cherrington, Nathan J; Manautou, José E

    2008-09-04

    The goal of this study was to identify alterations in mRNA and protein expression of various xenobiotic transport proteins in mouse kidney during cisplatin-induced acute renal failure. For this purpose, male C57BL/6J mice received a single dose of cisplatin (18 mg/kg, i.p.) or vehicle. Four days later, tissues were collected for assessment of plasma BUN, histopathological analysis of renal lesions, and mRNA and Western blot analysis of renal transporters including organic anion and cation transporters (Oat, Oct), organic anion transporting polypeptides (Oatp), multidrug resistance-associated proteins (Mrp), multidrug resistance proteins (Mdr), breast cancer resistance protein (Bcrp) and multidrug and toxin extrusion proteins (Mate). Cisplatin treatment caused necrosis of renal proximal tubules along with elevated plasma BUN and renal kidney injury molecule-1 mRNA expression. Cisplatin-induced renal injury increased mRNA and protein levels of the efflux transporters Mrp2, Mrp4, Mrp5, Mdr1a and Mdr1b. Uptake transporters Oatp2a1 and Oatp2b1 mRNA were also up-regulated following cisplatin. By contrast, expression of Oat1, Oat2, Oct2 and Oatp1a1 mRNA was reduced in cisplatin-treated mice. Expression of several uptake and efflux transporters was unchanged in cisplatin-treated mice. Apical staining of Mrp2 and Mrp4 proteins was enhanced in proximal tubules from cisplatin-treated mice. Collectively, these expression patterns suggest coordinated regulation of uptake and efflux pathways during cisplatin-induced renal injury. Reduced expression of basolateral and apical uptake transporters along with enhanced transcription of export transporters likely represents an adaptation to lower intracellular accumulation of chemicals, prevent their reabsorption and enhance urinary clearance.

  3. Renal myoglobin in drug addicts: occurrence and significance in a postmortem study

    DEFF Research Database (Denmark)

    Kock, Kirsten Friis; Simonsen, Kirsten Wiese

    1994-01-01

    In a 3-year period (1989–1991) a non-selected, consecutive series of 62 deaths in drug addicts was autopsied at the Forensic Institute in Odense. The kidney sections from these addicts were examined for the presence of renal myoglobin using immunohistochemical methods. A reference group consisting......, immobilization, hypovolemia). In sufficient amounts, renal myoglobin may be of importance as a cause of death or a contributing factor to death in both drug addicts and non-addicts....

  4. 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.

  5. Ubiquitination regulates the plasma membrane expression of renal UT-A urea transporters.

    Science.gov (United States)

    Stewart, Gavin S; O'Brien, Jennifer H; Smith, Craig P

    2008-07-01

    The renal UT-A urea transporters UT-A1, UT-A2, and UT-A3 are known to play an important role in the urinary concentrating mechanism. The control of the cellular localization of UT-A transporters is therefore vital to overall renal function. In the present study, we have investigated the effect of ubiquitination on UT-A plasma membrane expression in Madin-Darby canine kidney (MDCK) cell lines expressing each of the three renal UT-A transporters. Inhibition of the ubiquitin-proteasome pathway caused an increase in basal transepithelial urea flux across MDCK-rat (r)UT-A1 and MDCK-mouse (m)UT-A2 monolayers (P UT-A transporter expression in the plasma membrane (P UT-A3 expression in the plasma membrane (P UT-A urea transporters, but that this is not the mechanism primarily used by vasopressin to produce its physiological effects.

  6. Transporter-Mediated Drug–Drug Interactions with Oral Antidiabetic Drugs

    Directory of Open Access Journals (Sweden)

    Jörg König

    2011-10-01

    Full Text Available Uptake transporters (e.g., members of the SLC superfamily of solute carriers and export proteins (e.g., members of the ABC transporter superfamily are important determinants for the pharmacokinetics of drugs. Alterations of drug transport due to concomitantly administered drugs that interfere with drug transport may alter the kinetics of drug substrates. In vitro and in vivo studies indicate that many drugs used for the treatment of metabolic disorders and cardiovascular diseases (e.g., oral antidiabetic drugs, statins are substrates for uptake transporters and export proteins expressed in the intestine, the liver and the kidney. Since most patients with type 2 diabetes receive more than one drug, transporter-mediated drug-drug interactions are important molecular mechanisms leading to alterations in oral antidiabetic drug pharmacokinetics with the risk of adverse drug reactions. This review focuses on uptake transporters of the SLCO/SLC21 (OATP and SLC22 (OCT/OAT family of solute carriers and export pumps of the ABC (ATP-binding cassette transporter superfamily (especially P-glycoprotein as well as the export proteins of the SLC47 (MATE family and their role for transporter-mediated drug-drug interactions with oral antidiabetic drugs.

  7. Effect of Organophosphate Compounds on Renal Function and Transport.

    Science.gov (United States)

    1983-09-15

    cholinomimetic- induced diuresis , they do demonstrate a direct action of these compounds on renal cell electrolyte balance. Carter’s group did not examine the...Carrier. J. Friborg and 3. P. Onay, Vasodilators, intrarenal blood flow, and natriuresis in the dog. Amer. 3. Physiol., 221 (1971) 92- 98. 11. U.K...tylchol insestaraso activity. Diochem. Pharmacol., 7 (1961) 88-94. 19. 3.P. Hayslett, U. Kashgarian and F.H. Epstein, The diuresis of renal 17

  8. Rifampin Regulation of Drug Transporters Gene Expression and the Association of MicroRNAs in Human Hepatocytes

    Directory of Open Access Journals (Sweden)

    Eric A Benson

    2016-04-01

    Full Text Available Membrane drug transporters contribute to the disposition of many drugs. In human liver, drug transport is controlled by two main superfamilies of transporters, the solute carrier transporters (SLC and the ATP Binding Cassette transporters (ABC. Altered expression of these transporters due to drug-drug interactions can contribute to differences in drug exposure and possibly effect. In this study, we determined the effect of rifampin on gene expression of hundreds of membrane transporters along with all clinically relevant drug transporters. Methods: In this study, primary human hepatocytes (n=7 donors were cultured and treated for 24 hours with rifampin and vehicle control. RNA was isolated from the hepatocytes, mRNA expression was measured by RNA-seq, and miRNA expression was analyzed by Taqman OpenArray. The effect of rifampin on the expression of selected transporters was also tested in kidney cell lines. The impact of rifampin on the expression of 410 transporter genes from 19 different transporter gene families was compared with vehicle control. Results: Expression patterns of 12 clinically relevant drug transporter genes were changed by rifampin (FDR<0.05. For example, the expressions of ABCC2, ABCB1, and ABCC3 were increased 1.9-, 1.7-, and 1.2- fold, respectively. The effects of rifampin on four uptake drug transporters (SLCO1B3, SLC47A1, SLC29A1, SLC22A9 were negatively correlated with the rifampin effects on specific microRNA expression (SLCO1B3/miR-92a, SLC47A1/miR-95, SLC29A1/miR-30d#, and SLC22A9/miR-20; r<-0.79; p<0.05. Seven hepatic drug transporter genes (SLC22A1, SLC22A5, SLC15A1, SLC29A1, SLCO4C1, ABCC2, and ABCC4, whose expression was altered by rifampin in hepatocytes, were also present in a renal proximal tubular cell line, but in renal cells rifampin did not alter their gene expression. PXR expression was very low in the kidney cells; this may explain why rifampin induces gene expression in a tissue-specific manner

  9. Fever of unknown origin (FUO) in a renal transplant recipient due to drug fever from sirolimus.

    Science.gov (United States)

    Sharif, Sairah; Kong, May W; Drakakis, James; Cunha, Burke A

    2016-08-01

    A variety of medications may cause drug fever. Drug fevers may persist for days to weeks until diagnosis is considered. The diagnosis of drug fever is confirmed when there is resolution of fever within 3 days after the medication is discontinued. Only rarely do undiagnosed drug fevers persist for over 3 weeks to meet fever of unknown origin (FUO) criteria. FUOs due to drug fever are uncommon, and drug fevers due to immunosuppressive drugs are very rare. This is a case of a 58-year-old female renal transplant recipient who presented with FUO that remained undiagnosed for over 8 weeks. We believe this is the first reported case of an FUO due to drug fever from sirolimus in a renal transplant recipient.

  10. Biotransformation, transport and toxicity studies in rat renal proximal tubular cells.

    NARCIS (Netherlands)

    Haenen, H.E.M.G.

    1996-01-01

    SummaryRenal proximal tubular (RPT) cells can be exposed apically to glomerulary filtrated and basolaterally to non-filtrated nephrotoxic compounds. To excrete these compounds via the urine, RPT cells are equipped with transport systems able to transport nephrotoxicants from the basolateral to the a

  11. Biophysics of Cell Membrane Lipids in Cancer Drug Resistance: Implications for Drug Transport and Drug Delivery with Nanoparticles

    Science.gov (United States)

    Peetla, Chiranjeevi; Vijayaraghavalu, Sivakumar; Labhasetwar, Vinod

    2013-01-01

    In this review, we focus on the biophysics of cell membrane lipids, particularly when cancers develop acquired drug resistance, and how biophysical changes in resistant cell membrane influence drug transport and nanoparticle-mediated drug delivery. Recent advances in membrane lipid research show the varied roles of lipids in regulating membrane P-glycoprotein function, membrane trafficking, apoptotic pathways, drug transport, and endocytic functions, particularly endocytosis, the primary mechanism of cellular uptake of nanoparticle-based drug delivery systems. Since acquired drug resistance alters lipid biosynthesis, understanding the role of lipids in cell membrane biophysics and its effect on drug transport is critical for developing effective therapeutic and drug delivery approaches to overcoming drug resistance. Here we discuss novel strategies for (a) modulating the biophysical properties of membrane lipids of resistant cells to facilitate drug transport and regain endocytic function and (b) developing effective nanoparticles based on their biophysical interactions with membrane lipids to enhance drug delivery and overcome drug resistance. PMID:24055719

  12. The Role of Drug Transporters in the Pharmacokinetics of Antibiotics.

    Science.gov (United States)

    Hua, Wen Jin; Hua, Wei Xiao; Jian, Zhou; Wei, Peng Hong; Ni, Lu Yan; Hua, Li Yu; Wen, Cao Duan; Ying, Zhou; Li, Cao

    2016-01-01

    Various transporters, including efflux transporters and uptake transporters, play an important role in the pharmacokinetics of drugs. Currently, studies suggest that several antibiotics also serve as substrates for transporters. In addition, these antibiotics are usually combined with other drugs to treat diseases, more effectively. Therefore, it is necessary to focus on the role of transporters in pharmacokinetics and drug-drug interactions of antibiotics. This review summarizes the findings of recent studies as well as information retrieved from several databases (until June 2015): ISI Web of KnowledgeSM (ISI WoK), SciFinder (Caplus, Medline, Registry, Casreact, Chrmlist, and Chemcasts) and PubMed (indexed for Medline). The present review provides useful information for the study of transporters in the pharmacokinetics and drug-drug interactions of antibiotics, and should assist researchers investigating these topics. The drug transporters mediate intestinal absorption, hepatic uptake, and kidney or biliary excretion. It is necessary to focus on drug-drug interactions when these antibiotics are combined with other chemical substances that are also the substrates for transporters.

  13. Sex-Differences in Renal Expression of Selected Transporters and Transcription Factors in Lean and Obese Zucker Spontaneously Hypertensive Fatty Rats

    Directory of Open Access Journals (Sweden)

    Andrea Babelova

    2015-01-01

    Full Text Available The aim of this study was to identify sex-dependent expression of renal transporter mRNA in lean and obese Zucker spontaneously hypertensive fatty (ZSF1 rats and to investigate the interaction of the most altered transporter, organic anion transporter 2 (Oat2, with diabetes-relevant metabolites and drugs. Higher incidence of glomerulosclerosis, tubulointerstitial fibrosis, and protein casts in Bowman’s space and tubular lumen was detected by PAS staining in obese male compared to female ZSF1 rats. Real-time PCR on RNA isolated from kidney cortex revealed that Sglt1-2, Oat1-3, and Oct1 were higher expressed in kidneys of lean females. Oct2 and Mrp2 were higher expressed in obese males. Renal mRNA levels of transporters were reduced with diabetic nephropathy in females and the expression of transcription factors Hnf1β and Hnf4α in both sexes. The highest difference between lean and obese ZSF1 rats was found for Oat2. Therefore, we have tested the interaction of human OAT2 with various substances using tritium-labeled cGMP. Human OAT2 showed no interaction with diabetes-related metabolites, diabetic drugs, and ACE-inhibitors. However, OAT2-dependent uptake of cGMP was inhibited by furosemide. The strongly decreased expression of Oat2 and other transporters in female diabetic ZSF1 rats could possibly impair renal drug excretion, for example, of furosemide.

  14. Using Molecular Biology to Develop Drugs for Renal Cell Carcinoma

    Science.gov (United States)

    Cowey, C. Lance; Rathmell, W. Kimryn

    2010-01-01

    Background Renal cell carcinoma is a disease marked by a unique biology which has governed it’s long history of poor response to conventional cancer treatments. The discovery of the signaling pathway activated as a result of inappropriate constitutive activation of the hypoxia inducible factors (HIF), transcription factors physiologically and transiently stabilized in response to low oxygen, has provided a primary opportunity to devise treatment strategies to target this oncogenic pathway. Objective A review of the molecular pathogenesis of renal cell cancer as well as molecularly targeted therapies, both those currently available and those in development, will be provided. In addition, trials involving combination or sequential targeted therapy are discussed. Methods A detailed review of the literature describing the molecular biology of renal cell cancer and novel therapies was performed and summarized. Results/Conclusion Therapeutics targeting angiogenesis have provided the first class of agents which provide clinical benefit in a large majority of patients and heralded renal cell carcinoma as a solid tumor paradigm for the development of novel therapeutics. Multiple strategies targeting this pathway and now other identified pathways in renal cell carcinoma provide numerous potential opportunities to make major improvements in treating this historically devastating cancer. PMID:20648240

  15. Understanding renal replacement therapy and dosing of drugs in pediatric patients with kidney disease.

    Science.gov (United States)

    Zuppa, Athena F

    2012-01-01

    Multifaceted factors need to be considered when prescribing renal replacement therapy (RRT) and dosing of drugs in pediatric patients with kidney disease. RRTs in pediatrics such as intermittent hemodialysis, continuous venovenous hemofiltration, continuous venovenous hemodialysis, and continuous venovenous hemodiafiltration affect solute and drug clearance. Drug properties such as molecular weight, molecular charge, volume of distribution, and protein binding affect drug clearance. RRT prescription parameters such as blood flow rate, ultrafiltration rate, membrane size, and pore size can also influence drug clearance. Furthermore, the pediatric patient presents additional concerns because of developmental factors in children that affect both pharmacokinetics of drugs.

  16. Development of Human Membrane Transporters: Drug Disposition and Pharmacogenetics.

    Science.gov (United States)

    Mooij, Miriam G; Nies, Anne T; Knibbe, Catherijne A J; Schaeffeler, Elke; Tibboel, Dick; Schwab, Matthias; de Wildt, Saskia N

    2016-05-01

    Membrane transporters play an essential role in the transport of endogenous and exogenous compounds, and consequently they mediate the uptake, distribution, and excretion of many drugs. The clinical relevance of transporters in drug disposition and their effect in adults have been shown in drug-drug interaction and pharmacogenomic studies. Little is known, however, about the ontogeny of human membrane transporters and their roles in pediatric pharmacotherapy. As they are involved in the transport of endogenous substrates, growth and development may be important determinants of their expression and activity. This review presents an overview of our current knowledge on human membrane transporters in pediatric drug disposition and effect. Existing pharmacokinetic and pharmacogenetic data on membrane substrate drugs frequently used in children are presented and related, where possible, to existing ex vivo data, providing a basis for developmental patterns for individual human membrane transporters. As data for individual transporters are currently still scarce, there is a striking information gap regarding the role of human membrane transporters in drug therapy in children.

  17. Effect of reduced renal mass on renal ammonia transporter family, Rh C glycoprotein and Rh B glycoprotein, expression.

    Science.gov (United States)

    Kim, Hye-Young; Baylis, Chris; Verlander, Jill W; Han, Ki-Hwan; Reungjui, Sirirat; Handlogten, Mary E; Weiner, I David

    2007-10-01

    Kidneys can maintain acid-base homeostasis, despite reduced renal mass, through adaptive changes in net acid excretion, of which ammonia excretion is the predominant component. The present study examines whether these adaptations are associated with changes in the ammonia transporter family members, Rh B glycoprotein (Rhbg) and Rh C glycoprotein (Rhcg). We used normal Sprague-Dawley rats and a 5/6 ablation-infarction model of reduced renal mass; control rats underwent sham operation. After 1 wk, glomerular filtration rate, assessed as creatinine clearance, was decreased, serum bicarbonate was slightly increased, and Na(+) and K(+) were unchanged. Total urinary ammonia excretion was unchanged, but urinary ammonia adjusted for creatinine clearance, an index of per nephron ammonia metabolism, increased significantly. Although reduced renal mass did not alter total Rhcg protein expression, both light microscopy and immunohistochemistry with quantitative morphometric analysis demonstrated hypertrophy of both intercalated cells and principal cells in the cortical and outer medullary collecting duct that was associated with increased apical and basolateral Rhcg polarization. Rhbg expression, analyzed using immunoblot analysis, immunohistochemistry, and measurement of cell-specific expression, was unchanged. We conclude that altered subcellular localization of Rhcg contributes to adaptive changes in single-nephron ammonia metabolism and maintenance of acid-base homeostasis in response to reduced renal mass.

  18. Role of Renal Drug Exposure in Polymyxin B-Induced Nephrotoxicity

    Science.gov (United States)

    Manchandani, Pooja; Zhou, Jian; Babic, Jessica T.; Ledesma, Kimberly R.; Truong, Luan D.

    2017-01-01

    ABSTRACT Despite dose-limiting nephrotoxic potentials, polymyxin B has reemerged as the last line of therapy against multidrug-resistant Gram-negative bacterial infections. However, the handling of polymyxin B by the kidneys is still not thoroughly understood. The objectives of this study were to evaluate the impact of renal polymyxin B exposure on nephrotoxicity and to explore the role of megalin in renal drug accumulation. Sprague-Dawley rats (225 to 250 g) were divided into three dosing groups, and polymyxin B was administered (5 mg/kg, 10 mg/kg, and 20 mg/kg) subcutaneously once daily. The onset of nephrotoxicity over 7 days and renal drug concentrations 24 h after the first dose were assessed. The effects of sodium maleate (400 mg/kg intraperitoneally) on megalin homeostasis were evaluated by determining the urinary megalin concentration and electron microscopic study of renal tissue. The serum/renal pharmacokinetics of polymyxin B were assessed in megalin-shedding rats. The onset of nephrotoxicity was correlated with the daily dose of polymyxin B. Renal polymyxin B concentrations were found to be 3.6 ± 0.4 μg/g, 9.9 ± 1.5 μg/g, and 21.7 ± 4.8 μg/g in the 5-mg/kg, 10-mg/kg, and 20-mg/kg dosing groups, respectively. In megalin-shedding rats, the serum pharmacokinetics of polymyxin B remained unchanged, but the renal exposure was attenuated by 40% compared to that of control rats. The onset of polymyxin B-induced nephrotoxicity is correlated with the renal drug exposure. In addition, megalin appears to play a pivotal role in the renal accumulation of polymyxin B, which might contribute to nephrotoxicity. PMID:28096166

  19. Role of Renal Drug Exposure in Polymyxin B-Induced Nephrotoxicity.

    Science.gov (United States)

    Manchandani, Pooja; Zhou, Jian; Babic, Jessica T; Ledesma, Kimberly R; Truong, Luan D; Tam, Vincent H

    2017-04-01

    Despite dose-limiting nephrotoxic potentials, polymyxin B has reemerged as the last line of therapy against multidrug-resistant Gram-negative bacterial infections. However, the handling of polymyxin B by the kidneys is still not thoroughly understood. The objectives of this study were to evaluate the impact of renal polymyxin B exposure on nephrotoxicity and to explore the role of megalin in renal drug accumulation. Sprague-Dawley rats (225 to 250 g) were divided into three dosing groups, and polymyxin B was administered (5 mg/kg, 10 mg/kg, and 20 mg/kg) subcutaneously once daily. The onset of nephrotoxicity over 7 days and renal drug concentrations 24 h after the first dose were assessed. The effects of sodium maleate (400 mg/kg intraperitoneally) on megalin homeostasis were evaluated by determining the urinary megalin concentration and electron microscopic study of renal tissue. The serum/renal pharmacokinetics of polymyxin B were assessed in megalin-shedding rats. The onset of nephrotoxicity was correlated with the daily dose of polymyxin B. Renal polymyxin B concentrations were found to be 3.6 ± 0.4 μg/g, 9.9 ± 1.5 μg/g, and 21.7 ± 4.8 μg/g in the 5-mg/kg, 10-mg/kg, and 20-mg/kg dosing groups, respectively. In megalin-shedding rats, the serum pharmacokinetics of polymyxin B remained unchanged, but the renal exposure was attenuated by 40% compared to that of control rats. The onset of polymyxin B-induced nephrotoxicity is correlated with the renal drug exposure. In addition, megalin appears to play a pivotal role in the renal accumulation of polymyxin B, which might contribute to nephrotoxicity. Copyright © 2017 American Society for Microbiology.

  20. Transportation and retention in outpatient drug abuse treatment programs.

    Science.gov (United States)

    Friedmann, P D; Lemon, S C; Stein, M D

    2001-09-01

    To determine whether certain types of transportation assistance improve outpatient treatment retention beyond thresholds shown to have therapeutic benefits, we analyzed data from 1,144 clients in 22 outpatient methadone maintenance (OMM) programs and 2,031 clients in 22 outpatient drug-free (ODF) programs in the Drug Abuse Treatment Outcomes Study (DATOS), a national, 12-month, longitudinal study of drug abuse treatment programs. Directors' surveys provided information about provision of car, van, or contracted transportation services or individual vouchers/payment for public transportation. Chart-abstracted treatment retention was dichotomized at 365 days for OMM and 90 days for ODF. Separate multivariate hierarchical linear models revealed that provision of car, van, or contracted transportation services improved treatment retention beyond these thresholds for both OMM and ODF, but individual vouchers or payment for public transportation did not. Future research should validate whether car, van, or contracted transportation services improve retention and other treatment outcomes in outpatient drug abuse treatment.

  1. Stereoselectivity of chiral drug transport: a focus on enantiomer-transporter interaction.

    Science.gov (United States)

    Zhou, Quan; Yu, Lu-Shan; Zeng, Su

    2014-08-01

    Drug transporters and drug metabolism enzymes govern drug absorption, distribution, metabolism and elimination. Many literature works presenting important aspects related to stereochemistry of drug metabolism are available. However, there is very little literature on stereoselectivity of chiral drug transport and enantiomer-transporter interaction. In recent years, the experimental research within this field showed good momentum. Herein, an up-to-date review on this topic was presented. Breast Cancer Resistance Protein (BCRP), Multidrug Resistance Proteins (MRP), P-glycoprotein (P-gp), Organic Anion Transporters (OATs), Organic Anion Transporting Polypeptides (OATPs), Organic Cation Transporters (OCTs), Peptide Transport Proteins (PepTs), Human Proton-Coupled Folate Transporter (PCFT) and Multidrug and Toxic Extrusion Proteins (MATEs), have been reported to exhibit either positive or negative enantio-selective substrate recognition. The approaches utilized to study chirality in enantiomer-transporter interaction include inhibition experiments of specific transporters in cell models (e.g. Caco-2 cells), transport study using drug resistance cell lines or transgenic cell lines expressing transporters in wild type or variant, the use of transporter knockout mice, pharmacokinetics association of single nucleotide polymorphism in transporters, pharmacokinetic interaction study of racemate in the presence of specific transporter inhibitor or inducer, molecule cellular membrane affinity chromatography and pharmacophore modeling. Enantiomer-enantiomer interactions exist in chiral transport. The strength and/or enantiomeric preference of stereoselectivity may be species or tissue-specific, concentration-dependent and transporter family member-dependent. Modulation of specific drug transporter by pure enantiomers might exhibit opposite stereoselectivity. Further studies with integrated approaches will open up new horizons in stereochemistry of pharmacokinetics.

  2. Renal Transport of Uric Acid: Evolving Concepts and Uncertainties

    OpenAIRE

    Bobulescu, Ion Alexandru; Moe, Orson W.

    2012-01-01

    In addition to its role as a metabolic waste product, uric acid has been proposed to be an important molecule with multiple functions in human physiology and pathophysiology and may be linked to human diseases beyond nephrolithiasis and gout. Uric acid homeostasis is determined by the balance between production, intestinal secretion, and renal excretion. The kidney is an important regulator of circulating uric acid levels, by reabsorbing around 90% of filtered urate, while being responsible f...

  3. Role of monocarboxylate transporters in drug delivery to the brain.

    Science.gov (United States)

    Vijay, Nisha; Morris, Marilyn E

    2014-01-01

    Monocarboxylate transporters (MCTs) are known to mediate the transport of short chain monocarboxylates such as lactate, pyruvate and butyrate. Currently, fourteen members of this transporter family have been identified by sequence homology, of which only the first four members (MCT1- MCT4) have been shown to mediate the proton-linked transport of monocarboxylates. Another transporter family involved in the transport of endogenous monocarboxylates is the sodium coupled MCTs (SMCTs). These act as a symporter and are dependent on a sodium gradient for their functional activity. MCT1 is the predominant transporter among the MCT isoforms and is present in almost all tissues including kidney, intestine, liver, heart, skeletal muscle and brain. The various isoforms differ in terms of their substrate specificity and tissue localization. Due to the expression of these transporters in the kidney, intestine, and brain, they may play an important role in influencing drug disposition. Apart from endogenous short chain monocarboxylates, they also mediate the transport of exogenous drugs such as salicylic acid, valproic acid, and simvastatin acid. The influence of MCTs on drug pharmacokinetics has been extensively studied for γ-hydroxybutyrate (GHB) including distribution of this drug of abuse into the brain and the results will be summarized in this review. The physiological role of these transporters in the brain and their specific cellular localization within the brain will also be discussed. This review will also focus on utilization of MCTs as potential targets for drug delivery into the brain including their role in the treatment of malignant brain tumors.

  4. Mangiferin Inhibits Renal Urate Reabsorption by Modulating Urate Transporters in Experimental Hyperuricemia.

    Science.gov (United States)

    Yang, Hua; Gao, Lihui; Niu, Yanfen; Zhou, Yuanfang; Lin, Hua; Jiang, Jing; Kong, Xiangfu; Liu, Xu; Li, Ling

    2015-01-01

    Mangiferin, a natural glucosyl xanthone from the leaves of Mangifera indica L., was previously shown to exert potent hypouricemic effects associated with inhibition of the activity of xanthine dehydrogenase/oxidase. The present study aimed to evaluate its uricosuric effect and possible molecular mechanisms underlying the renal urate transporters responsible for urate reabsorption in vivo. Mangiferin (1.5-24.0 mg/kg) was administered intragastrically to hyperuricemic mice and rats induced by the intraperitoneal injection of uric acid and potassium oxonate, respectively. The uricosuric effect was evaluated by determining the serum and urinary urate levels as well as fractional excretion of uric acid (FEUA). The mRNA and protein levels of renal urate-anion transporter 1 (URAT1), organic anion transporter 10 (OAT10), glucose transporter 9 (GLUT9), and PDZ domain-containing protein (PDZK1) were analyzed. The administration of mangiferin significantly decreased the serum urate levels in hyperuricemic mice in a dose- and time-dependent manner. In hyperuricemic rats, mangiferin also reduced the serum urate levels and increased the urinary urate levels and FEUA. These results indicate that mangiferin has uricosuric effects. Further examination showed that mangiferin markedly inhibited the mRNA and protein expression of renal URAT1, OAT10, and GLUT9 in hyperuricemic rats, but did not interfere with PDZK1 expression. Taken together, these findings suggest that mangiferin promotes urate excretion by the kidney, which may be related to the inhibition of urate reabsorption via downregulation of renal urate transporters.

  5. Drug-related acute renal failure in hospitalised patients

    Directory of Open Access Journals (Sweden)

    Lujan Iavecchia

    2015-11-01

    Conclusions: Half of ARF episodes during hospitalisation were drug related. Patients with drug-related ARF had higher cardiovascular morbidity than those with ARF related to other causes, but they had a lower frequency of ARF risk factors and mortality.

  6. Effect of chronic accumulation of aluminum on renal function, cortical renal oxidative stress and cortical renal organic anion transport in rats.

    Science.gov (United States)

    Mahieu, Stella T; Gionotti, Marisa; Millen, Néstor; Elías, María Mónica

    2003-11-01

    The aim of the present work was to study the nephrotoxicity of aluminum lactate administered for 3 months (0.57 mg/100 g bodyweight aluminum, i.p., three times per week) to male Wistar rats. Renal function was studied after 6 weeks of treatment (urine was obtained from rats in metabolic cages) and at the end of the treatment using clearance techniques. Another group of rats was used as kidneys donors at the end of treatment. The renal cortex was separated and homogenized to determine glutathione (GSH) level, glutathione S-transferase (GST) activity and lipid peroxidation (LPO) level. Renal cortex slices were also used to study the p-aminohippuric acid (PAH) accumulation during steady-state conditions and the kinetics of uptake process. Clearance results, at the end of the treatment, indicated that renal functions in treated-rats were not different from those measured in control rats, although the renal concentration parameters differ when they were measured in treated rats after 24 h of food and water deprivation. Balances of water and sodium were also modified at both 1.5 and 3 months of treatment. The activity of alkaline phosphatase (AP) relative to inulin excreted in urine was significantly impaired: controls 2.2+/-0.6 IUI/mg, Al-treated 5.1+/-0.5 IU/mg, Prats. Renal accumulation of PAH, estimated as slice-to-medium ratio, decreased significantly in the Al-treated rats: control rats 3.06+/-0.02 ( n=12), Al-treated rats 2.26+/-0.04 ( n=12), Prats, while the apparent affinity remained unchanged. All these results indicate that aluminum accumulation in renal tissue affects cellular metabolism, promotes oxidative stress and induces alterations in renal tubular PAH transport, together with an impairment in sodium and water balance only detected under conditions of water deprivation, without other evident changes in glomerular filtration rate or other global functions measured by clearance techniques at least at this time of chronic toxicity.

  7. Roles of Akt and SGK1 in the Regulation of Renal Tubular Transport

    Directory of Open Access Journals (Sweden)

    Nobuhiko Satoh

    2015-01-01

    Full Text Available A serine/threonine kinase Akt is a key mediator in various signaling pathways including regulation of renal tubular transport. In proximal tubules, Akt mediates insulin signaling via insulin receptor substrate 2 (IRS2 and stimulates sodium-bicarbonate cotransporter (NBCe1, resulting in increased sodium reabsorption. In insulin resistance, the IRS2 in kidney cortex is exceptionally preserved and may mediate the stimulatory effect of insulin on NBCe1 to cause hypertension in diabetes via sodium retention. Likewise, in distal convoluted tubules and cortical collecting ducts, insulin-induced Akt phosphorylation mediates several hormonal signals to enhance sodium-chloride cotransporter (NCC and epithelial sodium channel (ENaC activities, resulting in increased sodium reabsorption. Serum- and glucocorticoid-inducible kinase 1 (SGK1 mediates aldosterone signaling. Insulin can stimulate SGK1 to exert various effects on renal transporters. In renal cortical collecting ducts, SGK1 regulates the expression level of ENaC through inhibition of its degradation. In addition, SGK1 and Akt cooperatively regulate potassium secretion by renal outer medullary potassium channel (ROMK. Moreover, sodium-proton exchanger 3 (NHE3 in proximal tubules is possibly activated by SGK1. This review focuses on recent advances in understanding of the roles of Akt and SGK1 in the regulation of renal tubular transport.

  8. ROLE OF TRANSPORTERS IN THE DISTRIBUTION OF PLATINUM-BASED DRUGS

    Directory of Open Access Journals (Sweden)

    Saliha eHarrach

    2015-04-01

    Full Text Available Platinum derivatives used as chemotherapeutic drugs such as cisplatin and oxaliplatin have a potent antitumor activity. However, severe side effects such as nephro-, oto-, and neurotoxicity are associated with their use. Effects and side effects of platinum-based drugs are in part caused by their transporter-mediated uptake in target and non target cells. In this mini review, the transport systems involved in cellular handling of platinum derivatives are illustrated, focusing on transporters for cisplatin. The copper transporter 1 seems to be of particular importance for cisplatin uptake in tumor cells, while the organic cation transporter (OCT 2, due to its specific organ distribution, may play a major role in the development of undesired cisplatin side effects. In polarized cells, e.g. in renal proximal tubule cells, apically expressed transporters, such as multidrug and toxin extrusion protein 1, mediate secretion of cisplatin and in this way contribute to the control of its toxic effects. Specific inhibition of cisplatin uptake transporters such as the OCTs may be an attractive therapeutic option to reduce its toxicity, without impairing its antitumor efficacy.

  9. Non-urate transporter 1-related renal hypouricemia and acute renal failure in an Israeli-Arab family.

    Science.gov (United States)

    Bahat, Hilla; Dinour, Dganit; Ganon, Liat; Feldman, Leonid; Holtzman, Eli J; Goldman, Michael

    2009-05-01

    Idiopathic renal hypouricemia (IRHU) is a rare hereditary disease, predisposing the individual to exercise-induced acute renal failure (EIARF) and nephrolithiasis, and it is characterized by increased clearance of renal uric acid. Most of the described patients are Japanese, who have loss-of-function mutations in the SLC22A12 gene coding for the human urate transporter 1 (URAT1) gene. An 18-year-old youth, who was admitted for EIARF due to IRHU, and six consanguineous Israeli-Arab family members were included in the study. The family members were tested for fractional excretion of uric acid and molecular analysis of the URAT1 gene. Four family members, including the proband, had very low levels of blood uric acid and high rate of fractional excretion (FE urate> 100%) of uric acid. Genetic analysis of the affected family members did not reveal a mutation in the coding regions and intron-exon boundaries of SCL22A12. Haplotype analysis excluded SCL22A12 involvement in the pathogenesis, suggesting a different gene as a cause of the disease. We herein describe the first Israeli-Arab family with IRHU. A non-URAT1 genetic defect that causes decreased reabsorption or, more probably, increased secretion of uric acid, induces IRHU. Further studies are required in order to elucidate the genetic defect.

  10. Testosterone increases urinary calcium excretion and inhibits expression of renal calcium transport proteins

    DEFF Research Database (Denmark)

    Hsu, Yu-Juei; Dimke, Henrik Anthony; Schoeber, Joost P H

    2010-01-01

    . Androgen deficiency increased the abundance of the renal mRNA and protein of both the luminal transient receptor potential vanilloid-subtype 5 (TRPV5) and intracellular calbindin-D(28K) transporters, which in turn were suppressed by testosterone treatment. There were no significant differences in serum...

  11. An Active Learning Exercise to Facilitate Understanding of Nephron Function: Anatomy and Physiology of Renal Transporters

    Science.gov (United States)

    Dirks-Naylor, Amie J.

    2016-01-01

    Renal transport is a central mechanism underlying electrolyte homeostasis, acid base balance and other essential functions of the kidneys in human physiology. Thus, knowledge of the anatomy and physiology of the nephron is essential for the understanding of kidney function in health and disease. However, students find this content difficult to…

  12. An Active Learning Exercise to Facilitate Understanding of Nephron Function: Anatomy and Physiology of Renal Transporters

    Science.gov (United States)

    Dirks-Naylor, Amie J.

    2016-01-01

    Renal transport is a central mechanism underlying electrolyte homeostasis, acid base balance and other essential functions of the kidneys in human physiology. Thus, knowledge of the anatomy and physiology of the nephron is essential for the understanding of kidney function in health and disease. However, students find this content difficult to…

  13. Effect of Diuretics on Renal Tubular Transport of Calcium and Magnesium

    DEFF Research Database (Denmark)

    Alexander, R Todd; Dimke, Henrik

    2017-01-01

    of clinical conditions, but most commonly for the management of blood pressure and fluid balance. The pharmacological targets of diuretics generally directly facilitate sodium (Na+) transport, but also indirectly affect renal Ca2+ and Mg2+ handling, i.e. by establishing a prerequisite electrochemical gradient...

  14. ABC transporters in anticancer drug transport – Less ons for Therapy, Drug Development and Delivery Systems

    Directory of Open Access Journals (Sweden)

    Suresh P.K

    2015-03-01

    Full Text Available The structural aspects as well as the classification of the ABC superfamily (the largest group of transmembrane proteins has been highlighted. Over-expression of one or more of these transporters, barring exceptions, can correlate with an increased drug resistance (the multidrug resistance phenotype. Hence, studying these proteins, using experimental and in silico approaches, has tremendous benefit for patient selection as well as stratification into “good” and “poor” drug responders. Further, the need to obtain a better insight into “intrinsic” and “extrinsic” mechanisms of resistance were reiterated upon, based on the relative recruitment of the different signal transduction molecules. The concept of the reversal of the MDR phenotype, has been discussed and extended in the context of combination therapy. This form of therapy involves the use of a cocktail of synthetic and biopharmaceutical drugs as well as nanotechnology-based approaches, for improvements in their pharmacokinetic (PK and pharmacodynamic (PD profile. Such strategies have targeted the heterogeneous cancer and cancer stem cells, signaling molecules, marker enzymes as well as the microenvironment for improved efficacy and safety as well as to minimize the chance of relapse

  15. [Pharmacokinetic principles and drug-dosing adjustments during continuous renal replacement therapies (CRRT)].

    Science.gov (United States)

    Morabito, S; Guzzo, I; Vitaliano, E; Muzi, L; Solazzo, A; Pistolesi, V; Pierucci, A

    2006-01-01

    In the critically ill, acute renal failure (ARF) and "Multiple Organ Dysfunction Syndrome" (MODS) can be associated with significant modifications of many pharmacokinetic parameters, such as protein binding, volume of distribution and total body clearance. The start of renal replacement therapy (RRT) represents an additional variable to take in consideration for drug-dosing adjustments. Drugs significantly eliminated by the kidney are likely to be removed during RRT and a supplemental dose or further dosing adjustments are required if extracorporeal clearance is more than 25-30% of total body clearance. The impact of RRT on plasma drug concentrations can be substantially different in relation to the type of treatment (diffusive, convective or both), membrane characteristics (low-flux or high-flux), filter surface area and prescribed dialysis dose. The molecular weight cut-offs of high-flux membrane are much higher than the molecular weight of most drugs. Therefore, molecular size will not be a limitation for the removal of the unbound fraction of the drugs most commonly used in the critically ill undergoing continuous renal replacement therapy (CRRT). However, diffusive clearance could be significantly lower than convective clearance for drugs in the middle molecular weight range. In any case, the extracorporeal clearances report-ed with the use of high-volume CRRT (>50-60 L/2 h) are often surprisingly elevated and can lead to drug underdosing in clinical conditions where adequate antibiotic treatment is essential.

  16. Renal Safety of Canagliflozin, a Sodium Glucose Co-transporter 2 Inhibitor, in Patients With Type 2 Diabetes Mellitus.

    Science.gov (United States)

    Desai, Mehul; Yavin, Yshai; Balis, Dainius; Sun, Don; Xie, John; Canovatchel, William; Rosenthal, Norm

    2017-01-12

    The incidence of renal-related adverse events (AEs) with canagliflozin in patients with type 2 diabetes mellitus from a pooled population of patients in 7 active- and placebo-controlled trials (N = 5,598) and in a 104-week study versus glimepiride (N = 1,450) was low and similar in canagliflozin and non-canagliflozin groups. In the study versus glimepiride, canagliflozin was associated with an initial acute decrease in estimated glomerular filtration rate (eGFR) that attenuated over time, while eGFR declined progressively over 104 weeks with glimepiride; the incidence of renal-related AEs with canagliflozin was generally stable over time, while the incidence with glimepiride increased over 104 weeks. In the analysis reported in this manuscript based on postmarketing reports from the US Food and Drug Administration Adverse Event Reporting System, a potential signal was identified for acute kidney injury with all approved sodium glucose co-transporter 2 (SGLT2) inhibitors (ie, canagliflozin, dapagliflozin, empagliflozin). The early onset of acute kidney injury events with SGLT2 inhibitors in postmarketing reports likely reflects the acute changes in eGFR due to the known renal haemodynamic effects of SGLT2 inhibition.

  17. Transport of peptidomimetic drugs by the intestinal Di/tri-peptide transporter, PepT1

    DEFF Research Database (Denmark)

    Brodin, Birger; Nielsen, Carsten Uhd; Steffansen, Bente;

    2002-01-01

    peptide transport mechanism and enter the systemic circulation. As the number of new peptide and peptidomimetic drugs are rapidly increasing, the peptide transport system has gained increasing attention as a possible drug delivery system for small peptides and peptide-like compounds. In this paper we give...... capable of transporting a number of orally administered peptidomimetic drugs. Absorbed peptides may be hydrolysed in the cells due to the high peptidase activity present in the cytosol. Peptidomimetic drugs may, if resistant to the cellular enzyme activity, pass the basolateral membrane via a basolateral...

  18. Yohimbine-induced cutaneous drug eruption, progressive renal failure, and lupus-like syndrome.

    Science.gov (United States)

    Sandler, B; Aronson, P

    1993-04-01

    Yohimbine is an indole alkaloid obtained from the yohimbe tree, a common tree in West Africa. We describe a forty-two-year black man in whom a generalized erythrodermic skin eruption, progressive renal failure, and lupus-like syndrome developed following treatment with the drug, yohimbine. A literature review failed to reveal any reported association of these side effects. We review current information on yohimbine's use in male impotence, reported side effects, and its role as a drug allergen.

  19. Divide and conquer: processive transport enables multidrug transporters to tackle challenging drugs.

    Science.gov (United States)

    Fluman, Nir; Bibi, Eitan

    2014-09-23

    Multidrug transporters are membrane proteins that catalyze efflux of antibiotics and other toxic compounds from cells, thereby conferring drug resistance on various organisms. Unlike most solute transporters that transport a single type of compound or similar analogues, multidrug transporters are extremely promiscuous. They transport a broad spectrum of dissimilar drugs and represent a serious obstacle to antimicrobial or anticancer chemotherapy. Many challenging aspects of multidrug transporters, which are unique, have been studied in detail, including their ability to interact with chemically unrelated drugs, and how they utilize energy to drive efflux of compounds that are not only structurally but electrically different. A new and surprising dimension of the promiscuous nature of multidrug transporters has been described recently: they can move long molecules through the membrane in a processive manner.

  20. Divide and conquer: processive transport enables multidrug transporters to tackle challenging drugs

    Directory of Open Access Journals (Sweden)

    Nir Fluman

    2014-09-01

    Full Text Available Multidrug transporters are membrane proteins that catalyze efflux of antibiotics and other toxic compounds from cells, thereby conferring drug resistance on various organisms. Unlike most solute transporters that transport a single type of compound or similar analogues, multidrug transporters are extremely promiscuous. They transport a broad spectrum of dissimilar drugs and represent a serious obstacle to antimicrobial or anticancer chemotherapy. Many challenging aspects of multidrug transporters, which are unique, have been studied in detail, including their ability to interact with chemically unrelated drugs, and how they utilize energy to drive efflux of compounds that are not only structurally but electrically different. A new and surprising dimension of the promiscuous nature of multidrug transporters has been described recently: they can move long molecules through the membrane in a processive manner.

  1. Hereditary tubular transport disorders: implications for renal handling of Ca2+ and Mg2+

    DEFF Research Database (Denmark)

    Dimke, Henrik; Hoenderop, Joost G; Bindels, René J;

    2010-01-01

    The kidney plays an important role in maintaining the systemic Ca2+ and Mg2+ balance. Thus the renal reabsorptive capacity of these cations can be amended to adapt to disturbances in plasma Ca2+ and Mg2+ concentrations. The reabsorption of Ca2+ and Mg2+ is driven by transport of other electrolytes......, sometimes through selective channels and often supported by hormonal stimuli. It is, therefore, not surprising that monogenic disorders affecting such renal processes may impose a shift in, or even completely blunt, the reabsorptive capacity of these divalent cations within the kidney. Accordingly, in Dent......'s disease, a disorder with defective proximal tubular transport, hypercalciuria is frequently observed. Dysfunctional thick ascending limb transport in Bartter's syndrome, familial hypomagnesaemia with hypercalciuria and nephrocalcinosis, and diseases associated with Ca2+-sensing receptor defects, markedly...

  2. [Drug utilization in renal transplant patients: medication practices and representations].

    Science.gov (United States)

    de Arruda, Guilherme Oliveira; Renovato, Rogério Dias

    2012-12-01

    Qualitative research approach, descriptive and exploratory with objective of to know the practices and representations of medication on the use of drugs by people transplanted kidney. 18 people participated in the Dourados (MS), through semistructured interview. The theoretical contributions of medication practices were Peter Conrad and representation of Stuart Hall. The definition of the categories of theoretical analysis was Michel Foucault. Respondents had a mean age of 53.5 years, 13 males and 5 females, with median time to transplant eight years. The medications predominantly used were immunosuppresssive. We developed three categories of analysis: the drug as part of everyday life, the central role of the drug and correlation with rejection, and medicine and the autonomy of the transplanted kidney. The drugs are part of everyday life and the representations of autonomy and quality enhance your daily use.

  3. Effect of selected ABC-drug transporters and anticancer drug disposition in vitro and in vivo

    NARCIS (Netherlands)

    Marchetti, S.

    2013-01-01

    Studies described in the thesis that is lying in front of you aim to address the possible implications of selected ABC-drug transporters on the disposition of a number of important anticancer drugs. Although variability in drug disposition has been known for as long as pharmacological studies

  4. Atrial Natriuretic Peptide Stimulates Dopamine Tubular Transport by Organic Cation Transporters: A Novel Mechanism to Enhance Renal Sodium Excretion

    Science.gov (United States)

    Kouyoumdzian, Nicolás M.; Rukavina Mikusic, Natalia L.; Kravetz, María C.; Lee, Brenda M.; Carranza, Andrea; Del Mauro, Julieta S.; Pandolfo, Marcela; Gironacci, Mariela M.; Gorzalczany, Susana; Toblli, Jorge E.; Fernández, Belisario E.

    2016-01-01

    The aim of this study was to demonstrate the effects of atrial natriuretic peptide (ANP) on organic cation transporters (OCTs) expression and activity, and its consequences on dopamine urinary levels, Na+, K+-ATPase activity and renal function. Male Sprague Dawley rats were infused with isotonic saline solution during 120 minutes and randomized in nine different groups: control, pargyline plus tolcapone (P+T), ANP, dopamine (DA), D-22, DA+D-22, ANP+D-22, ANP+DA and ANP+DA+D-22. Renal functional parameters were determined and urinary dopamine concentration was quantified by HPLC. Expression of OCTs and D1-receptor in membrane preparations from renal cortex tissues were determined by western blot and Na+, K+-ATPase activity was determined using in vitro enzyme assay. 3H-DA renal uptake was determined in vitro. Compared to P+T group, ANP and dopamine infusion increased diuresis, urinary sodium and dopamine excretion significantly. These effects were more pronounced in ANP+DA group and reversed by OCTs blockade by D-22, demonstrating that OCTs are implied in ANP stimulated-DA uptake and transport in renal tissues. The activity of Na+, K+-ATPase exhibited a similar fashion when it was measured in the same experimental groups. Although OCTs and D1-receptor protein expression were not modified by ANP, OCTs-dependent-dopamine tubular uptake was increased by ANP through activation of NPR-A receptor and protein kinase G as signaling pathway. This effect was reflected by an increase in urinary dopamine excretion, natriuresis, diuresis and decreased Na+, K+-ATPase activity. OCTs represent a novel target that links the activity of ANP and dopamine together in a common mechanism to enhance their natriuretic and diuretic effects. PMID:27392042

  5. Atrial Natriuretic Peptide Stimulates Dopamine Tubular Transport by Organic Cation Transporters: A Novel Mechanism to Enhance Renal Sodium Excretion.

    Directory of Open Access Journals (Sweden)

    Nicolás M Kouyoumdzian

    Full Text Available The aim of this study was to demonstrate the effects of atrial natriuretic peptide (ANP on organic cation transporters (OCTs expression and activity, and its consequences on dopamine urinary levels, Na+, K+-ATPase activity and renal function. Male Sprague Dawley rats were infused with isotonic saline solution during 120 minutes and randomized in nine different groups: control, pargyline plus tolcapone (P+T, ANP, dopamine (DA, D-22, DA+D-22, ANP+D-22, ANP+DA and ANP+DA+D-22. Renal functional parameters were determined and urinary dopamine concentration was quantified by HPLC. Expression of OCTs and D1-receptor in membrane preparations from renal cortex tissues were determined by western blot and Na+, K+-ATPase activity was determined using in vitro enzyme assay. 3H-DA renal uptake was determined in vitro. Compared to P+T group, ANP and dopamine infusion increased diuresis, urinary sodium and dopamine excretion significantly. These effects were more pronounced in ANP+DA group and reversed by OCTs blockade by D-22, demonstrating that OCTs are implied in ANP stimulated-DA uptake and transport in renal tissues. The activity of Na+, K+-ATPase exhibited a similar fashion when it was measured in the same experimental groups. Although OCTs and D1-receptor protein expression were not modified by ANP, OCTs-dependent-dopamine tubular uptake was increased by ANP through activation of NPR-A receptor and protein kinase G as signaling pathway. This effect was reflected by an increase in urinary dopamine excretion, natriuresis, diuresis and decreased Na+, K+-ATPase activity. OCTs represent a novel target that links the activity of ANP and dopamine together in a common mechanism to enhance their natriuretic and diuretic effects.

  6. Prevention of Renal Complications Induced by Non- Steroidal Anti-Inflammatory Drugs.

    Science.gov (United States)

    Ković, Sonja Vuč; Vujović, Katarina Savić; Srebro, Dragana; Medić, Branislava; Ilic-Mostic, Tatjana

    2016-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed for the treatment of pain, inflamation and fever. They are usually well tolerated in healthy persons, but in patients with risk factors (advanced age, renal impairment, heart failure, liver disease, concurrent medications with antihypertensive drugs), NSAIDs can induce serious renal adverse effects. They include sodium and water retention with edema, worsening of heart failure, hypertension, hyponatremia, hyperkalemia, acute kidney injury, chronic kidney disease, renal papillary necrosis and acute interstitial nephritis. The majority of these adverse effects are due to the inhibition of prostaglandins synthesis and they are dose and duration-dependent. Acute forms of kidney injuries are transient and often reversible upon drug withdrawal. Chronic use of NSAIDs in some patients may result in chronic kidney disease. It is recommended that patients at risk should have preventative strategies in place, including the use of the "lowest effective dose" of NSAID for the "shortest possible time" and monitoring renal function, fluid retention and electrolyte abnormalities. Patients who are taking antihypertensive medications should be monitored for high blood pressure and the doses of antihypertensive medications should be adjusted if needed. In general, the combination of NSAIDs and angiotensin inhibitors should be avoided. Some other preventive measures are dietary salt restriction, use of topical NSAIDs/non-pharmacological therapies and use of calcium channel blockers for treating hypertension.

  7. Transportation of drug-gold nanocomposites by actinomyosin motor system

    Energy Technology Data Exchange (ETDEWEB)

    Kaur, Harsimran, E-mail: microsimbac@gmail.com; Chaudhary, Archana; Kaur, Inderpreet [Council of Scientific and Industrial Research (CSIR), Biomolecular Electronics and Nanotechnology Division (BEND), Central Scientific Instruments Organization - CSIO (India); Singh, Kashmir [Panjab University, Department of Biotechnology (India); Bharadwaj, Lalit M. [Council of Scientific and Industrial Research (CSIR), Biomolecular Electronics and Nanotechnology Division (BEND), Central Scientific Instruments Organization - CSIO (India)

    2011-06-15

    Nanotechnology is playing an important role in drug delivery to overcome limitations of conventional drug delivery systems in terms of solubility, in vivo stability, pharmacokinetics, and bio-distribution. The controlled transportation of drug into the cell and within the cell is a major challenge to be addressed. Cellular molecular motors have been exploited for their cargo carrying capacity for various applications including engineering and health care. Combination of nanotechnology and biomolecular motors can address some of the challenges in drug delivery. In the present study, transportation of drug nanocomposites has been demonstrated. Nanocomposites of 6-mercaptopurine and levodopa drugs (cancer and Parkinson's disease, respectively) were prepared with gold nanoparticles (GNPs) by covalent attachment and these nanocomposites were attached to actin filaments. These nanocomposites were in-turn transported by actin filaments on myosin tracks. Characterization of drug nanocomposites formation was done by UV-Vis spectroscopy, field emission scanning electron microscopy, transmission electron microscopy, and confocal microscopy. GNP composites of 6-mercaptopurine and levodopa were formed by sulfide and amide bond formation, respectively. Average velocity of actin filament attached to nanocomposites was found to be 3.17 and 3.89 {mu}m/s for levodopa and 6-mercaptopurine, respectively, as compared to actin filaments with velocity of 4.0-6.0 {mu}m/s. Three concepts have been proposed for the study of drug transportation into the cell based on polycationic complex formation, interaction of actin with cellular myosin and Biomolecular Adaptor for Retrograde Transport (BART) technology. The aspects of this study heads toward the development of an approach to utilize molecular motors for nanoscale transportation endogenously.

  8. Evaluation of drug therapy problems among renal patients receiving ...

    African Journals Online (AJOL)

    Pharmacotherapy Group, Faculty of Pharmacy, University of Benin, Benin City, ... Results: Out of 234 DTPs identified, 90 (38.46%) had drug choice problem, .... 71. 24.74. ˃ 100,000 Naira. 32. 11.15. Employment Status N = 287. Student. 13 ..... Arch Intern Med 1990; ... hospital inpatient care: Factors influencing identification.

  9. Upregulation of renal sodium transporters in D5 dopamine receptor-deficient mice.

    Science.gov (United States)

    Wang, Xiaoyan; Luo, Yingjin; Escano, Crisanto S; Yang, Zhiwei; Asico, Laureano; Li, Hewang; Jones, John E; Armando, Ines; Lu, Quansheng; Sibley, David R; Eisner, Gilbert M; Jose, Pedro A

    2010-06-01

    D(5) dopamine receptor (D(5)R)-deficient (D(5)(-/-)) mice have hypertension that is aggravated by an increase in sodium intake. The present experiments were designed to test the hypothesis that a dysregulation of renal sodium transporters is related to the salt sensitivity in D(5)(-/-) mice. D(5)R was expressed in the renal proximal tubule, thick ascending limb, distal convoluted tubule, and cortical and outer medullary collecting ducts in D(5)(+/+) mice. On a control Na(+) diet, renal protein expressions of NKCC2 (sodium-potassium-2 chloride cotransporter), sodium chloride cotransporter, and alpha and gamma subunits of the epithelial sodium channel were greater in D(5)(-/-) than in D(5)(+/+) mice. Renal renin abundance and urine aldosterone levels were similar but renal angiotensin II type 1 receptor (AT(1)R) protein expression was increased in D(5)(-/-) mice. An elevated Na(+) diet increased further the elevated blood pressure of D(5)(-/-) mice but did not affect the normal blood pressure of D(5)(+/+) mice. The increased levels of NKCC2, sodium chloride cotransporter, and alpha and gamma subunits of the epithelial sodium channel persisted with the elevated Na(+) diet and unaffected by chronic AT(1)R blockade (losartan) in D(5)(-/-) mice. The expressions of proximal sodium transporters NHE3 (sodium hydrogen exchanger type 3) and NaPi2 (sodium phosphate cotransporter type 2) were increased by the elevated Na(+) diet in D(5)(-/-) mice; the increased expression of NHE3 but not NaPi2 was abolished by AT(1)R blockade. Our findings suggest that the increased protein expression of sodium transporters/channels in distal nephron segments may be the direct consequence of the disruption of D(5)R, independent of the renin-angiotensin aldosterone system.

  10. Renal elimination of organic anions in cholestasis

    Institute of Scientific and Technical Information of China (English)

    Adriana Mónica Tortes

    2008-01-01

    The disposition of most drugs is highly dependent on specialized transporters.OAT1 and OAT3 are two organic anion transporters expressed in the basolateral membrane of renal proximal tubule cells,identified as contributors to xenobiotic and endogenous organic anion secretion.It is well known that cholestasis may cause renal damage.Impairment of kidney function produces modifications in the renal elimination of drugs.Recent studies have demonstrated that the renal abundance of OAT1 and OAT3 plays an important role in the renal elimination of organic anions in the presence of extrahepatic cholestasis.Time elapsed after obstructive cholestasis has an important impact on the regulation of both types of organic anion transporters.The renal expression of OAT1 and OAT3 should be taken into account in order to improve pharmacotherapeutic efficacy and to prevent drug toxicity during the onset of this hepatic disease.

  11. Functional expression of pig renal organic anion transporter 3 (pOAT3).

    Science.gov (United States)

    Hagos, Yohannes; Braun, Isabella M; Krick, Wolfgang; Burckhardt, Gerhard; Bahn, Andrew

    2005-05-01

    With the cloning of pig renal organic anion transporter 1 (pOAT1) (Biochimie 84 (2002) 1219) we set up a model system for comparative studies of cloned and natively isolated membrane located transport proteins. Meanwhile, another transport protein involved in p-aminohippurate (PAH) uptake on the basolateral side of the proximal tubule cells was identified, designated organic anion transporter 3 (OAT3). To explore the contribution of pOAT1 to the PAH clearance in comparison to OAT3, it was the aim of this study to extend our model by cloning of the pig ortholog of OAT3. Sequence comparisons of human organic anion transporter 3 (hOAT3) with the expressed sequence tag (EST) database revealed a clone and partial sequence of the pig renal organic anion transporter 3 (pOAT3) ortholog. Sequencing of the entire open reading frame resulted in a protein of 543 amino acid residues encoded by 1632 base pairs (EMBL Acc. No. AJ587003). It showed high homologies of 81%, 80%, 76%, and 77% to the human, rabbit, rat, and mouse OAT3, respectively. A functional characterization of pOAT3 in Xenopus laevis oocytes yielded an apparent Km (Kt) for [3H]estrone sulfate of 7.8 +/- 1.3 microM. Moreover, pOAT3 mediated [3H]estrone sulfate uptake was almost abolished by 0.5 mM of glutarate, dehydroepiandosterone sulfate, or probenecid consistent with the hallmarks of OAT3 function.

  12. Vasopressin regulation of the renal UT-A3 urea transporter.

    Science.gov (United States)

    Stewart, G S; Thistlethwaite, A; Lees, H; Cooper, G J; Smith, Craig

    2009-03-01

    Facilitative urea transporters in the mammalian kidney play a vital role in the urinary concentrating mechanism. The urea transporters located in the renal inner medullary collecting duct, namely UT-A1 and UT-A3, are acutely regulated by the antidiuretic hormone vasopressin. In this study, we investigated the vasopressin regulation of the basolateral urea transporter UT-A3 using an MDCK-mUT-A3 cell line. Within 10 min, vasopressin stimulates urea flux through UT-A3 transporters already present at the plasma membrane, via a PKA-dependent process. Within 1 h, vasopressin significantly increases UT-A3 localization at the basolateral membrane, causing a further increase in urea transport. While the basic trafficking of UT-A3 to basolateral membranes involves both protein kinase C and calmodulin, its regulation by vasopressin specifically occurs through a casein kinase II-dependent pathway. In conclusion, this study details the effects of vasopressin on UT-A3 urea transporter function and hence its role in regulating urea permeability within the renal inner medullary collecting duct.

  13. Use of nonsteroidal anti-inflammatory drugs prior to chronic renal replacement therapy initiation

    DEFF Research Database (Denmark)

    Fosbøl, Emil L; Kamper, Anne-Lise; Køber, Lars;

    2012-01-01

    PURPOSE: Nonsteroidal anti-inflammatory drugs (NSAIDs) may be associated with severe renal complications, including acute renal failure, reduced glomerular filtration rate and interstitial nephritis. Caution against NSAIDs is therefore recommended in advanced chronic kidney disease. In this study......, we examined NSAID use, aetiology and comorbidity among a national cohort of patients before the initiation of chronic renal replacement therapy (RRT). METHODS: Patients initiated on chronic RRT in the period 1997-2006 were identified in the Danish National Registry on Regular Dialysis...... and Transplantation, including etiological diagnosis. The use of NSAID before the start of RRT was studied by linkage to the National Prescription Register and comorbidity by linkage to the National Patient Registry. RESULTS: A total of 6663 patients were included in the study, and 2407 patients (36.1%) were...

  14. Human membrane transporter database: a Web-accessible relational database for drug transport studies and pharmacogenomics.

    Science.gov (United States)

    Yan, Q; Sadée, W

    2000-01-01

    The human genome contains numerous genes that encode membrane transporters and related proteins. For drug discovery, development, and targeting, one needs to know which transporters play a role in drug disposition and effects. Moreover, genetic polymorphisms in human membrane transporters may contribute to interindividual differences in the response to drugs. Pharmacogenetics, and, on a genome-wide basis, pharmacogenomics, address the effect of genetic variants on an individual's response to drugs and xenobiotics. However, our knowledge of the relevant transporters is limited at present. To facilitate the study of drug transporters on a broad scale, including the use of microarray technology, we have constructed a human membrane transporter database (HMTD). Even though it is still largely incomplete, the database contains information on more than 250 human membrane transporters, such as sequence, gene family, structure, function, substrate, tissue distribution, and genetic disorders associated with transporter polymorphisms. Readers are invited to submit additional data. Implemented as a relational database, HMTD supports complex biological queries. Accessible through a Web browser user interface via Common Gateway Interface (CGI) and Java Database Connection (JDBC), HMTD also provides useful links and references, allowing interactive searching and downloading of data. Taking advantage of the features of an electronic journal, this paper serves as an interactive tutorial for using the database, which we expect to develop into a research tool.

  15. [Drugs dosing in intensive care unit during continuous renal replacement therapy].

    Science.gov (United States)

    Bourquin, Vincent; Ponte, Belén; Saudan, Patrick; Martin, Pierre-Yves

    2009-11-01

    Drug dosing in the intensive care unit can be challenging. Acute kidney injury (AKI) is a common complication of sepsis and a part of multiple organ dysfunction syndrome. Continuous renal replacement therapy (CRRT) is increasingly used as dialysis therapy in this critically ill population. Available data demonstrate that sepsis, AKI and different modalities of CRRT can profoundly change drugs pharmacokinetic. The severity of these changes depends on molecules characteristics (volume of distribution, plasma protein binding, molecular weight, plasma half-life, plasma clearance), patient itself (volemia, residual renal function, tissue perfusion, hepatic dysfunction) and modality of CRRT (diffusion, convection, adsorption). There are no available recommendations to adapt drug dosing in a given critically ill patient with a given modality of CRRT. It is necessary to fully understand the different methods of CRRT and drug pharmacokinetic to prescribe the appropriate dose and to avoid under or potentially toxic overdosing. Monitoring the plasma level of drug - when available - can establish a relation between the blood concentration and its effect; thus, facilitating drug dosing.

  16. Transporter assays and assay ontologies: useful tools for drug discovery.

    Science.gov (United States)

    Zdrazil, Barbara; Chichester, Christine; Zander Balderud, Linda; Engkvist, Ola; Gaulton, Anna; Overington, John P

    2014-06-01

    Transport proteins represent an eminent class of drug targets and ADMET (absorption, distribution, metabolism, excretion, toxicity) associated genes. There exists a large number of distinct activity assays for transport proteins, depending on not only the measurement needed (e.g. transport activity, strength of ligand–protein interaction), but also due to heterogeneous assay setups used by different research groups. Efforts to systematically organize this (divergent) bioassay data have large potential impact in Public-Private partnership and conventional commercial drug discovery. In this short review, we highlight some of the frequently used high-throughput assays for transport proteins, and we discuss emerging assay ontologies and their application to this field. Focusing on human P-glycoprotein (Multidrug resistance protein 1; gene name: ABCB1, MDR1), we exemplify how annotation of bioassay data per target class could improve and add to existing ontologies, and we propose to include an additional layer of metadata supporting data fusion across different bioassays.

  17. Impact of fungal drug transporters on fungicide sensitivity, multidrug resistance and virulence

    NARCIS (Netherlands)

    Waard, de M.A.; Andrade, A.C.; Hayashi, K.; Schoonbeek, H.; Stergiopoulos, I.; Zwiers, L.H.

    2006-01-01

    Drug transporters are membrane proteins that provide protection for organisms against natural toxic products and fungicides. In plant pathogens, drug transporters function in baseline sensitivity to fungicides, multidrug resistance (MDR) and virulence on host plants. This paper describes drug transp

  18. Multiple Drug Transport Pathways through Human P-Glycoprotein.

    Science.gov (United States)

    McCormick, James W; Vogel, Pia D; Wise, John G

    2015-07-21

    P-Glycoprotein (P-gp) is a plasma membrane efflux pump that is commonly associated with therapy resistances in cancers and infectious diseases. P-gp can lower the intracellular concentrations of many drugs to subtherapeutic levels by translocating them out of the cell. Because of the broad range of substrates transported by P-gp, overexpression of P-gp causes multidrug resistance. We reported previously on dynamic transitions of P-gp as it moved through conformations based on crystal structures of homologous ABCB1 proteins using in silico targeted molecular dynamics techniques. We expanded these studies here by docking transport substrates to drug binding sites of P-gp in conformations open to the cytoplasm, followed by cycling the pump through conformations that opened to the extracellular space. We observed reproducible transport of two substrates, daunorubicin and verapamil, by an average of 11-12 Å through the plane of the membrane as P-gp progressed through a catalytic cycle. Methylpyrophosphate, a ligand that should not be transported by P-gp, did not show this movement through P-gp. Drug binding to either of two subsites on P-gp appeared to determine the initial pathway used for drug movement through the membrane. The specific side-chain interactions with drugs within each pathway seemed to be, at least in part, stochastic. The docking and transport properties of a P-gp inhibitor, tariquidar, were also studied. A mechanism of inhibition by tariquidar that involves stabilization of an outward open conformation with tariquidar bound in intracellular loops or at the drug binding domain of P-gp is presented.

  19. Pharmacokinetic interactions between herbal medicines and prescribed drugs: focus on drug metabolic enzymes and transporters.

    Science.gov (United States)

    Meng, Qiang; Liu, Kexin

    2014-01-01

    Herbal medicines have been widely used for thousands of years, and now are gaining continued popularity worldwide as a complementary or alternative treatment for a variety of diseases, rehabilitation and health care. Since herbal medicines contain more than one pharmacologically active ingredient and are commonly used with many prescribed drugs, there are potential herb-drug interactions. A variety of reported herb-drug interactions are of pharmacokinetic origin, arising from the effects of herbal medicines on metabolic enzymes and/or transporters. Such an alteration in metabolism or transport can result in changes in absorption, distribution, metabolism, and excretion (e.g., induction or inhibition of metabolic enzymes, and modulation of uptake and efflux transporters), leading to changed pharmacokinetics of the concomitantly prescribed drugs. Pharmacokinetic herb-drug interactions have more clinical significance as pharmacokinetic parameters such as the area under the plasma concentration-time curve (AUC), the maximum plasma concentration (Cmax) or the elimination half-life (t1/2) of the concomitant drug alter. This review summarizes the mechanism underlying herb-drug interactions and the approaches to identify the interactions, and discusses pharmacokinetic interactions of eight widely used herbal medicines (Ginkgo biloba, ginseng, garlic, black cohosh, Echinacea, milk thistle, kava, and St. John's wort) with conventional drugs, using various in vitro, animal in vivo, and clinical studies. The increasing understanding of pharmacokinetic herb-drug interactions will make health care professionals and patients pay more attention to the potential interactions.

  20. Dopamine and angiotensin type 2 receptors cooperatively inhibit sodium transport in human renal proximal tubule cells.

    Science.gov (United States)

    Gildea, John J; Wang, Xiaoli; Shah, Neema; Tran, Hanh; Spinosa, Michael; Van Sciver, Robert; Sasaki, Midori; Yatabe, Junichi; Carey, Robert M; Jose, Pedro A; Felder, Robin A

    2012-08-01

    Little is known regarding how the kidney shifts from a sodium and water reclaiming state (antinatriuresis) to a state where sodium and water are eliminated (natriuresis). In human renal proximal tubule cells, sodium reabsorption is decreased by the dopamine D(1)-like receptors (D(1)R/D(5)R) and the angiotensin type 2 receptor (AT(2)R), whereas the angiotensin type 1 receptor increases sodium reabsorption. Aberrant control of these opposing systems is thought to lead to sodium retention and, subsequently, hypertension. We show that D(1)R/D(5)R stimulation increased plasma membrane AT(2)R 4-fold via a D(1)R-mediated, cAMP-coupled, and protein phosphatase 2A-dependent specific signaling pathway. D(1)R/D(5)R stimulation also reduced the ability of angiotensin II to stimulate phospho-extracellular signal-regulated kinase, an effect that was partially reversed by an AT(2)R antagonist. Fenoldopam did not increase AT(2)R recruitment in renal proximal tubule cells with D(1)Rs uncoupled from adenylyl cyclase, suggesting a role of cAMP in mediating these events. D(1)Rs and AT(2)Rs heterodimerized and cooperatively increased cAMP and cGMP production, protein phosphatase 2A activation, sodium-potassium-ATPase internalization, and sodium transport inhibition. These studies shed new light on the regulation of renal sodium transport by the dopaminergic and angiotensin systems and potential new therapeutic targets for selectively treating hypertension.

  1. Copper transport systems are involved in multidrug resistance and drug transport.

    Science.gov (United States)

    Furukawa, Tatsuhiko; Komatsu, Masaharu; Ikeda, Ryuji; Tsujikawa, Kazutake; Akiyama, Shin-ichi

    2008-01-01

    Copper is an essential trace element and several copper containing proteins are indispensable for such processes as oxidative respiration, neural development and collagen remodeling. Copper metabolism is precisely regulated by several transporters and chaperone proteins. Copper Transport Protein 1 (CTR1) selectively uptakes copper into cells. Subsequently three chaperone proteins, HAH1 (human atx1 homologue 1), Cox17p and CCS (copper chaperone for superoxide dismutase) transport copper to the Golgi apparatus, mitochondria and copper/zinc superoxide dismutase respectively. Defects in the copper transporters ATP7A and ATP7B are responsible for Menkes disease and Wilson's disease respectively. These proteins transport copper via HAH1 to the Golgi apparatus to deliver copper to cuproenzymes. They also prevent cellular damage from an excess accumulation of copper by mediating the efflux of copper from the cell. There is increasing evidence that copper transport mechanisms may play a role in drug resistance. We, and others, found that ATP7A and ATP7B are involved in drug resistance against the anti-tumor drug cis-diamminedichloroplatinum (II) (CDDP). A relationship between the expression of ATP7A or ATP7B in tumors and CDDP resistance is supported by clinical studies. In addition, the copper uptake transporter CTR1 has also been reported to play a role in CDDP sensitivity. Furthermore, we have recently found that the effect of ATP7A on drug resistance is not limited to CDDP. Using an ex vivo drug sensitivity assay, the histoculture drug response assay (HDRA), the expression of ATP7A in human surgically resected colon cancer cells correlated with sensitivity to 7-ethyl-10-hydroxy-camptothecin (SN-38). ATP7A-overexpressing cells are resistant to many anticancer drugs including SN-38, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin (CPT-11), vincristine, paclitaxel, etoposide, doxorubicin (Dox), and mitoxantron. The mechanism by which ATP7A and copper

  2. Enhanced cellular transport and drug targeting using dendritic nanostructures

    Science.gov (United States)

    Kannan, R. M.; Kolhe, Parag; Kannan, Sujatha; Lieh-Lai, Mary

    2003-03-01

    Dendrimers and hyperbranched polymers possess highly branched architectures, with a large number of controllable, tailorable, peripheral' functionalities. Since the surface chemistry of these materials can be modified with relative ease, these materials have tremendous potential in targeted drug delivery. The large density of end groups can also be tailored to create enhanced affinity to targeted cells, and can also encapsulate drugs and deliver them in a controlled manner. We are developing tailor-modified dendritic systems for drug delivery. Synthesis, drug/ligand conjugation, in vitro cellular and in vivo drug delivery, and the targeting efficiency to the cell are being studied systematically using a wide variety of experimental tools. Results on PAMAM dendrimers and polyol hyperbranched polymers suggest that: (1) These materials complex/encapsulate a large number of drug molecules and release them at tailorable rates; (2) The drug-dendrimer complex is transported very rapidly through a A549 lung epithelial cancel cell line, compared to free drug, perhaps by endocytosis. The ability of the drug-dendrimer-ligand complexes to target specific asthma and cancer cells is currently being explored using in vitro and in vivo animal models.

  3. Impaired insulin signaling affects renal organic anion transporter 3 (Oat3 function in streptozotocin-induced diabetic rats.

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    Anusorn Lungkaphin

    Full Text Available Organic anion transporter 3 (Oat3 is a major renal Oats expressed in the basolateral membrane of renal proximal tubule cells. We have recently reported decreases in renal Oat3 function and expression in diabetic rats and these changes were recovered after insulin treatment for four weeks. However, the mechanisms by which insulin restored these changes have not been elucidated. In this study, we hypothesized that insulin signaling mediators might play a crucial role in the regulation of renal Oat3 function. Experimental diabetic rats were induced by a single intraperitoneal injection of streptozotocin (65 mg/kg. One week after injection, animals showing blood glucose above 250 mg/dL were considered to be diabetic and used for the experiment in which insulin-treated diabetic rats were subcutaneously injected daily with insulin for four weeks. Estrone sulfate (ES uptake into renal cortical slices was examined to reflect the renal Oat3 function. The results showed that pre-incubation with insulin for 30 min (short term stimulated [3H]ES uptake into the renal cortical slices of normal control rats. In the untreated diabetic rats, pre-incubation with insulin for 30 min failed to stimulate renal Oat3 activity. The unresponsiveness of renal Oat3 activity to insulin in the untreated diabetic rats suggests the impairment of insulin signaling. Indeed, pre-incubation with phosphoinositide 3-kinase (PI3K and protein kinase C zeta (PKCζ inhibitors inhibited insulin-stimulated renal Oat3 activity. In addition, the expressions of PI3K, Akt and PKCζ in the renal cortex of diabetic rats were markedly decreased. Prolonged insulin treatment in diabetic rats restored these alterations toward normal levels. Our data suggest that the decreases in both function and expression of renal Oat3 in diabetes are associated with an impairment of renal insulin-induced Akt/PKB activation through PI3K/PKCζ/Akt/PKB signaling pathway.

  4. Roles of renal proximal tubule transport in the pathogenesis of hypertension.

    Science.gov (United States)

    Horita, Shoko; Seki, George; Yamada, Hideomi; Suzuki, Masashi; Koike, Kazuhiko; Fujita, Toshiro

    2013-05-01

    Hypertension is a key factor of cardiovascular disease. Many organs and systems including heart, blood vessel, kidney, sympathetic nerve, and endocrine systems are involved in the regulation of blood pressure. In particular, the kidney plays an essential role in the regulation of blood pressure, but is also quite vulnerable to hypertensive tissue damage. For example, most chronic kidney disease (CKD) patients have hypertension and are revealed to have higher mortality than normal population. Furthermore, hypertensive renal sclerosis is emerging as the third main cause of dialysis patients. This mini review is to summarize the effects of angiotensin II and dopamine on renal proximal tubule transport, which may have important roles in the regulation of blood pressure.

  5. Cytostatic drugs are without significant effect on digitoxin plasma level and renal excretion.

    Science.gov (United States)

    Kuhlmann, J; Wilke, J; Rietbrock, N

    1982-11-01

    In three patients with malignant lymphoma who received 0.5 mg digitoxin before and 24 hr after combination therapy with cyclophosphamide, Oncovin, procarbazine, and prednisone (COPP) or cyclophosphamide, Oncovin, and prednisone (COP), plasma glycoside concentrations and renal excretion were measured 0 to 168 hr after digitoxin and the areas under plasma concentration-time curves *(AUCs) were calculated. In 10 patients receiving 0.1 mg digitoxin, daily plasma glycoside concentration and daily renal excretion were measured before and after COPP, COP, or cyclophosphamide, Oncovin, cytosine-arabinoside, and prednisone (COAP) treatment schemes. In contrast to previous reports on digoxin, cytostatic drug therapy does not lead to a reduction in steady-state digitoxin plasma levels and daily renal excretion. During cytostatic therapy attainment of peak digitoxin level was delayed after a single dose, showing that the rate of digitoxin absorption was reduced, but that the AUCs and renal excretion of digitoxin (parameters of the extent of digitoxin absorption) were not diminished. Since the absorption rate is not clinically relevant in patients on long-term glycoside therapy, our results indicate that digitoxin is preferable to digoxin in such patients.

  6. Tempol, a Superoxide Dismutase-Mimetic Drug, Ameliorates Progression of Renal Disease in CKD Mice

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    Wei Ding

    2015-07-01

    Full Text Available Background: Oxidative stress has been implicated in the pathogenesis of chronic kidney disease (CKD and antioxidants may ameliorate disease progression. We investigate the beneficial effect of Tempol, a superoxide dismutase-mimetic drug, on progression of disease in a mouse model of CKD. Methods: CKD was surgically induced in c57BL/6 mice by 5/6 nephrectomy. Mice were randomly divided into 3 groups: sham group, 5/6 nephrectomized group (Nx and Nx+Tempol (2 mmol/l in drinking water. Mice were sacrificed at the end of 12 weeks. Renal function, structure as well as expression of key molecules involved in the pathogenesis of inflammation, fibrosis and progression in mice were measured. Results: Reduced body weight and impaired renal function (elevation on serum creatinine, blood urea nitrogen, urine albumin, segmental sclerosis and tubulointerstitial damage was demonstrated in Nx mice but was significantly improved by Tempol administration. Nx animals exhibited significantly elevated proinflammatory and profibrotic factors, activation of NF-κB, increased expression of NADPH oxidase related subunits (p47phox, p67phox, gp91phox, and elevated activation of TGF-ß/Smad3, EGFR, MAPK signaling pathway. Tempol inhibited NF-κB mediated inflammation, TGF-ß/Smad3-induced renal fibrosis as well as EGFR and MAPK signaling pathway activation. Conclusions: Tempol administration attenuated renal injury in CKD mice through NF-κB, TGF-ß/Smad3, redox-senstive EGFR activation and c-Raf/MEK/ERK pathways.

  7. Acute renal failure secondary to drug-related crystalluria and/or drug reaction with eosinophilia and systemic symptom syndrome in a patient with metastatic lung cancer

    Directory of Open Access Journals (Sweden)

    Saime Paydas

    2017-01-01

    Full Text Available Drug reaction with eosinophilia and systemic symptoms (DRESS or drug-induced hypersensitivity is a severe adverse drug-induced reaction. Aromatic anticonvulsants, such as phenytoin, phenobarbital, and carbamazepine, and some drugs, can induce DRESS. Atypical crystalluria can be seen in patients treated with amoxycillin or some drugs and can cause acute renal failure. We describe a 66-year-old man who presented fever and rash and acute renal failure three days after starting amoxycillin. He was also using phenytoin because of cerebral metastatic lung cancer. Investigation revealed eosinophilia and atypical crystalluria. The diagnosis of DRESS syndrome was made, amoxicillin was stopped, and dose of phenytoin was reduced. No systemic corticosteroid therapy was prescribed. Symptoms began to resolve within three to four days. The aim of this paper is to highlight the importance of microscopic examination of urine in a case with acute renal failure and skin lesions to suspect DRESS syndrome.

  8. Consequences of monocarboxylate transporter 8 deficiency for renal transport and metabolism of thyroid hormones in mice

    NARCIS (Netherlands)

    M. Trajkovic-Arsic (Marija); T.J. Visser (Theo); V.M. Darras (Veerle); E.C.H. Friesema (Edith); B. Schlott (Bernhard); J. Mittag (Jens); K. Bauer (Karl); H. Heuer (Heike)

    2010-01-01

    textabstractPatients carrying inactivating mutations in the gene encoding the thyroid hormone transporting monocarboxylate transporter (MCT)-8 suffer from a severe form of psychomotor retardation and exhibit abnormal serum thyroid hormone levels. The thyroidal phenotype characterized by highserum T3

  9. Renal Drug Dosage Adjustment According to Estimated Creatinine Clearance in Hospitalized Patients With Heart Failure.

    Science.gov (United States)

    Altunbas, Gokhan; Yazc, Mehmet; Solak, Yalcin; Gul, Enes E; Kayrak, Mehmet; Kaya, Zeynettin; Akilli, Hakan; Aribas, Alpay; Gaipov, Abduzhappar; Yazc, Raziye; Ozdemir, Kurtulus

    2016-01-01

    It is of clinical importance to determine creatinine clearance and adjust doses of prescribed drugs accordingly in patients with heart failure to prevent untoward effects. There is a scarcity of studies in the literature investigating this issue particularly in patients with heart failure, in whom many have impaired kidney function. The purpose of this study was to determine the degree of awareness of medication prescription as to creatinine clearance in patients hospitalized with heart failure. Patients hospitalized with a diagnosis of heart failure were retrospectively evaluated. Among screened charts, patients with left ventricular ejection fraction renal dose adjustment were determined and evaluated for appropriate dosing according to eGFR. A total of 388 patients with concomitant heart failure and renal dysfunction were included in the study. The total number of prescribed medications was 2808 and 48.3% (1357 medications) required renal dose adjustment. Of the 1357 medications, 12.6% (171 medications) were found to be inappropriately prescribed according to eGFR. The most common inappropriately prescribed medications were famotidine, metformin, perindopril, and ramipril. A significant portion of medications used in heart failure requires dose adjustment. Our results showed that in a typical cohort of patients with heart failure, many drugs are prescribed at inappropriately high doses according to creatinine clearance. Awareness should be increased among physicians caring for patients with heart failure to prevent adverse events related to medications.

  10. Use of Drug-Eluting Stents in Patients With Coronary Artery Disease and Renal Insufficiency

    Science.gov (United States)

    El-Menyar, Ayman A.; Al Suwaidi, Jassim; Holmes, David R.

    2010-01-01

    Renal insufficiency (RI) has been shown to be associated with increased major adverse cardiovascular events after percutaneous coronary intervention. We reviewed the impact of RI on the pathogenesis of coronary artery disease and outcomes after percutaneous coronary intervention in the form of drug-eluting stent (DES) implantation in these high-risk patients. We searched the English-language literature indexed in MEDLINE, Scopus, and EBSCO Host research databases from 1990 through January 2009, using as search terms coronary revascularization, drug-eluting stent, and renal insufficiency. Studies that assessed DES implantation in patients with various degrees of RI were selected for review. Most of the available data were extracted from observational studies, and data from randomized trials formed the basis of a post hoc analysis. The outcomes after coronary revascularization were less favorable in patients with RI than in those with normal renal function. In patients with RI, DES implantation yielded better outcomes than did use of bare-metal stents. Randomized trials are needed to define optimal treatment of these high-risk patients with coronary artery disease. PMID:20118392

  11. Transport of dicationic drugs pentamidine and furamidine by human organic cation transporters.

    Science.gov (United States)

    Ming, Xin; Ju, Wujian; Wu, Huali; Tidwell, Richard R; Hall, James E; Thakker, Dhiren R

    2009-02-01

    The antiparasitic activity of aromatic diamidine drugs, pentamidine and furamidine, depends on their entry into the pathogenic protozoa via membrane transporters. However, no such diamidine transporter has been identified in mammalian cells. The goal of this study is to investigate whether these dicationic drugs are substrates for human organic cation transporters (hOCTs, solute carrier family 22A1-3) and whether hOCTs play a role in their tissue distribution, elimination, and toxicity. Inhibitory and substrate activities of pentamidine and furamidine were studied in stably transfected Chinese hamster ovary (CHO) cells. The results of [(3)H]1-methyl-4-phenylpyridinium uptake study showed that pentamidine is a potent inhibitor for all three OCT isoforms (IC50 pentamidine and furamidine was 4.4- and 9.3-fold greater, respectively, in CHO-hOCT1 cells compared with the mock cells. Ranitidine, an hOCT1 inhibitor, reversed this hOCT1-mediated potentiation of cytotoxicity. This is the first finding that dicationic drugs, such as pentamidine and furamidine, are substrates for hOCT1. In humans, aromatic diamidines are primarily eliminated in the bile but are distributed and cause toxicity in both liver and kidney. These transporters may play important roles in the disposition of aromatic diamidines in humans, as well as resultant drug-drug interactions and toxicity involving diamidine drugs.

  12. Effects of cytostatic drugs on plasma level and renal excretion of beta-acetyldigoxin.

    Science.gov (United States)

    Kuhlmann, J; Zilly, W; Wilke, J

    1981-10-01

    Mucosal defects decrease digoxin absorption in patients with malabsorption syndromes. Since the intestinal mucosa can be damaged by cytostatic drugs, we investigated their effects on digoxin plasma levels and urinary digoxin excretion. In six patients with malignant lymphoma who received 0.8 mg beta-acetyldigoxin before and 24 hr after treatment with a combination of cyclophosphamide, oncovin, procarbazine, and prednisone (COPP) or cyclophosphamide, oncovin, and prednisone (COP), plasma digoxin concentrations were measured 0 to 8 hr after the dose and areas under the plasma concentration-time curves were calculated. In 15 patients on 0.3 mg of beta-acetyldigoxin daily, plasma glycoside concentrations and renal excretion were measured daily before and after COPP, COP, cyclophosphamide, oncovin, cytosine-arabinosine, and prednisone (COAP), or adriamycin, bleomycin, and prednisone (ABP) treatment schemes. The diminished steady-state glycoside plasma concentrations and daily renal glycoside excretion during the 24 to 168 hr after the cytostatic drug established reversible impairment of digoxin absorption. The delayed time to peak after a single dose of digoxin during cytostatic drug therapy shows that extent and rate of digoxin absorption are reduced. To maintain adequate control of digoxin therapy in patients treated with cytostatic drugs, plasma levels should be monitored.

  13. Amphetamines, new psychoactive drugs and the monoamine transporter cycle.

    Science.gov (United States)

    Sitte, Harald H; Freissmuth, Michael

    2015-01-01

    In monoaminergic neurons, the vesicular transporters and the plasma membrane transporters operate in a relay. Amphetamine and its congeners target this relay to elicit their actions: most amphetamines are substrates, which pervert the relay to elicit efflux of monoamines into the synaptic cleft. However, some amphetamines act as transporter inhibitors. Both compound classes elicit profound psychostimulant effects, which render them liable to recreational abuse. Currently, a surge of new psychoactive substances occurs on a global scale. Chemists bypass drug bans by ingenuous structural variations, resulting in a rich pharmacology. A credible transport model must account for their distinct mode of action and link this to subtle differences in activity and undesired, potentially deleterious effects.

  14. Amphetamines, new psychoactive drugs and the monoamine transporter cycle

    Science.gov (United States)

    Sitte, Harald H.; Freissmuth, Michael

    2015-01-01

    In monoaminergic neurons, the vesicular transporters and the plasma membrane transporters operate in a relay. Amphetamine and its congeners target this relay to elicit their actions: most amphetamines are substrates, which pervert the relay to elicit efflux of monoamines into the synaptic cleft. However, some amphetamines act as transporter inhibitors. Both compound classes elicit profound psychostimulant effects, which render them liable to recreational abuse. Currently, a surge of new psychoactive substances occurs on a global scale. Chemists bypass drug bans by ingenuous structural variations, resulting in a rich pharmacology. A credible transport model must account for their distinct mode of action and link this to subtle differences in activity and undesired, potentially deleterious effects. PMID:25542076

  15. Clopidogrel attenuates lithium-induced alterations in renal water and sodium channels/transporters in mice.

    Science.gov (United States)

    Zhang, Yue; Peti-Peterdi, János; Heiney, Kristina M; Riquier-Brison, Anne; Carlson, Noel G; Müller, Christa E; Ecelbarger, Carolyn M; Kishore, Bellamkonda K

    2015-12-01

    Lithium (Li) administration causes deranged expression and function of renal aquaporins and sodium channels/transporters resulting in nephrogenic diabetes insipidus (NDI). Extracellular nucleotides (ATP/ADP/UTP), via P2 receptors, regulate these transport functions. We tested whether clopidogrel bisulfate (CLPD), an antagonist of ADP-activated P2Y(12) receptor, would affect Li-induced alterations in renal aquaporins and sodium channels/transporters. Adult mice were treated for 14 days with CLPD and/or Li and euthanized. Urine and kidneys were collected for analysis. When administered with Li, CLPD ameliorated polyuria, attenuated the rise in urine prostaglandin E2 (PGE2), and resulted in significantly higher urinary arginine vasopressin (AVP) and aldosterone levels as compared to Li treatment alone. However, urine sodium excretion remained elevated. Semi-quantitative immunoblotting revealed that CLPD alone increased renal aquaporin 2 (AQP2), Na-K-2Cl cotransporter (NKCC2), Na-Cl cotransporter (NCC), and the subunits of the epithelial Na channel (ENaC) in medulla by 25-130 %. When combined with Li, CLPD prevented downregulation of AQP2, Na-K-ATPase, and NKCC2 but was less effective against downregulation of cortical α- or γ-ENaC (70 kDa band). Thus, CLPD primarily attenuated Li-induced downregulation of proteins involved in water conservation (AVP-sensitive), with modest effects on aldosterone-sensitive proteins potentially explaining sustained natriuresis. Confocal immunofluorescence microscopy revealed strong labeling for P2Y(12)-R in proximal tubule brush border and blood vessels in the cortex and less intense labeling in medullary thick ascending limb and the collecting ducts. Therefore, there is the potential for CLPD to be directly acting at the tubule sites to mediate these effects. In conclusion, P2Y(12)-R may represent a novel therapeutic target for Li-induced NDI.

  16. Pharmacokinetics of netivudine, a potent anti-varicella zoster virus drug, in patients with renal impairment.

    Science.gov (United States)

    Fillastre, J P; Godin, M; Legallicier, B; Chretien, P; Bidault, R; Gillotin, C; Wooton, R; Posner, J; Peck, R W

    1996-05-01

    The pharmacokinetics of a single oral 200 mg dose of netivudine (1-(beta-D-arabinofuranosyl)-5-(1-propynyl)uracil), a nucleoside analogue under development for use in varicella zoster virus infections, were studied in 12 renal failure (RF) subjects (creatinine clearance 15 +/- 7 mL/min) and 12 age-matched healthy subjects with normal creatinine clearance. Blood and urine samples were collected up to nine days after drug administration. Concentrations of netivudine and of its main metabolite, the pyrimidine base 5-(1-propynyl)uracil (5 PU), were determined by a specific high performance liquid chromatography assay. The mean peak plasma concentrations of netivudine, Tmax, and volume of distribution were not significantly affected by RF. The elimination half-life of netivudine was approximately 15 h in subjects with normal renal function and 60 h in RF patients. Plasma and renal clearances of netivudine were significantly reduced in RF patients and AUC was three to four times higher in these patients. Cmax and AUC of 5 PU were higher in RF patients, and the half-life was also significantly longer. However, the half-life of this metabolite was much lower than that of the parent compound. Tmax and the lag time were similar in the two groups. There were highly significant correlations for netivudine and 5 PU between half-life and creatinine clearance and between renal clearance and creatinine clearance. These findings suggest that netivudine dosage may need to be reduced in patients with severe renal failure, and confirm that formation of the 5 PU is independent of the elimination of netivudine from plasma.

  17. Hepatic drug transporters and nuclear receptors: Regulation by therapeutic agents

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    The canalicular membrane represents the excretory pole of hepatocytes. Bile is an important route of elimina-tion of potentially toxic endo- and xenobiotics (including drugs and toxins), mediated by the major canalicular transporters: multidrug resistance protein 1 (MDR1, ABCB1), also known as P-glycoprotein, multidrug re-sistance-associated protein 2 (MRP2, ABCC2), and the breast cancer resistance protein (BCRP, ABCG2). Their activities depend on regulation of expression and proper localization at the canalicular membrane, as regulated by transcriptional and post-transcriptional events, re-spectively. At transcriptional level, specific nuclear re-ceptors (NR)s modulated by ligands, co-activators and co-repressors, mediate the physiological requirements of these transporters. This complex system is also re-sponsible for alterations occurring in specific liver pa-thologies. We briefly describe the major Class Ⅱ NRs, pregnane X receptor (PXR) and constitutive androstane receptor (CAR), and their role in regulating expression of multidrug resistance proteins. Several therapeutic agents regulate the expression of relevant drug trans-porters through activation/inactivation of these NRs. We provide some representative examples of the action of therapeutic agents modulating liver drug transporters, which in addition, involve CAR or PXR as mediators.

  18. Designing Novel Nanoformulations Targeting Glutamate Transporter Excitatory Amino Acid Transporter 2: Implications in Treating Drug Addiction.

    Science.gov (United States)

    Rao, Pss; Yallapu, Murali M; Sari, Youssef; Fisher, Paul B; Kumar, Santosh

    Chronic drug abuse is associated with elevated extracellular glutamate concentration in the brain reward regions. Deficit of glutamate clearance has been identified as a contributing factor that leads to enhanced glutamate concentration following extended drug abuse. Importantly, normalization of glutamate level through induction of glutamate transporter 1 (GLT1)/ excitatory amino acid transporter 2 (EAAT2) expression has been described in several in vivo studies. GLT1 upregulators including ceftriaxone, a beta-lactam antibiotic, have been effective in attenuating drug-seeking and drug-consumption behavior in rodent models. However, potential obstacles toward clinical translation of GLT1 (EAAT2) upregulators as treatment for drug addiction might include poor gastrointestinal absorption, serious peripheral adverse effects, and/or suboptimal CNS concentrations. Given the growing success of nanotechnology in targeting CNS ailments, nanoformulating known GLT1 (EAAT2) upregulators for selective uptake across the blood brain barrier presents an ideal therapeutic approach for treating drug addiction. In this review, we summarize the results obtained with promising GLT1 (EAAT2) inducing compounds in animal models recapitulating drug addiction. Additionally, the various nanoformulations that can be employed for selectively increasing the CNS bioavailability of GLT1 (EAAT2) upregulators are discussed. Finally, the applicability of GLT1 (EAAT2) induction via central delivery of drug-loaded nanoformulations is described.

  19. Cyclosporine-inhibitable Cerebral Drug Transport Does not Influence Clinical Methadone Pharmacodynamics

    Science.gov (United States)

    Meissner, Konrad; Blood, Jane; Francis, Amber M.; Yermolenka, Viktar; Kharasch, Evan D.

    2015-01-01

    Background Interindividual variability and drug interaction studies suggest that blood-brain barrier drug transporters mediate human methadone brain biodistribution. In vitro and animal studies suggest that methadone is a substrate for the efflux transporter P-glycoprotein, and that P-glycoprotein-mediated transport influences brain access and pharmacologic effect. This investigation tested whether methadone is a transporter substrate in humans. Methods Healthy volunteers received oral (N=16) or IV (N=12) methadone in different crossover protocols after nothing (control) or the validated P-glycoprotein inhibitor cyclosporine (4.5 mg/kg orally twice daily for 4 days, or 5 mg/kg IV over 2 hr). Plasma and urine methadone and metabolite concentrations were measured by mass spectrometry. Methadone effects were measured by miosis and thermal analgesia (maximally tolerated temperature and verbal analog scale rating of discreet temperatures). Results Cyclosporine marginally but significantly decreased methadone plasma concentrations and apparent oral clearance, but had no effect on methadone renal clearance or on hepatic N-demethylation. Cyclosporine had no effect on miosis, or on R-methadone concentration-miosis relationships after either oral or IV methadone. Peak miosis was similar in controls and cyclosporine-treated subjects after oral methadone (1.4 ± 0.4 and 1.3 ± 0.5 mm/mg, respectively) and IV methadone (3.1 ± 1.0 and 3.2 ± 0.8 mm respectively). Methadone increased maximally tolerated temperature, but analgesia testing was confounded by cyclosporine-related pain. Conclusions Cyclosporine did not affect methadone pharmacodynamics. This result does not support a role for cyclosporine-inhibitable transporters mediating methadone brain access and biodistribution. PMID:25072223

  20. Comparative study of renal sodium transport between ouabain-hypertensive rats and ouabain-nonhypertensive rats

    Institute of Scientific and Technical Information of China (English)

    GE Heng; Lü Zhuo-ren

    2006-01-01

    Objective: To compare renal sodium transport, using fractional excretions of lithium(FEii)as a marker of proximal tubule sodium reabsorption, between hypertensive and non-hypertensive ouabaintreated rats and further to elucidate the role of ouabain in pathogenesis of hypertension. Methods:Thirty male Sprague-Dawley rats weighting 180-200 g were randomly divided into normal control group and ouabain treated group. Rats were infused with 1 ml/kg · d normal saline or 27.8 μg/kg · d ouabain intraperitoneally once a day respectively. Systolic blood pressure (SBP), heart rate and body weight were recorded weekly. Rats were sacrificed 6 weeks after treatment. Blood and 24-hour urine sample were collected to measure the serum and urinary concentration of sodium, trace lithium and creatinine. Endogenous creatinine clearance rate (Ccr), fractional excretions of sodium (FENa), fractional excretions of lithium (FELi) and fractional reabsorption of sodium in the postproximal tubules (FDRNa) were calculated.Ouabain levels of plasma and renal tissue, plasma renin activity, angiotensin Ⅱ and aldosterone concentration were determined. Results: 65% of the ouabain-treated rats achieved significantly higher SBP after 4weeks, compared with that of the saline control groups or self baseline (P<0. 01). But in the other 35%of the ouabain-treated rats, their SBP was similar with control group during the experiment (P>0. 05).The body weight, heart rate and food intake between the 3 groups were no significant differences (P>0.05). FELi and FDRNa were significantly lower in ouabain-hypertensive group compared with ouabain-nonhypertensive group and control group(P<0.01 and P<0.05). The FELi and FDRNa of ouabain-nonhypertensive groups were similar with control group(P>0.05). Ccr and FENa were comparable between the 3 groups (P>0. 05). Plasma and renal tissue ouabain levels, plasma renin activity, angiotensin Ⅱ and aldosterone contents in ouabain-hypertensive rats were

  1. Structure and localisation of drug binding sites on neurotransmitter transporters.

    Science.gov (United States)

    Ravna, Aina W; Sylte, Ingebrigt; Dahl, Svein G

    2009-10-01

    The dopamine (DAT), serotontin (SERT) and noradrenalin (NET) transporters are molecular targets for different classes of psychotropic drugs. The crystal structure of Aquifex aeolicus LeuT(Aa) was used as a template for molecular modeling of DAT, SERT and NET, and two putative drug binding sites (pocket 1 and 2) in each transporter were identified. Cocaine was docked into binding pocket 1 of DAT, corresponding to the leucine binding site in LeuT(Aa), which involved transmembrane helices (TMHs) 1, 3, 6 and 8. Clomipramine was docked into binding pocket 2 of DAT, involving TMHs 1, 3, 6, 10 and 11, and extracellular loops 4 and 6, corresponding to the clomipramine binding site in a crystal structure of a LeuT(Aa)-clomipramine complex. The structures of the proposed cocaine- and tricyclic antidepressant-binding sites may be of particular interest for the design of novel DAT interacting ligands.

  2. Inhibitory effect of caffeic acid on human organic anion transporters hOAT1 and hOAT3: a novel candidate for food-drug interaction.

    Science.gov (United States)

    Uwai, Yuichi; Ozeki, Yukihiro; Isaka, Tomonori; Honjo, Hiroaki; Iwamoto, Kikuo

    2011-01-01

    Several kinds of food have been shown to influence the absorption and metabolism of drugs, although there is little information about their effect on the renal excretion of drugs. In this study, we performed uptake experiments using Xenopus laevis oocytes to assess the inhibitory effects of chlorogenic acid, caffeic acid and quinic acid, which are contained in coffee, fruits and vegetables, on human organic anion transporters hOAT1 and hOAT3; these transporters mediate renal tubular uptake of anionic drugs from blood. Injection of hOAT1 and hOAT3 cRNA into oocytes stimulated uptake of typical substrates of hOAT1 and hOAT3 (p-aminohippurate and estrone sulfate, respectively); among the three compounds tested, caffeic acid most strongly inhibited these transporters. The apparent 50% inhibitory concentrations of caffeic acid were estimated to be 16.6 µM for hOAT1 and 5.4 µM for hOAT3. Eadie-Hofstee plot analysis showed that caffeic acid inhibited both transporters in a competitive manner. In addition to the transport of p-aminohippurate and estrone sulfate, that of antifolates and antivirals was inhibited by caffeic acid. These findings show that caffeic acid has inhibitory potential against hOAT1 and hOAT3, suggesting that renal excretion of their substrates could be affected in patients consuming a diet including caffeic acid.

  3. Mathematical modelling of transport of a non-diffusible indicator to estimate renal blood supply

    Energy Technology Data Exchange (ETDEWEB)

    Gelfand, I.N.; Narkevich, V.Y.

    1985-01-01

    A new method is recommended to interpret the results in radionuclide studies of renal blood flow with the mathematical modelling of transport of a non-diffusible indicator in the blood vessels. The analytic proportions are ascertained between mean transit time of indicator, mean retention time (both at impulse influence and at occurence of any signal at the input) for different forms of transport function, and impulse-shaped retention function of the studied physiological system. By means of external measuring of radioactivity this allows to estimate the mean transit time of the indicator by the studied element of hemodynamics, an index, used in classically physiological studies. The recommended system of physiological indices describes the statistic and dynamic parameters of the vessel network in each kidney adequately. The use of this method showed its efficiency on principle in 7 healthy persons and in 4 patients with clinically manifest kidney diseases. (author).

  4. The Role of Transporters in the Toxicity of Chemotherapeutic Drugs: Focus on Transporters for Organic Cations.

    Science.gov (United States)

    Hucke, Anna; Ciarimboli, Giuliano

    2016-07-01

    The introduction of chemotherapy in the treatment of cancer is one of the most important achievements of modern medicine, even allowing the cure of some lethal diseases such as testicular cancer and other malignant neoplasms. The number and type of chemotherapeutic agents available have steadily increased and have developed until the introduction of targeted tumor therapy. It is now evident that transporters play an important role for determining toxicity of chemotherapeutic drugs not only against target but also against nontarget cells. This is of special importance for intracellularly active hydrophilic drugs, which cannot freely penetrate the plasma membrane. Because many important chemotherapeutic agents are substrates of transporters for organic cations, this review discusses the known interaction of these substances with these transporters. A particular focus is given to the role of transporters for organic cations in the development of side effects of chemotherapy with platinum derivatives and in the efficacy of recently developed tyrosine kinase inhibitors to specifically target cancer cells. It is evident that specific inhibition of uptake transporters may be a possible strategy to protect against undesired side effects of platinum derivatives without compromising their antitumor efficacy. These transporters are also important for efficient targeting of tyrosine kinase inhibitors to cancer cells. However, in order to achieve the aims of protecting from undesired toxicities and improving the specificity of uptake by tumor cells, an exact knowledge of transporter expression, function, regulation under normal and pathologic conditions, and of genetically and epigenetically regulation is mandatory.

  5. Extra-Renal Elimination of Uric Acid via Intestinal Efflux Transporter BCRP/ABCG2

    Science.gov (United States)

    Hosomi, Atsushi; Nakanishi, Takeo; Fujita, Takuya; Tamai, Ikumi

    2012-01-01

    Urinary excretion accounts for two-thirds of total elimination of uric acid and the remainder is excreted in feces. However, the mechanism of extra-renal elimination is poorly understood. In the present study, we aimed to clarify the mechanism and the extent of elimination of uric acid through liver and intestine using oxonate-treated rats and Caco-2 cells as a model of human intestinal epithelium. In oxonate-treated rats, significant amounts of externally administered and endogenous uric acid were recovered in the intestinal lumen, while biliary excretion was minimal. Accordingly, direct intestinal secretion was thought to be a substantial contributor to extra-renal elimination of uric acid. Since human efflux transporter BCRP/ABCG2 accepts uric acid as a substrate and genetic polymorphism causing a decrease of BCRP activity is known to be associated with hyperuricemia and gout, the contribution of rBcrp to intestinal secretion was examined. rBcrp was confirmed to transport uric acid in a membrane vesicle study, and intestinal regional differences of expression of rBcrp mRNA were well correlated with uric acid secretory activity into the intestinal lumen. Bcrp1 knockout mice exhibited significantly decreased intestinal secretion and an increased plasma concentration of uric acid. Furthermore, a Bcrp inhibitor, elacridar, caused a decrease of intestinal secretion of uric acid. In Caco-2 cells, uric acid showed a polarized flux from the basolateral to apical side, and this flux was almost abolished in the presence of elacridar. These results demonstrate that BCRP contributes at least in part to the intestinal excretion of uric acid as extra-renal elimination pathway in humans and rats. PMID:22348008

  6. The effect of Cratylia floribunda lectin on renal hemodynamics and ion transport

    Directory of Open Access Journals (Sweden)

    Alexandre Havt

    2015-09-01

    Full Text Available Lectins have been described as glycoproteins that reversibly and specifically bind to carbohydrates. Legume lectins isolated from the subtribe Diocleinae (Canavalia, Dioclea andCratylia are structurally homologous with respect to their primary structures. The Diocleinae lectins of Canavalia brasiliensis, Dioclea guianensis andCanavalia ensiformis have been shown to distinctly alter physiological parameters in isolated rat kidneys. Thus, the aim of this study was to investigate the effect of Cratylia floribunda lectin (CFL on renal hemodynamics and ion transport in rats. In isolated perfused kidneys, CFL (10 mg/mL, n=5 increased RPP, RVR and decreased %TK+, but did not change urinary flow, glomerular filtration rate, sodium or chloride tubular transport. In isolated perfused mesenteric bed, CFL (3 and 10 mg/mL/min; n=4 did not alter tissue basal tonus or tissue contraction by phenylephrine (1 mM/mL/min. In conclusion, the seed lectin of Cratylia floribunda increased renal hemodynamic parameters showing a kaliuretic effect. This effect could be of tubular origin, rather than a result from haemodynamic alterations.

  7. From kidney development to drug delivery and tissue engineering strategies in renal regenerative medicine

    NARCIS (Netherlands)

    Dankers, Patricia Y. W.; Boomker, Jasper M.; Meijer, E. W.; Popa, Eliane R.; van Luyn, Marja J. A.

    2011-01-01

    Deterioration of renal function is typically slow but progressive, and therefore renal disease is often diagnosed in a late stage when already serious complaints occur. Ultimately when renal function has dropped below 10%, renal replacement is required. Renal transplantation provides a long-term sol

  8. Adjacent central venous catheters can result in immediate aspiration of infused drugs during renal replacement therapy.

    Science.gov (United States)

    Kam, K Y R; Mari, J M; Wigmore, T J

    2012-02-01

    Dual-lumen haemodiafiltration catheters enable continuous renal replacement therapy in the critically ill and are often co-located with central venous catheters used to infuse drugs. The extent to which infusions are immediately aspirated by an adjacent haemodiafiltration catheter remains unknown. A bench model was constructed to evaluate this effect. A central venous catheter and a haemodiafiltration catheter were inserted into a simulated central vein and flow generated using centrifugal pumps within the simulated vein and haemodiafiltration circuit. Ink was used as a visual tracer and creatinine solution as a quantifiable tracer. Tracers were completely aspirated by the haemodiafiltration catheter unless the infusion was at least 1 cm downstream to the arterial port. No tracer was aspirated from catheters infusing at least 2 cm downstream. Orientation of side ports did not affect tracer elimination. Co-location of central venous and haemodiafiltration catheters may lead to complete aspiration of infusions into the haemodiafilter with resultant drug under-dosing.

  9. The role of new immunosuppressive drugs in nonmelanoma skin cancer in renal transplant recipients.

    Science.gov (United States)

    Bernat-García, J; Morales Suárez-Varela, M; Vilata-Corell, J J; Marquina-Vila, A; Pallardo, L; Crespo, J

    2014-12-01

    Nonmelanoma skin cancer (NMSC) is the most common malignancy in patients who have received a solid organ transplant. Multiple factors are involved in the onset of posttransplant NMSC. To analyze the relationship between new immunosuppressive drugs and the onset of NMSC in renal transplant recipients. This was a combined retrospective and prospective observational study in which we studied 289 patients who received a kidney transplant between January 1996 and December 2010 at Hospital Universitario Doctor Peset in Valencia, Spain. Seventy-three patients (25.2%) developed 162 NMSCs over a median follow-up of 72 months. There were no statistically significant differences in the onset of NMSC on comparing different induction therapy strategies involving monoclonal and polyclonal antibodies. NMSCs occurred less frequently in patients treated with mammalian target of rapamycin (mTOR) inhibitors than in those treated with other immunosuppressive regimens, although the differences were not statistically significant. Three of 5 patients with recurrent NMSC who were switched from calcineurin inhibitors to mTOR inhibitors developed additional NMSCs despite the change. Induction therapy with monoclonal and polyclonal antibodies in renal transplant recipients is not associated with an increased risk of NMSC. While mTOR inhibitors are associated with a lower risk of posttransplant NMSC, it remains to be determined whether a switch to these drugs is useful in the management of patients who develop multiple NMSCs. Copyright © 2014. Published by Elsevier Espana.

  10. Antiepileptic Drug Removal by Continuous Renal Replacement Therapy: A Review of the Literature.

    Science.gov (United States)

    Mahmoud, Sherif Hanafy

    2017-01-01

    Continuous renal replacement therapy (CRRT) is used for managing acute kidney injury in critically ill patients. Removal of antiepileptic drugs (AEDs) by CRRT could be significant and may complicate patients' intensive care unit stay. The objective of the current review was to summarize the available evidence for AED removal by CRRT. An electronic literature search of PubMed (1946 to May 2016), Medline (1946 to May 2016), and Embase (1974 to May 2016) databases for studies discussing AED removal by CRRT was conducted. A total of 31 case reports discussing 32 patients were found. AEDs reported were levetiracetam (n = 3), valproic acid (n = 9), carbamazepine (n = 10), phenytoin (n = 3), phenobarbital (n = 4), lacosamide (n = 1), gabapentin (n = 1), and topiramate (n = 1). Two-thirds of the reports were about using CRRT in drug overdose and one-third was about AED removal by CRRT during therapy. Based on the current limited evidence and pharmacokinetic characteristics of AEDs, renally eliminated AEDs and/or AEDs with limited protein binding such as levetiracetam are more likely to be removed by CRRT than AEDs that are mainly metabolized and extensively protein bound such as carbamazepine. In conclusion, there is not enough evidence to provide robust dosing recommendations for AEDs in patients undergoing CRRT. Further studies are needed.

  11. Intriguing possibilities and beneficial aspects of transporter-conscious drug design.

    Science.gov (United States)

    Tashima, Toshihiko

    2015-08-01

    It has been revealed that many types of drugs interact with transporter proteins within an organism. Transporter proteins absorb or excrete materials, including drugs and nutrients, across the cell membrane. Some hydrophobic drugs are excreted from the cell as xenobiotics by ATP-binding cassette (ABC) transporters. However, solute carrier (SLC) transporters are tissue-specifically expressed and have substrate specificities. Thus, transporter-conscious drug design is an excellent method of delivering drugs to pharmaceutical target organs and provides advantages in absorption, distribution, excretion, and toxicity of drugs (ADMET) due to transport systems. In fact, based on this strategy, the bioavailability of prodrugs designed as peptide transporter 1 (PEPT1) substrates was better than that of the corresponding parent compounds due to the transport system in the small intestine. Furthermore, in central nervous system (CNS) drug developing, drug delivery into brain across the blood-brain barrier (BBB) is a serious problem. However, this problem can be also solved by the use of the transport systems at the BBB. Therefore, transporter-consciously designed drugs not only may effectively elicit activity but also may control adverse side effects caused by off-targets and drug-drug interactions and, consequently, may show good performance in clinical trials. In this review, I introduce possibilities and advantages of transporter-conscious drug designs.

  12. Next generation renal denervation: chemical “perivascular” renal denervation with alcohol using a novel drug infusion catheter

    Energy Technology Data Exchange (ETDEWEB)

    Fischell, Tim A. [Borgess Heart Institute, 1521 Gull Road, Kalamazoo, MI, 49008 (United States); Ablative Solutions, 801 Hermosa Way, Menlo Park, CA, 94025 (United States); Fischell, David R.; Ghazarossian, Vartan E. [Ablative Solutions, 801 Hermosa Way, Menlo Park, CA, 94025 (United States); Vega, Félix [Preclinical Consultation, San Francisco, CA (United States); Ebner, Adrian [Clinics, Ascension (Paraguay)

    2015-06-15

    Background/Purpose: We update the pre-clinical and early clinical results using a novel endovascular approach, to perform chemical renal denervation, via peri-adventitial injection of micro-doses of dehydrated alcohol (ethanol–EtOH). Methods/Materials: A novel, three-needle delivery device (Peregrine™) was used to denervate the renal arteries of adult swine (n = 17) and in a first-in-man feasibility study (n = 18). In the pre-clinical testing EtOH was infused bilaterally with one infusion per renal artery into to the perivascular space, using EtOH doses of 0.3 ml/artery (n = 8), and 0.6 ml/artery (n = 9), and with saline sham control (0.4 ml/artery n = 3). Renal parenchymal norepinephrine (NE) concentration (performed blindly), and safety were the primary endpoints. Data from the first-in-man study (n = 18) to evaluate device performance, safety and peri-procedural pain are reported. Results: In the pre-clinical testing renal function was unchanged at 3-month follow-up. Angiography at 90 days (n = 34 arteries) demonstrated normal appearing renal arteries, unchanged from baseline, and without stenosis or other abnormalities. The reductions in mean renal parenchymal NE reductions at 3 months were 68% and 88% at doses of 0.3 and 0.6 ml, respectively (p < 0.001 vs. controls). In the first-in-man study, there was 100% device success, no complications, a mean treatment time of 4.3 ± 3 minutes/artery, and minimal or no patient discomfort during treatment. Angiography at 6-months showed no evidence of renal artery stenosis, and evidence of a reduction of blood pressure from baseline. Conclusion: Perivascular RDN using micro-doses of alcohol is a promising alternative to energy-based systems to achieve dose-dependent, predictable, safe and essentially painless renal denervation. Further clinical evaluation is warranted. Summary: (For annotated table of contents) This paper describes the preclinical results, in a porcine model, and the early first-in-man results, using

  13. Characterization of Organic Anion Transporter 2 (SLC22A7): A Highly Efficient Transporter for Creatinine and Species-Dependent Renal Tubular Expression.

    Science.gov (United States)

    Shen, Hong; Liu, Tongtong; Morse, Bridget L; Zhao, Yue; Zhang, Yueping; Qiu, Xi; Chen, Cliff; Lewin, Anne C; Wang, Xi-Tao; Liu, Guowen; Christopher, Lisa J; Marathe, Punit; Lai, Yurong

    2015-07-01

    The contribution of organic anion transporter OAT2 (SLC22A7) to the renal tubular secretion of creatinine and its exact localization in the kidney are reportedly controversial. In the present investigation, the transport of creatinine was assessed in human embryonic kidney (HEK) cells that stably expressed human OAT2 (OAT2-HEK) and isolated human renal proximal tubule cells (HRPTCs). The tubular localization of OAT2 in human, monkey, and rat kidney was characterized. The overexpression of OAT2 significantly enhanced the uptake of creatinine in OAT2-HEK cells. Under physiologic conditions (creatinine concentrations of 41.2 and 123.5 µM), the initial rate of OAT2-mediated creatinine transport was approximately 11-, 80-, and 80-fold higher than OCT2, multidrug and toxin extrusion protein (MATE)1, and MATE2K, respectively, resulting in approximately 37-, 1850-, and 80-fold increase of the intrinsic transport clearance when normalized to the transporter protein concentrations. Creatinine intracellular uptake and transcellular transport in HRPTCs were decreased in the presence of 50 µM bromosulfophthalein and 100 µM indomethacin, which inhibited OAT2 more potently than other known creatinine transporters, OCT2 and multidrug and toxin extrusion proteins MATE1 and MATE2K (IC50: 1.3 µM vs. > 100 µM and 2.1 µM vs. > 200 µM for bromosulfophthalein and indomethacin, respectively) Immunohistochemistry analysis showed that OAT2 protein was localized to both basolateral and apical membranes of human and cynomolgus monkey renal proximal tubules, but appeared only on the apical membrane of rat proximal tubules. Collectively, the findings revealed the important role of OAT2 in renal secretion and possible reabsorption of creatinine and suggested a molecular basis for potential species difference in the transporter handling of creatinine.

  14. A new human NHERF1 mutation decreases renal phosphate transporter NPT2a expression by a PTH-independent mechanism.

    Directory of Open Access Journals (Sweden)

    Marie Courbebaisse

    Full Text Available BACKGROUND: The sodium-hydrogen exchanger regulatory factor 1 (NHERF1 binds to the main renal phosphate transporter NPT2a and to the parathyroid hormone (PTH receptor. We have recently identified mutations in NHERF1 that decrease renal phosphate reabsorption by increasing PTH-induced cAMP production in the renal proximal tubule. METHODS: We compared relevant parameters of phosphate homeostasis in a patient with a previously undescribed mutation in NHERF1 and in control subjects. We expressed the mutant NHERF1 protein in Xenopus Oocytes and in cultured cells to study its effects on phosphate transport and PTH-induced cAMP production. RESULTS: We identified in a patient with inappropriate renal phosphate reabsorption a previously unidentified mutation (E68A located in the PDZ1 domain of NHERF1.We report the consequences of this mutation on NHERF1 function. E68A mutation did not modify cAMP production in the patient. PTH-induced cAMP synthesis and PKC activity were not altered by E68A mutation in renal cells in culture. In contrast to wild-type NHERF1, expression of the E68A mutant in Xenopus oocytes and in human cells failed to increase phosphate transport. Pull down experiments showed that E68A mutant did not interact with NPT2a, which robustly interacted with wild type NHERF1 and previously identified mutants. Biotinylation studies revealed that E68A mutant was unable to increase cell surface expression of NPT2a. CONCLUSIONS: Our results indicate that the PDZ1 domain is critical for NHERF1-NPT2a interaction in humans and for the control of NPT2a expression at the plasma membrane. Thus we have identified a new mechanism of renal phosphate loss and shown that different mutations in NHERF1 can alter renal phosphate reabsorption via distinct mechanisms.

  15. Structural determinants of NH3 and NH4+ transport by mouse Rhbg, a renal Rh glycoprotein.

    Science.gov (United States)

    Abdulnour-Nakhoul, Solange; Le, Trang; Rabon, Edd; Hamm, L Lee; Nakhoul, Nazih L

    2016-12-01

    Renal Rhbg is localized to the basolateral membrane of intercalated cells and is involved in NH3/NH4(+) transport. The structure of Rhbg is not yet resolved; however, a high-resolution crystal structure of AmtB, a bacterial homolog of Rh, has been determined. We aligned the sequence of Rhbg to that of AmtB and identified important sites of Rhbg that may affect transport. Our analysis positioned three conserved amino acids, histidine 183 (H183), histidine 342 (H342), and tryptophan 230 (W230), within the hydrophobic pore where they presumably serve to control NH3 transport. A fourth residue, phenylalanine 128 (F128) was positioned at the upper vestibule, presumably contributing to recruitment of NH4(+) We generated three mutations each of H183, H342, W230, and F128 and expressed them in frog oocytes. Immunolabeling showed that W230 and F128 mutants were localized to the cell membrane, whereas H183 and H342 staining was diffuse and mostly intracellular. To determine function, we compared measurements of NH3/NH4(+) and methyl amine (MA)/methyl ammonium (MA(+))-induced currents, intracellular pH, and surface pH (pHs) among oocytes expressing the mutants, Rhbg, or injected with H2O. In H183 and W230 mutants, NH4(+)-induced current and intracellular acidification were inhibited compared with that of Rhbg, and MA-induced intracellular alkalinization was completely absent. Expression of H183A or W230A mutants inhibited NH3/NH4(+)- and MA/MA(+)-induced decrease in pHs to the level observed in H2O-injected oocytes. Mutations of F128 did not significantly affect transport of NH3 or NH4(+) These data demonstrated that mutating H183 or W230 caused loss of function but not F128. H183 and H342 may affect membrane expression of the transporter.

  16. Maritime Transportation of Illegal Drugs from South America

    Science.gov (United States)

    2017-01-01

    18, 2002. J. Kandel , Traffickers using submarines to transport drugs, NBC Los Angeles. September 14, 2012. B. Kennedy, More than $110...CBS-Miami (2012) Go-fast 2 ONDCP (2013,2014), CBS-Miami (2011) SPSS 5—10 UNODC (2012) SPSS 6 Kandel (2012) Fishing vessel 2.4 Kennedy (2014) Panga...Hodgson (2002) Go-fast 50 Selsky (2005) Go-fast 25 ONDCP (2014) SPSS 10 United States Coast Guard (2008) SPSS 13 Kandel (2012) Table A.7

  17. Therapeutic Drug Monitoring in Neonatal HSV Infection on Continuous Renal Replacement Therapy.

    Science.gov (United States)

    Funaki, Takanori; Miyata, Ippei; Shoji, Kensuke; Enomoto, Yuki; Sakamoto, Seisuke; Kasahara, Mureo; Miyairi, Isao

    2015-07-01

    Optimal acyclovir dosing under continuous renal replacement therapy (CRRT) in neonates is unknown. We monitored serum acyclovir levels and herpes simplex virus 1 (HSV-1) DNA levels in a neonate with disseminated HSV-1 infection and renal failure undergoing CRRT. A full-term, 5-day-old female presented with a 2-day history of lethargy and fever. She developed fulminant hepatitis and was diagnosed with HSV-1 infection by real-time polymerase chain reaction. Acyclovir was initiated at 60 mg/kg/day, which was lowered to 20 mg/kg/day because of development of renal failure. She was placed on continuous hemodialysis. Acyclovir dosing was adjusted according to serum acyclovir levels, and HSV-1 viral load was sequentially monitored. Semiquantification of serum HSV-1 levels was performed by real-time polymerase chain reaction. Acyclovir levels were measured by using liquid chromatography-tandem mass spectrometry. Acyclovir was administered at 20 mg/kg intravenously over 1 hour; peak concentration was 18.9 μg/mL. The half-life of acyclovir was estimated to be 2 to 3 h. Viral load remained high during dosing every 24 hours, with a decline of 0.17 log copies/24 hours. Acyclovir dosing was changed to 20 mg/kg/dose every 8 hours, with an average viral load decline of 0.44 log copies/24 hours. Despite the guideline recommendation of 24-hour redosing, acyclovir was dialyzed at a rate that resulted in suboptimal treatment. Individual therapeutic drug monitoring for acyclovir and dosing adjustment may be required to optimize therapy for patients undergoing CRRT. Copyright © 2015 by the American Academy of Pediatrics.

  18. Drug Transport by the Blood-Aqueous Humor Barrier of the Eye.

    Science.gov (United States)

    Lee, Jonghwa; Pelis, Ryan M

    2016-10-01

    The ocular barriers (cornea, blood-retinal barrier, and blood-aqueous humor barrier) make treating eye diseases with therapeutic drugs challenging. The tight capillary endothelium of the iris and the ciliary body epithelium form the blood-aqueous humor barrier. The iris and ciliary body (iris-ciliary body) express a variety of drug transporters in the ATP-binding cassette and solute carrier (SLC) families. ATP-binding cassette family drug transporters that are present in the iris-ciliary body include P-glycoprotein, breast cancer resistance protein, and several multidrug resistance-associated proteins. SLC family drug transporters that are present in the iris-ciliary body include organic anion transporters, organic anion transporting polypeptides, bile acid transporters (apical sodium-dependent bile salt transporter and sodium taurocholate cotransporter), organic cation transporters (novel organic cation transporter and multidrug and toxin extrusion transporter) and peptide transporters. Freshly dissected iris-ciliary body preparations actively accumulate a variety of substrates of SLC drug transporters that are expressed in the tissue. The ciliary body in vitro supports active transport in the aqueous humor-to-blood direction of several substrates of organic anion transporters and multidrug resistance-associated proteins, consistent with the subcellular localization of these transporters in the ciliary body epithelium. In vivo data suggest that drug transporters in the iris-ciliary body reduce the permeation of drugs in the direction of blood-to-aqueous humor, thereby reducing ocular drug bioavailability, and are also involved in active drug elimination from the aqueous humor. An understanding of the influence on pharmacokinetics of drug transporters in the blood-aqueous humor barrier should help improve drug delivery and efficacy in the eye. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

  19. Common drugs for stabilization of renal function in the progression of diabetic nephropathy and their relations with hypertension therapy.

    Science.gov (United States)

    Wang, Yuxuan; Wang, Chengcheng; Zhang, Xiuli; Gu, Harvest F; Wu, Liang

    2017-02-14

    Diabetic nephropathy is characterized by hypertension, progressive albuminuria, glomerulosclerosis and declines in glomerular filtration rate leading to end stage renal disease. Although the pathogenesis of diabetic nephropathy is not fully understood, current treatment of the patients with diabetic nephropathy is mainly based upon the control of hyperglycaemia and management of blood pressures. Several drugs, which are originally developed for hypertension therapy, have been adopted for stabilization of renal function in diabetic nephropathy. In this review, we first discuss the relationships between diabetic nephropathy and hypertension particularly in the renin-angiotensin-aldosterone system. We then summarize chemical structures, pharmacological characteristics and clinical studies of the common drugs used for treatment of diabetic nephropathy, while these drugs have effects against hypertension. This review may provide the constructive information for further drug development in diabetic nephropathy.

  20. Renal denervation, adjusted drugs, or combined therapy for resistant hypertension: A meta-regression.

    Science.gov (United States)

    Qi, Xiao-Yu; Cheng, Bin; Li, Ying-Li; Wang, Yue-Feng

    2016-07-01

    The objective of this study is to systematically evaluate the efficacy of renal denervation (RD), adjusted drugs, or combined therapy for resistant hypertension (RH) through a systematic review and meta-analysis of controlled studies.Publications were comprehensively searched. Studies that investigated the effects of RD and/or adjusted drugs in lowering blood pressure (BP) were included. After quality assessment and data extraction, subgroup analyzes were first performed according to blinding method. Meta-regression and inverted funnel plots were also conducted.A total of 13 studies containing 1604 RH patients were included. Compared with control, the meta-analysis showed that RD significantly reduced office-based BP and ambulatory BP in 6 months in the unblinded studies, while no significant difference was found in the blinded studies. Meta-regression demonstrated the significant influence of blinding method on BP reduction, and further analysis revealed a significant BP reduction compared with baseline even in the control arm of blinded studies. RD had similar effects compared with adjusted drugs, and combined therapy seemed to further reduce the level of BP.The efficacy of RD was different between blinded and unblinded studies, and our data revealed a significant BP-lowering effect in the control arm of blinded studies, which was helpful to explain this finding. Furthermore, RD seemed to be equivalent to adjusted drugs, and also we suggested a potential advantage of combined therapy of RD and adjusted drugs compared with monotherapy for RH. However, more studies are warranted to better address the issue.

  1. Non-steroidal anti-inflammatory drugs and renal response to exercise

    DEFF Research Database (Denmark)

    Olsen, Niels Vidiendal; Jensen, N G; Hansen, J M

    1999-01-01

    at baseline, during graded 20-min exercise sessions at 25%, 50% and 75% of the maximal oxygen uptake rate, and subsequently during two 1-h recovery periods. Heart rate, arterial blood pressure, cardiac output and plasma catecholamines at rest and during exercise were not altered by indomethacin or nabumetone......Nabumetone, a newer non-steroidal anti-inflammatory drug (NSAID) which preferentially blocks cyclo-oxygenase-2 activity, may be less nephrotoxic than indomethacin. This study tested whether nabumetone has effects different from those of indomethacin on exercise-induced changes in renal function....... Indomethacin decreased urinary rates of excretion of 6-oxo-prostaglandin F(1alpha) (6-oxo-PGF(1alpha)) and thromboxane B(2) in all study periods. Nabumetone decreased 6-oxo-PGF(1alpha) excretion during and after exercise. Excretion rates for PGE(2) did not change. Neither indomethacin nor nabumetone changed...

  2. Renal accumulation of [{sup 111}In]DOTATOC in rats: influence of inhibitors of the organic ion transport and diuretics

    Energy Technology Data Exchange (ETDEWEB)

    Stahl, A.R. [Technische Universitaet Muenchen, Klinikum rechts der Isar, Department of Nuclear Medicine, Munich (Germany); Universitaetsklinikum Essen, Department of Radiology, Essen (Germany); Wagner, B.; Heemann, U.; Lutz, J. [Technische Universitaet Muenchen, Klinikum rechts der Isar, Department of Nephrology, Munich (Germany); Poethko, T.; Perutka, M.; Wester, H.J.; Essler, M.; Schwaiger, M. [Technische Universitaet Muenchen, Klinikum rechts der Isar, Department of Nuclear Medicine, Munich (Germany)

    2007-12-15

    Radiation exposure to the kidney limits therapy with radiometal labelled DOTATOC. This study evaluates the organic anion and cation transport (inhibitors: probenecid and cimetidine/dexamethason) as well as diuresis (furosemide and mannitol) regarding renal uptake of [{sup 111}In]DOTATOC. One hundred eight male Fisher rats were injected with [{sup 111}In]DOTATOC via the tail vein. Prior to activity injection a total of 84 rats underwent injection with probenecid vs. sodium chloride 0.9% (48 rats), cimetidine vs. dexamethasone vs. sodium chloride 0.9% (18 rats), and furosemide vs. mannitol vs. sodium chloride 0.9% (18 rats). Rats were sacrificed at predetermined time points up to 48 h after activity injection. Kidneys, adrenal glands, pancreas, spleen, blood, liver, and muscle were harvested and injected activity per gram tissue was determined. Autoradiographic images of the kidneys were acquired in a total of 24 rats. Probenecid led to a reduction in renal uptake by up to 30% while not significantly changing the activity accumulation in the other organs investigated. This reduction was attributable to the renal cortex (ratio cortex/medulla 1.72 vs. 1.99; p = 0.006). Cimetidine and dexamethasone had no effect in any of the organs. Furosemide led to a 44% increase in renal activity accumulation attributable to enhanced renal medullary uptake (ratio cortex/medulla 1.44 versus 1.69; p = 0.006). Mannitol had no effect on renal activity uptake. Inhibition of the organic anion transport by probenecid may help reduce renal uptake regarding therapy with radiometal labelled DOTATOC. The enhancing effect of furosemide may be unfavourable for therapy. The results must be confirmed by human studies. (orig.)

  3. Renal teratogens.

    Science.gov (United States)

    Morgan, Thomas M; Jones, Deborah P; Cooper, William O

    2014-09-01

    In utero exposure to certain drugs early in pregnancy may adversely affect nephrogenesis. Exposure to drugs later in pregnancy may affect the renin-angiotensin system, which could have an impact on fetal or neonatal renal function. Reduction in nephron number and renal function could have adverse consequences for the child several years later. Data are limited on the information needed to guide decisions for patients and providers regarding the use of certain drugs in pregnancy. The study of drug nephroteratogenicity has not been systematized, a large, standardized, global approach is needed to evaluate the renal risks of in utero drug exposures.

  4. Drug Dosing in Patients with Renal Insufficiency in a Hospital Setting using Electronic Prescribing and Automated Reporting of Estimated Glomerular Filtration Rate

    DEFF Research Database (Denmark)

    Nielsen, Anita L.; Henriksen, Daniel Pilsgaard; Marinakis, Christianna;

    2014-01-01

    . We conclude that despite implementation of electronic prescribing and automated reporting of eGFR, patients with renal insufficiency may still be exposed to inappropriate drug use, with potential increased risk of adverse effects. Initiatives to reduce medication errors such as the use of electronic......GFR in the range of 10-49 ml/min/1.73m(2) were included. We identified 436 episodes with administration of renal risk drugs (prescribed to 183 patients): 410 drugs required dose adjustment according to the eGFR and 26 should be avoided. In total, the use or dosing of 66 (15%) of the 436 renal risk drugs...

  5. A novel sorbitol transport mechanism in cultured renal papillary epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Siebens, A.W.; Spring, K.R. (National Heart, Lung, and Blood Institute, Bethesda, MD (USA))

    1989-12-01

    The renal papillary epithelial cell line, GRB-PAP1, accumulates sorbitol when grown in a hypertonic (500 mosmol/kgH2O) bathing medium. When the cells are returned to a 300 mosmol/kgH2O medium, they lose their sorbitol rapidly to the bath. Sorbitol movement across the membranes of these cells was investigated by studying the uptake of radioactive sorbitol and related compounds. Sorbitol uptake increased 71-fold when cells grown in 500 mosmol/kgH2O medium were exposed to a 300 mosmol/kgH2O test solution. The magnitude of the permeability increase was proportional to the size of the change in the osmolality of the bathing medium and not the absolute osmolality. Sorbitol uptake was a linear function of medium sorbitol concentration with no sign of saturation at sorbitol concentrations up to 315 mM. Although the permeability of other polyols was increased when the osmolality was reduced, competition between sorbitol and related sugars and polyols could not be demonstrated. Both the increased sorbitol uptake after a decrease in medium osmolality and the decrease to control permeability after return to the original osmolality were complete within 30 s. A wide variety of transport inhibitors and ion substitutions failed to alter the magnitude of the sorbitol permeability increase. The most effective inhibitor was quinidine, 1 mM reducing sorbitol uptake by 73%. The sorbitol permeability increase could also be blocked by reducing the temperature to 0 degrees C. Nonspecific uptake of sorbitol, such as endocytosis, was shown to be of only minor significance. The large increase in sorbitol permeability and subsequent sorbitol efflux enables these cells to withstand large decreases in osmolality without excessive swelling and consequent damage. A similar compensatory mechanism may operate in vivo in the renal papilla during the onset of diuresis.

  6. Expression of Genes for Drug Transporters in the Human Female Genital Tract and Modulatory Effect of Antiretroviral Drugs.

    Directory of Open Access Journals (Sweden)

    Karolin Hijazi

    Full Text Available Anti-retroviral (ARV -based microbicides are one of the strategies pursued to prevent HIV-1 transmission. Delivery of ARV drugs to subepithelial CD4+ T cells at concentrations for protection is likely determined by drug transporters expressed in the cervicovaginal epithelium. To define the role of drug transporters in mucosal disposition of topically applied ARV-based microbicides, these must be tested in epithelial cell line-based biopharmaceutical assays factoring the effect of relevant drug transporters. We have characterised gene expression of influx and efflux drug transporters in a panel of cervicovaginal cell lines and compared this to expression in cervicovaginal tissue. We also investigated the effect of dapivirine, darunavir and tenofovir, currently at advanced stages of microbicides development, on expression of drug transporters in cell lines. Expression of efflux ABC transporters in cervical tissue was best represented in HeLa, Ect1/E6E7 and End1/E6E7 cell lines. Expression of influx OCT and ENT transporters in ectocervix matched expression in Hela while expression of influx SLCO transporters in vagina was best reflected in VK2/E6E7 cell line. Stimulation with darunavir and dapivirine upregulated MRP transporters, including MRP5 involved in transport of tenofovir. Dapivirine also significantly downregulated tenofovir substrate MRP4 in cervical cell lines. Treatment with darunavir and dapivirine showed no significant effect on expression of BCRP, MRP2 and P-glycoprotein implicated in efflux of different ARV drugs. Darunavir strongly induced expression in most cell lines of CNT3 involved in cell uptake of nucleotide/nucleoside analogue reverse transcriptase inhibitors and SLCO drug transporters involved in cell uptake of protease inhibitors. This study provides insight into the suitability of cervicovaginal cell lines for assessment of ARV drugs in transport kinetics studies. The modulatory effect of darunavir and dapivirine on

  7. From nose to brain: understanding transport capacity and transport rate of drugs.

    Science.gov (United States)

    Wu, Hongbing; Hu, Kaili; Jiang, Xinguo

    2008-10-01

    The unique relationship between nasal cavity and cranial cavity tissues in anatomy and physiology makes intranasal delivery to the brain feasible. An intranasal delivery provides some drugs with short channels to bypass the blood-brain barrier (BBB), especially for those with fairly low brain concentrations after a routine delivery, thus greatly enhancing the therapeutic effect on brain diseases. In the past two decades, a good number of encouraging outcomes have been reported in the treatment of diseases of the brain or central nervous system (CNS) through nasal administration. In spite of the significant merit of bypassing the BBB, direct nose-to-brain delivery still bears the problems of low efficiency and volume for capacity due to the limited volume of the nasal cavity, the small area ratio of olfactory mucosa to nasal mucosa and the limitations of low dose and short retention time of drug absorption. It is crucial that selective distribution and retention time of drugs or preparations on olfactory mucosa should be enhanced so as to increase the direct delivery efficiency. In this article, we first briefly review the nose-to-brain transport pathways, before detailing the impacts on them, followed by a comprehensive summary of effective methods, including formulation modification, agglutinant-mediated transport and a brain-homing, peptide-mediated delivery based on phage display screening technique, with a view to providing a theoretic reference for elevating the therapeutic effects on brain diseases.

  8. Establishing a human renal cell carcinoma tumorgraft platform for preclinical drug testing.

    Science.gov (United States)

    Pavía-Jiménez, Andrea; Tcheuyap, Vanina Toffessi; Brugarolas, James

    2014-08-01

    Traditionally, xenograft models have been used to study tumors in vivo. However, their utility is reduced by the use of tumor cell lines for implantation. Tumorgrafts (TGs; also known as patient-derived xenografts (PDXs)), which involve patient-derived tumor samples, are increasingly recognized as more representative models than traditional xenografts. Furthermore, we showed previously that renal cell carcinoma (RCC) TGs retain the histology, gene expression, DNA copy number alterations, mutations and treatment responsiveness of patient tumors. In skilled hands, implantations require ≤5 min per mouse, and TGs typically grow to 1 cm in 1-4 months. Here we outline the process of implantation of patient-derived RCC samples into the kidneys of immunodeficient mice, as well as the s.c. implantation for preclinical drug testing, including guidelines for the design and execution of drug trials. TGs have extensive applications besides therapeutic studies and may identify biomarkers and mechanisms of resistance. In addition, they may provide insights into tumor biology.

  9. Enhancements and limits in drug membrane transport using supersaturated solutions of poorly water soluble drugs.

    Science.gov (United States)

    Raina, Shweta A; Zhang, Geoff G Z; Alonzo, David E; Wu, Jianwei; Zhu, Donghua; Catron, Nathaniel D; Gao, Yi; Taylor, Lynne S

    2014-09-01

    Amorphous solid dispersions (ASDs) give rise to supersaturated solutions (solution concentration greater than equilibrium crystalline solubility). We have recently found that supersaturating dosage forms can exhibit the phenomenon of liquid-liquid phase separation (LLPS). Thus, the high supersaturation generated by dissolving ASDs can lead to a two-phase system wherein one phase is an initially nanodimensioned and drug-rich phase and the other is a drug-lean continuous aqueous phase. Herein, the membrane transport of supersaturated solutions, at concentrations above and below the LLPS concentration has been evaluated using a side-by-side diffusion cell. Measurements of solution concentration with time in the receiver cell yield the flux, which reflects the solute thermodynamic activity in the donor cell. As the nominal concentration of solute in the donor cell increases, a linear increase in flux was observed up to the concentration where LLPS occurred. Thereafter, the flux remained essentially constant. Both nifedipine and felodipine solutions exhibit such behavior as long as crystallization is absent. This suggests that there is an upper limit in passive membrane transport that is dictated by the LLPS concentration. These results have several important implications for drug delivery, especially for poorly soluble compounds requiring enabling formulation technologies.

  10. Export of a single drug molecule in two transport cycles by a multidrug efflux pump.

    Science.gov (United States)

    Fluman, Nir; Adler, Julia; Rotenberg, Susan A; Brown, Melissa H; Bibi, Eitan

    2014-08-08

    Secondary multidrug transporters use ion concentration gradients to energize the removal from cells of various antibiotics. The Escherichia coli multidrug transporter MdfA exchanges a single proton with a single monovalent cationic drug molecule. This stoichiometry renders the efflux of divalent cationic drugs energetically unfavourable, as it requires exchange with at least two protons. Here we show that surprisingly, MdfA catalyses efflux of divalent cations, provided that they have a unique architecture: the two charged moieties must be separated by a long linker. These drugs are exchanged for two protons despite the apparent inability of MdfA to exchange two protons for a single drug molecule. Our results suggest that these drugs are transported in two consecutive transport cycles, where each cationic moiety is transported as if it were a separate substrate. We propose that secondary transport can adopt a processive-like mode of action, thus expanding the substrate spectrum of multidrug transporters.

  11. Modeling the transport of drugs eluted from stents: physical phenomena driving drug distribution in the arterial wall.

    Science.gov (United States)

    Bozsak, Franz; Chomaz, Jean-Marc; Barakat, Abdul I

    2014-04-01

    Despite recent data that suggest that the overall performance of drug-eluting stents (DES) is superior to that of bare-metal stents, the long-term safety and efficacy of DES remain controversial. The risk of late stent thrombosis associated with the use of DES has also motivated the development of a new and promising treatment option in recent years, namely drug-coated balloons (DCB). Contrary to DES where the drug of choice is typically sirolimus and its derivatives, DCB use paclitaxel since the use of sirolimus does not appear to lead to satisfactory results. Since both sirolimus and paclitaxel are highly lipophilic drugs with similar transport properties, the reason for the success of paclitaxel but not sirolimus in DCB remains unclear. Computational models of the transport of drugs eluted from DES or DCB within the arterial wall promise to enhance our understanding of the performance of these devices. The present study develops a computational model of the transport of the two drugs paclitaxel and sirolimus eluted from DES in the arterial wall. The model takes into account the multilayered structure of the arterial wall and incorporates a reversible binding model to describe drug interactions with the constituents of the arterial wall. The present results demonstrate that the transport of paclitaxel in the arterial wall is dominated by convection while the transport of sirolimus is dominated by the binding process. These marked differences suggest that drug release kinetics of DES should be tailored to the type of drug used.

  12. Na+-dependent and Na+-independent betaine transport across the apical membrane of rat renal epithelium.

    Science.gov (United States)

    Cano, Mercedes; Calonge, María L; Ilundáin, Anunciación A

    2015-10-01

    The low renal excretion of betaine indicates that the kidney efficiently reabsorbs the betaine filtered by the glomeruli but the mechanisms involved in such a process have been scarcely investigated. We have detected concentrative and non-concentrative betaine transport activity in brush-border membrane vesicles (BBMV) from rat renal cortex and medulla. The concentrative system is the Sodium/Imino-acid Transporter 1 (SIT1) because it is Na+- and Cl--dependent, electrogenic and is inhibited by an anti-SIT1 antibody. Its apparent affinity constant for betaine, Kt, is 1.1±0.5 mM and its maximal transport velocity, Vmax, 0.5±0.1 nmol betaine/mg protein/s. Inhibitors of the Na+/Cl-/betaine uptake are L-proline (75%) and cold betaine, L-carnitine and choline (40-60%). Neither creatine, TEA, taurine, β-alanine, GABA nor glycine significantly inhibited Na+/Cl-/betaine uptake. The non-concentrative betaine transport system is Na+- and H+-independent, electroneutral, with a Kt for betaine of 47±7 μM and a Vmax of 7.8±1 pmol betaine/mg protein/s. Its transport activity is nearly abolished by betaine, followed by L-carnitine (70-80%) and proline (40-50%), but a difference from the Na+/Cl-/betaine transport is that it is inhibited by TEA (approx. 50%) and unaffected by choline. The underlying carrier functions as an antiporter linking betaine entry into the BBMV with the efflux of either L-carnitine or betaine, an exchange unaffected by the anti-SIT1 antibody. As far as we know this is the first work reporting that betaine crosses the apical membrane of rat renal epithelium by SIT1 and by a Na+- and H+-independent transport system.

  13. The Role of the Renal Ammonia Transporter Rhcg in Metabolic Responses to Dietary Protein

    Science.gov (United States)

    Bounoure, Lisa; Ruffoni, Davide; Müller, Ralph; Kuhn, Gisela Anna; Devuyst, Olivier

    2014-01-01

    High dietary protein imposes a metabolic acid load requiring excretion and buffering by the kidney. Impaired acid excretion in CKD, with potential metabolic acidosis, may contribute to the progression of CKD. Here, we investigated the renal adaptive response of acid excretory pathways in mice to high-protein diets containing normal or low amounts of acid-producing sulfur amino acids (SAA) and examined how this adaption requires the RhCG ammonia transporter. Diets rich in SAA stimulated expression of enzymes and transporters involved in mediating NH4+ reabsorption in the thick ascending limb of the loop of Henle. The SAA-rich diet increased diuresis paralleled by downregulation of aquaporin-2 (AQP2) water channels. The absence of Rhcg transiently reduced NH4+ excretion, stimulated the ammoniagenic pathway more strongly, and further enhanced diuresis by exacerbating the downregulation of the Na+/K+/2Cl− cotransporter (NKCC2) and AQP2, with less phosphorylation of AQP2 at serine 256. The high protein acid load affected bone turnover, as indicated by higher Ca2+ and deoxypyridinoline excretion, phenomena exaggerated in the absence of Rhcg. In animals receiving a high-protein diet with low SAA content, the kidney excreted alkaline urine, with low levels of NH4+ and no change in bone metabolism. Thus, the acid load associated with high-protein diets causes a concerted response of various nephron segments to excrete acid, mostly in the form of NH4+, that requires Rhcg. Furthermore, bone metabolism is altered by a high-protein acidogenic diet, presumably to buffer the acid load. PMID:24652796

  14. Expression of Trans- and Paracellular Calcium and Magnesium Transport Proteins in Renal and Intestinal Epithelia During Lactation

    DEFF Research Database (Denmark)

    Beggs, Megan R; Appel, Ida; Svenningsen, Per

    2017-01-01

    Significant alterations in maternal calcium (Ca2+) and magnesium (Mg2+) balance occur during lactation. Ca2+ is the primary divalent cation mobilized into breast milk by demineralization of the skeleton and alterations in intestinal and renal Ca2+ transport. Mg2+ is also concentrated in breast milk......, but the underlying mechanisms are not well understood. To determine the molecular alterations in Ca2+ and Mg2+ transport in the intestine and kidney during lactation, 3 groups of female mice consisting of either non-pregnant controls, lactating mice, or mice undergoing involution were examined. The fractional...... excretion of Ca2+, but not Mg2+, rose significantly during lactation. Renal 1-alpha hydroxylase and 24-OHase mRNA levels increased markedly as did plasma 1,25 dihydroxyvitamin D levels. This was accompanied by significant increases in intestinal expression of Trpv6 and S100g in lactating mice. However...

  15. Non-steroidal anti-inflammatory drugs and renal response to exercise: a comparison of indomethacin and nabumetone.

    Science.gov (United States)

    Olsen, N V; Jensen, N G; Hansen, J M; Christensen, N J; Fogh-Andersen, N; Kanstrup, I L

    1999-10-01

    Nabumetone, a newer non-steroidal anti-inflammatory drug (NSAID) which preferentially blocks cyclo-oxygenase-2 activity, may be less nephrotoxic than indomethacin. This study tested whether nabumetone has effects different from those of indomethacin on exercise-induced changes in renal function and the renin-aldosterone system. In a randomized fashion, ten subjects were studied after indomethacin (100 mg), nabumetone (1 g) or no medication (control) administered orally at 22.00 hours on the day before each study day, and again at 8.00 hours upon arrival at the laboratory. Renal function was studied at baseline, during graded 20-min exercise sessions at 25%, 50% and 75% of the maximal oxygen uptake rate, and subsequently during two 1-h recovery periods. Heart rate, arterial blood pressure, cardiac output and plasma catecholamines at rest and during exercise were not altered by indomethacin or nabumetone. Indomethacin decreased urinary rates of excretion of 6-oxo-prostaglandin F(1alpha) (6-oxo-PGF(1alpha)) and thromboxane B(2) in all study periods. Nabumetone decreased 6-oxo-PGF(1alpha) excretion during and after exercise. Excretion rates for PGE(2) did not change. Neither indomethacin nor nabumetone changed baseline values or exercise-induced decreases in renal plasma flow or glomerular filtration rate. Indomethacin, but not nabumetone, decreased sodium excretion, urine flow rate and free water clearance. The renal response to exercise, however, remained unchanged. In contrast with nabumatone, indomethacin decreased the plasma renin concentration. Thus, during exercise, nabumetone may decrease the excretion of 6-oxo-PGF(1alpha) by inhibition of cyclo-oxygenase-1 or by inhibition of specific exercise-induced activation of cyclo-oxygenase-2, or both. None of the drugs changed the renal response to exercise. Inhibition by indomethacin of angiotensin II and thromboxane A(2) synthesis may, during exercise, counterbalance renal vasoconstriction caused by blockade of

  16. Renal targeting potential of a polymeric drug carrier, poly-l-glutamic acid, in normal and diabetic rats

    Science.gov (United States)

    Chai, Hann-Juang; Kiew, Lik-Voon; Chin, Yunni; Norazit, Anwar; Mohd Noor, Suzita; Lo, Yoke-Lin; Looi, Chung-Yeng; Lau, Yeh-Siang; Lim, Tuck-Meng; Wong, Won-Fen; Abdullah, Nor Azizan; Abdul Sattar, Munavvar Zubaid; Johns, Edward J; Chik, Zamri; Chung, Lip-Yong

    2017-01-01

    Background and purpose Poly-l-glutamic acid (PG) has been used widely as a carrier to deliver anticancer chemotherapeutics. This study evaluates PG as a selective renal drug carrier. Experimental approach 3H-deoxycytidine-labeled PGs (17 or 41 kDa) and 3H-deoxycytidine were administered intravenously to normal rats and streptozotocin-induced diabetic rats. The biodistribution of these compounds was determined over 24 h. Accumulation of PG in normal kidneys was also tracked using 5-(aminoacetamido) fluorescein (fluoresceinyl glycine amide)-labeled PG (PG-AF). To evaluate the potential of PGs in ferrying renal protective anti-oxidative stress compounds, the model drug 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride (AEBSF) was conjugated to 41 kDa PG to form PG-AEBSF. PG-AEBSF was then characterized and evaluated for intracellular anti-oxidative stress efficacy (relative to free AEBSF). Results In the normal rat kidneys, 17 kDa radiolabeled PG (PG-Tr) presents a 7-fold higher, while 41 kDa PG-Tr shows a 15-fold higher renal accumulation than the free radiolabel after 24 h post injection. The accumulation of PG-AF was primarily found in the renal tubular tissues at 2 and 6 h after an intravenous administration. In the diabetic (oxidative stress-induced) kidneys, 41 kDa PG-Tr showed the greatest renal accumulation of 8-fold higher than the free compound 24 h post dose. Meanwhile, the synthesized PG-AEBSF was found to inhibit intracellular nicotinamide adenine dinucleotide phosphate oxidase (a reactive oxygen species generator) at an efficiency that is comparable to that of free AEBSF. This indicates the preservation of the anti-oxidative stress properties of AEBSF in the conjugated state. Conclusion/Implications The favorable accumulation property of 41 kDa PG in normal and oxidative stress-induced kidneys, along with its capabilities in conserving the pharmacological properties of the conjugated renal protective drugs, supports its role as a potential renal

  17. Pharmacokinetics of gyrase inhibitors, Part 2: Renal and hepatic elimination pathways and drug interactions.

    Science.gov (United States)

    Sörgel, F; Kinzig, M

    1993-03-22

    This article focuses on the relationship of the physicochemical properties of gyrase inhibitors to their hepatic and renal elimination pathways. Luminal fluid concentrations of gyrase inhibitors are affected by an active process and can be inhibited by agents such as probenecid that inhibit tubular secretion of anions. Probenecid may inhibit base transport in the proximal tubule and appears to inhibit base transport as well. Available data suggest that all gyrase inhibitors can be secreted as anions by the proximal tubules. Cimetidine, which is cationic at physiologic pH, inhibits base transport in the proximal tubule and appears to inhibit base transport of gyrase inhibitors. Reabsorption also affects tubular concentrations. Models that describe the effects of urinary flow and pH are discussed. The N4'-methylated derivatives are the most lipophilic, and addition or removal of the methyl group can, but does not always, affect reabsorption. The data indicate that all gyrase inhibitors undergo tubular secretion as either acids or bases and that some also are significantly reabsorbed. Hepatic handling and resultant excretion of metabolites are also influenced by the presence or absence of N4'-methylation. A step in the hepatic handling of N4'-methylated gyrase inhibitors that leads to N4'-oxidation has not yet been found in rufloxacin. Rebiotransformation of N4'-oxides was described in liver perfusion experiments. The potential for interaction with theophylline is not identical for all gyrase inhibitors. Enoxacin is the strongest inhibitor of theophylline and caffeine metabolism, followed by tosufloxacin, ciprofloxacin, and pefloxacin. Fleroxacin, ofloxacin, rufloxacin, and sparfloxacin have no or negligible effects. A likely mechanism for this interaction is the inhibition of subsets of the cytochrome P-450 enzyme. Structure activity relationships were established for this interaction. Piperazine ring-cleaved compounds and naphthyridine nuclei were shown to be most

  18. A Human Renal Proximal Tubule Cell Line with Stable Organic Anion Transporter 1 and 3 Expression Predictive for Antiviral-Induced Toxicity

    NARCIS (Netherlands)

    Nieskens, Tom T G; Peters, Janny G P; Schreurs, Marieke J; Smits, Niels; Woestenenk, Rob; Jansen, Katja; van der Made, Thom K; Röring, Melanie; Hilgendorf, Constanze; Wilmer, Martijn J; Masereeuw, Roos

    2016-01-01

    Drug-induced nephrotoxicity still hampers drug development, because current translation from in vitro or animal studies to human lacks high predictivity. Often, renal adverse effects are recognized only during clinical stages of drug development. The current study aimed to establish a robust and a m

  19. A RETROSPECTIVE STUDY ON THE POTENTIAL DRUG INTERACTION BETWEEN ANGIOTENSIN CONVERTING ENZYME INHIBITOR OR ANGIOTENSIN RECEPTOR ANTAGONIST AND OTHER DRUGS IN END-STAGE CHRONIC RENAL FAILURE PATIENTS

    Directory of Open Access Journals (Sweden)

    Honey Iskandar

    2012-10-01

    Full Text Available Increasing number of chronic renal failure (CRF patients had reflected an increase in the number of patients with diabetes and hypertension. Therefore, health practitioners would be faced with management of complicated medical problems for the patients of chronic renal disease. In this way, various complications of chronic renal failure would lead to polypharmacy, where the patients receive three to five drugs in a dose. Development of polypharmacy had made the potential of drug interaction greater. The objective was to determine whether CRF patients admitted to hospital with specific adverse drug reactions were likely to have been prescribed with interacting drugs. Retrospective study was designed. The study was conducted at the General Practice Rooms Floor 1 – Floor VI of Central Army Hospital Gatot Soebroto Jakarta. The study was conducted from December 2011 – February 2012. The data were collected in a retrospective way for a year (January – December 2011. End-stage CRF patients who were having hemodialysis therapy and receiving ACE Inhibitor drugs or Angiotensin II Receptor Antagonist (AIIRA and receiving treatment at the General Practice Rooms at Central Army Hospital Gatot Soebroto Jakarta. During the period of January – December 2011, 84 patients were treated with end-stage CRF at the Central Army Hospital and having routine hemodialysis and 44 patients were receiving therapy with ACE Inhibitor and AIIRA. Other drugs simultaneously given with ACE Inhibitor and AIIRA were captopril-spironolactone, captopril-aspirin, captopril-allopurinol, captopril-KSR, captopril-furosemide, lisinopril-furosemide and valsartan-mefenemic acid. An increase in adverse effects of the drugs was found based on the clinical evaluation and laboratory examination. The adverse effects included hyperkalemia (9,09%, decrease in anti-hypertension effect (6,8%, acute hypotension (40%, and declining renal function (11,36%. The study identifies drug interaction

  20. Effect of Hypotensive Drugs on Dynamics of Nitroxide-Producing Renal Function in Rats with Nephrogenic Hypertension.

    Science.gov (United States)

    Eliseeva, E V; Romanchenko, E F; Dyuizen, I V; Tyrtyshnikova, A V; Pigolkin, Yu I

    2017-01-01

    An original model of nephrogenic hypertension in rats was used for histochemical mapping of NADPH diaphorase (NO synthase) in various renal segments to examine the effect of hypotensive drugs furosemide, bendazol, and clonidine on the time course of nitroxide production in the kidneys. In various nephron segments, these drugs modulated NO synthesis in different ways. Clonidine induced a stable up-regulation of NO synthesis, which can maintain active vasodilation and gradually diminish the rennin production. Bendazol also enhanced NO synthase activity in renal glomeruli and collecting tubules, but this effect was less pronounced and short lasting. During the first week after injection of bendazol, insignificant elevation of NO synthase activity was observed in the proximal nephron segments. Furosemide exerted the least effect on NO production in kidneys.

  1. Therapeutic Drug Monitoring of Continuous Infusion Doripenem in a Pediatric Patient on Continuous Renal Replacement Therapy.

    Science.gov (United States)

    Cies, Jeffrey J; Moore, Wayne S; Conley, Susan B; Shea, Paul; Enache, Adela; Chopra, Arun

    2017-01-01

    An 11-year-old African American male with severe combined immunodeficiency variant, non-cystic fibrosis bronchiectasis, pancreatic insufficiency, chronic mycobacterium avium-intracellulare infection, chronic sinusitis, and malnutrition presented with a 1-week history of fevers. He subsequently developed respiratory decompensation and cefepime was discontinued and doripenem was initiated. Doripenem was the carbapenem used due to a national shortage of meropenem. By day 7 the patient (24.7 kg) had a positive fluid balance of 6925 mL (28% FO), and on days 7 into 8 developed acute kidney injury evidenced by an elevated serum creatinine of 0.68 mg/dL, an increase from the baseline of 0.28 mg/dL. On day 9, the patient was initiated on continuous renal replacement therapy (CRRT) and the doripenem dosing was changed to a continuous infusion of 2.5 mg/kg/hr (60 mg/kg/day). Approximately 12.5 hours after the start of the doripenem a serum concentration was obtained, which was 4.01 mg/L corresponding to a clearance of 10.5 mL/min/kg. The pediatric dosing and pharmacokinetic data available for doripenem suggest a clearance estimate of 4.4 to 4.8 mL/min/kg, and the adult clearance estimate is 2.4 to 3.78 mL/min/kg. The calculated clearance in our patient of 10.5 mL/min/kg is over double the highest clearance estimate in the pediatric literature. This case demonstrates that doripenem clearance is significantly increased with CRRT in comparison with the published pediatric and adult data. An appropriate pharmacodynamic outcome (time that free drug concentration > minimum inhibitory concentration) can be achieved by continuous infusion doripenem with concurrent therapeutic drug monitoring.

  2. Drug therapy of renal cell carcinoma%肾癌的药物治疗

    Institute of Scientific and Technical Information of China (English)

    康马飞

    2008-01-01

    肾癌的药物治疗目前仍以免疫化学治疗为主,单纯化疗也有效,吉西他滨联合顺铂是目前的标准化疗方案.靶向治疗药物的出现使肾癌的治疗发生了改变,多靶点受体酪氨酸激酶抑制剂(如舒尼替尼和索拉非尼)、哺乳动物雷帕霉素靶蛋白抑制剂(temsirolimus)和抗肿瘤单克隆抗体(如贝伐单抗)等已成为肾癌的一线治疗选择.%Immunochemotherapy is still the primary drug therapy of renal cell carcinoma(RCC), and chemotherapy is effective too. The combination of gemcitabine and cisplatin is the standard regimen now. How-ever, emerge of targeted therapeutic agents has altered the treatment of RCC. Multitargeted tyrosine kinase in-hibitor, such as sunitinib and sorafenib, and mammalian target of rapamycin (roTOR) inhibitors( temsiroll-mus), and anti-tumor monoclonal antibody, such as bevacizumab, have already become the first line election.

  3. [Carboxyl nanodiamond as intracellular transporters of anticancer drug--podophyllotoxin].

    Science.gov (United States)

    Sun, Tao-Li; Wang, Bin; Peng, Yan; Ni, Jing-Man

    2013-01-01

    The purpose of this study is to investigate the intracellular transporters effect and the cytotoxicity of carboxyl nanodiamond (CND) - podophyllotoxin (PPT). Nanodiamond (ND) was treated with mixed carboxylic acid and finally got 64 nm CND by centrifugation, and then it was reacted with PPT to form CND-PPT. UV spectrophotometry was used to calculate the content of PPT in CND-PPT, the particle size distribution and zeta potential were measured by Dynamic laser scattering instrument. CND, PPT, CND-PPT and CND + PPT (physical mixture of CND and PPT) were characterized by Fourier transform infrared spectroscopy, at the same time, thermal analysis and element analysis were used to estimate the content of the PPT in CND-PPT. The affect of CND, PPT, CND-PPT on HeLa cell was measured with MTT assay. The results showed that content of PPT combined with CND accounted for about 10%. MTT assay showed that CND has low cytotoxicity and CND-PPT can increase the water soluble of PPT. As a conclusion, CND as a hydrophilic pharmaceutical carrier combined with PPT is able to increase the water solubility of PPT, at low concentration, CND-PPT can enhance the antitumor activity in comparison with PPT, so CND can be used as a potential anticancer drug carrier.

  4. Human kidney proximal tubule-on-a-chip for drug transport and nephrotoxicity assessment.

    Science.gov (United States)

    Jang, Kyung-Jin; Mehr, Ali Poyan; Hamilton, Geraldine A; McPartlin, Lori A; Chung, Seyoon; Suh, Kahp-Yang; Ingber, Donald E

    2013-09-01

    Kidney toxicity is one of the most frequent adverse events reported during drug development. The lack of accurate predictive cell culture models and the unreliability of animal studies have created a need for better approaches to recapitulate kidney function in vitro. Here, we describe a microfluidic device lined by living human kidney epithelial cells exposed to fluidic flow that mimics key functions of the human kidney proximal tubule. Primary kidney epithelial cells isolated from human proximal tubule are cultured on the upper surface of an extracellular matrix-coated, porous, polyester membrane that splits the main channel of the device into two adjacent channels, thereby creating an apical 'luminal' channel and a basal 'interstitial' space. Exposure of the epithelial monolayer to an apical fluid shear stress (0.2 dyne cm(-2)) that mimics that found in living kidney tubules results in enhanced epithelial cell polarization and primary cilia formation compared to traditional Transwell culture systems. The cells also exhibited significantly greater albumin transport, glucose reabsorption, and brush border alkaline phosphatase activity. Importantly, cisplatin toxicity and Pgp efflux transporter activity measured on-chip more closely mimic the in vivo responses than results obtained with cells maintained under conventional culture conditions. While past studies have analyzed kidney tubular cells cultured under flow conditions in vitro, this is the first report of a toxicity study using primary human kidney proximal tubular epithelial cells in a microfluidic 'organ-on-a-chip' microdevice. The in vivo-like pathophysiology observed in this system suggests that it might serve as a useful tool for evaluating human-relevant renal toxicity in preclinical safety studies.

  5. Exploiting Specific Interactions toward Next-Generation Polymeric Drug Transporters

    NARCIS (Netherlands)

    Wieczorek, Sebastian; Krause, Eberhard; Hackbarth, Steffen; Roeder, Beate; Hirsch, Anna K. H.; Boerner, Hans G.

    2013-01-01

    A generic method describes advanced tailoring of polymer drug carriers based on polymer-block-peptides. Combinatorial means are used to select suitable peptide segments to specifically complex small-molecule drugs. The resulting specific drug formulation agents render insoluble drugs water-soluble a

  6. A useful tool for drug interaction evaluation: The University of Washington Metabolism and Transport Drug Interaction Database

    Directory of Open Access Journals (Sweden)

    Hachad Houda

    2010-10-01

    Full Text Available Abstract The Metabolism and Transport Drug Interaction Database (http://www.druginteractioninfo.org is a web-based research and analysis tool developed in the Department of Pharmaceutics at the University of Washington. The database has the largest manually curated collection of data related to drug interactions in humans. The tool integrates information from the literature, public repositories, reference textbooks, guideline documents, product prescribing labels and clinical review sections of new drug approval (NDA packages. The database's easy-to-use web portal offers tools for visualisation, reporting and filtering of information. The database helps scientists to mine kinetics information for drug-metabolising enzymes and transporters, to assess the extent of in vivo drug interaction studies, as well as case reports for drugs, therapeutic proteins, food products and herbal derivatives. This review provides a brief description of the database organisation, its search functionalities and examples of use.

  7. Role of copper transporters in the uptake and efflux of platinum containing drugs.

    Science.gov (United States)

    Safaei, Roohangiz

    2006-03-08

    Cellular mechanisms for the uptake, intracellular distribution and efflux of the platinum (Pt) containing compounds cisplatin (DDP), carboplatin (CBDCA) and oxaliplatin (LOHP) are unknown. Current data suggest that specialized transporters/carriers mediate the transport of Pt drugs across the cellular membranes. Specific roles for the copper (Cu) transporters CTR1, ATP7A and ATP7B have been demonstrated during recent years. The finding that in cultured cells and tumor samples a correlation can be found between the expression of Cu transporters and the degree of the acquired resistance to Pt drug suggests that the Cu transporters are important constituents of the program that regulates sensitivity to Pt drugs. A model is presented that describes the function of Cu transporters in the regulation of Pt drug uptake and efflux.

  8. Regulation of renal phosphate transport by FGF23 is mediated by FGFR1 and FGFR4.

    Science.gov (United States)

    Gattineni, Jyothsna; Alphonse, Priyatharshini; Zhang, Qiuyu; Mathews, Nisha; Bates, Carlton M; Baum, Michel

    2014-02-01

    Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that acts on the proximal tubule to decrease phosphate reabsorption and serum levels of 1,25-dihydroxyvitamin D₃ [1,25(OH)₂ Vitamin D₃]. Abnormal FGF23 metabolism has been implicated in several debilitating hypophosphatemic and hyperphosphatemic disorders. The renal receptors responsible for the phosphaturic actions of FGF23 have not been elucidated. There are four fibroblast growth factor receptors (FGFR); 1-4 with "b" and "c" isoforms for receptors 1, 2, and 3. FGFR1, 3, and 4 are expressed in the mouse proximal tubule, and deletion of any one receptor did not affect serum phosphate levels, suggesting that more than one receptor is involved in mediating the phosphaturic actions of FGF23. To determine the receptors responsible for the phosphaturic actions of FGF23, we studied Fgfr1 (kidney conditional) and Fgfr4 (global) double mutant mice (Fgfr1⁻/⁻/Fgfr4⁻/⁻). Fgfr1⁻/⁻/Fgfr4⁻/⁻ mice have higher FGF23 levels than their wild-type counterparts (108.1 ± 7.3 vs. 4,953.6 ± 675.0 pg/ml; P Fgfr4⁻/⁻ mice have elevated serum phosphorus levels, increased brush-border membrane vesicle (BBMV) phosphate transport, and increased Na-P(i) cotransporter 2c (NaPi-2c) protein expression compared with wild-type mice. These data are consistent with FGFR1 and FGFR4 being the critical receptors for the phosphaturic actions of FGF23.

  9. THE EXPRESSION PROFILING OF INTESTINAL NUTRIENT TRANSPORTER GENES IN RATS WITH RENAL FAILURE

    Directory of Open Access Journals (Sweden)

    Hironori Yamamoto

    2012-06-01

    has been still unclear how different of the intestinal function in CKD. In this study, we demonstrated the microarray analysis of global gene expression in intestine of adenine-induced CKD rat. DNA microarray analysis using Affymextrix rat gene chip revealed that CKD caused great changes in gene expression in the rat duodenum: about 400 genes exhibited more than a two-fold change in expression level. Gene ontology analysis showed that a global regulation of genes by CKD involved in iron ion binding, alcoholic, organic acid and lipid metabolism. Furthermore, we found markedly changes of a number of intestinal transporters gene expression related to iron metabolism. These results suggest that CKD may alter some nutrient metabolism in the small intestine by modifying the expression of specific genes. The intestinal transcriptome database of CKD might be useful to develop the novel drugs or functional foods for CKD patients.

  10. Targeting Receptors, Transporters and Site of Absorption to Improve Oral Drug Delivery

    Directory of Open Access Journals (Sweden)

    J.H. Hamman

    2007-01-01

    Full Text Available Although the oral route of drug administration is the most acceptable way of self-medication with a high degree of patient compliance, the intestinal absorption of many drugs is severely hampered by different biological barriers. These barriers comprise of biochemical and physical components. The biochemical barrier includes enzymatic degradation in the gastrointestinal lumen, brush border and in the cytoplasm of the epithelial cells as well as efflux transporters that pump drug molecules from inside the epithelial cell back to the gastrointestinal lumen. The physical barrier consists of the epithelial cell membranes, tight junctions and mucus layer. Different strategies have been applied to improve the absorption of drugs after oral administration, which range from chemical modification of drug molecules and formulation technologies to the targeting of receptors, transporters and specialized cells such as the gut-associated lymphoid tissues. This review focuses specifically on the targeting of receptor-mediated endocytosis, transporters and the absorption-site as methods of optimizing intestinal drug absorption. Intestinal epithelial cells express several nutrient transporters that can be targeted by modifying the drug molecule in such a way that it is recognized as a substrate. Receptor-mediated endocytosis is a transport mechanism that can be targeted for instance by linking a receptor substrate to the drug molecule of interest. Many formulation strategies exist for enhancing drug absorption of which one is to deliver drugs at a specific site in the gastrointestinal tract where optimum drug absorption takes place.

  11. Targeting receptors, transporters and site of absorption to improve oral drug delivery.

    Science.gov (United States)

    Hamman, J H; Demana, P H; Olivier, E I

    2007-01-01

    Although the oral route of drug administration is the most acceptable way of self-medication with a high degree of patient compliance, the intestinal absorption of many drugs is severely hampered by different biological barriers. These barriers comprise of biochemical and physical components. The biochemical barrier includes enzymatic degradation in the gastrointestinal lumen, brush border and in the cytoplasm of the epithelial cells as well as efflux transporters that pump drug molecules from inside the epithelial cell back to the gastrointestinal lumen. The physical barrier consists of the epithelial cell membranes, tight junctions and mucus layer. Different strategies have been applied to improve the absorption of drugs after oral administration, which range from chemical modification of drug molecules and formulation technologies to the targeting of receptors, transporters and specialized cells such as the gut-associated lymphoid tissues. This review focuses specifically on the targeting of receptor-mediated endocytosis, transporters and the absorption-site as methods of optimizing intestinal drug absorption. Intestinal epithelial cells express several nutrient transporters that can be targeted by modifying the drug molecule in such a way that it is recognized as a substrate. Receptor-mediated endocytosis is a transport mechanism that can be targeted for instance by linking a receptor substrate to the drug molecule of interest. Many formulation strategies exist for enhancing drug absorption of which one is to deliver drugs at a specific site in the gastrointestinal tract where optimum drug absorption takes place.

  12. Chronic Renal Transplant Rejection and Possible Anti-Proliferative Drug Targets.

    Science.gov (United States)

    Bhatti, Adnan Bashir; Usman, Muhammad

    2015-11-06

    The global prevalence of renal transplants is increasing with time, and renal transplantation is the only definite treatment for end-stage renal disease. We have limited the acute and late acute rejection of kidney allografts, but the long-term survival of renal tissues still remains a difficult and unanswered question as most of the renal transplants undergo failure within a decade of their transplantation. Among various histopathological changes that signify chronic allograft nephropathy (CAN), tubular atrophy, fibrous thickening of the arteries, fibrosis of the kidney interstitium, and glomerulosclerosis are the most important. Moreover, these structural changes are followed by a decline in the kidney function as well. The underlying mechanism that triggers the long-term rejection of renal transplants involves both humoral and cell-mediated immunity. T cells, with their related cytokines, cause tissue damage. In addition, CD 20+ B cells and their antibodies play an important role in the long-term graft rejection. Other risk factors that predispose a recipient to long-term graft rejection include HLA-mismatching, acute episodes of graft rejection, mismatch in donor-recipient age, and smoking. The purpose of this review article is the analyze current literature and find different anti-proliferative agents that can suppress the immune system and can thus contribute to the long-term survival of renal transplants. The findings of this review paper can be helpful in understanding the long-term survival of renal transplants and various ways to improve it.

  13. Drug Transporter Expression and Activity in Human Hepatoma HuH-7 Cells

    Directory of Open Access Journals (Sweden)

    Elodie Jouan

    2016-12-01

    Full Text Available Human hepatoma cells may represent a valuable alternative to the use of human hepatocytes for studying hepatic drug transporters, which is now a regulatory issue during drug development. In the present work, we have characterized hepatic drug transporter expression, activity and regulation in human hepatoma HuH-7 cells, in order to determine the potential relevance of these cells for drug transport assays. HuH-7 cells displayed notable multidrug resistance-associated protein (MRP activity, presumed to reflect expression of various hepatic MRPs, including MRP2. By contrast, they failed to display functional activities of the uptake transporters sodium taurocholate co-transporting polypeptide (NTCP, organic anion-transporting polypeptides (OATPs and organic cation transporter 1 (OCT1, and of the canalicular transporters P-glycoprotein and breast cancer resistance protein (BCRP. Concomitantly, mRNA expressions of various sinusoidal and canalicular hepatic drug transporters were not detected (NTCP, OATP1B1, organic anion transporter 2 (OAT2, OCT1 and bile salt export pump or were found to be lower (OATP1B3, OATP2B1, multidrug and toxin extrusion protein 1, BCRP and MRP3 in hepatoma HuH-7 cells than those found in human hepatocytes, whereas other transporters such as OAT7, MRP4 and MRP5 were up-regulated. HuH-7 cells additionally exhibited farnesoid X receptor (FXR- and nuclear factor erythroid 2-related factor 2 (Nrf2-related up-regulation of some transporters. Such data indicate that HuH-7 cells, although expressing rather poorly some main hepatic drug transporters, may be useful for investigating interactions of drugs with MRPs, notably MRP2, and for studying FXR- or Nrf2-mediated gene regulation.

  14. Impact of a renal drug dosing service on dose adjustment in hospitalized patients with chronic kidney disease.

    Science.gov (United States)

    Hassan, Yahaya; Al-Ramahi, Rowa' J; Aziz, Noorizan Abd; Ghazali, Rozina

    2009-10-01

    Appropriate drug selection and dosing for patients with chronic kidney disease (CKD) is important to avoid unwanted drug effects and ensure optimal patient outcomes. To assess the rate of inappropriate dosing in patients with CKD in a nephrology unit and to evaluate the impact on dose adjustment, adverse drug events (ADEs), and drug cost of having a pharmacist accompany a team of physicians on their rounds. This was a comparative study with a preintervention and postintervention design. The preintervention phase served as the control; it was prospective and observational only and was conducted from the beginning of February to the end of May 2007. The second phase (intervention phase) was conducted from the beginning of March to the end of June 2008. Two random samples of 300 patients with an estimated creatinine clearance less than or equal to 50 mL/min were included. During the intervention phase, a clinical pharmacist made rounds with the nephrology unit team and gave dosing adjustment recommendations when needed. A collection of reliable and up-to-date drug information references that are commonly used globally were used during the intervention. In the preintervention group, drug dosage adjustment or avoidance, based on renal function, was necessary in 607 of 2814 (21.6%) prescriptions. Of these, 322 (53.0%) did not comply with guidelines. In the intervention group, adjustment was necessary for 640 of 2981 (21.5%) prescriptions. The pharmacist made 388 recommendations related to dosing adjustment, 212 (54.6%) of which were accepted by physicians. Clinicians' noncompliance with dosing guidelines decreased to 176 (27.5%) (p < 0.001). In the preintervention group, 64 (21.3%) patients had a suspected ADE, with a total of 73 events. In the intervention group, this number was significantly lower with 49 events in 48 (16.0%) patients (p < 0.05). The intervention resulted in drug cost savings of $2250 US. A renal drug dosing service for patients hospitalized with CKD

  15. Transporter-Enzyme Interplay: Deconvoluting Effects of Hepatic Transporters and Enzymes on Drug Disposition Using Static and Dynamic Mechanistic Models.

    Science.gov (United States)

    Varma, Manthena V; El-Kattan, Ayman F

    2016-07-01

    A large body of evidence suggests hepatic uptake transporters, organic anion-transporting polypeptides (OATPs), are of high clinical relevance in determining the pharmacokinetics of substrate drugs, based on which recent regulatory guidances to industry recommend appropriate assessment of investigational drugs for the potential drug interactions. We recently proposed an extended clearance classification system (ECCS) framework in which the systemic clearance of class 1B and 3B drugs is likely determined by hepatic uptake. The ECCS framework therefore predicts the possibility of drug-drug interactions (DDIs) involving OATPs and the effects of genetic variants of SLCO1B1 early in the discovery and facilitates decision making in the candidate selection and progression. Although OATP-mediated uptake is often the rate-determining process in the hepatic clearance of substrate drugs, metabolic and/or biliary components also contribute to the overall hepatic disposition and, more importantly, to liver exposure. Clinical evidence suggests that alteration in biliary efflux transport or metabolic enzymes associated with genetic polymorphism leads to change in the pharmacodynamic response of statins, for which the pharmacological target resides in the liver. Perpetrator drugs may show inhibitory and/or induction effects on transporters and enzymes simultaneously. It is therefore important to adopt models that frame these multiple processes in a mechanistic sense for quantitative DDI predictions and to deconvolute the effects of individual processes on the plasma and hepatic exposure. In vitro data-informed mechanistic static and physiologically based pharmacokinetic models are proven useful in rationalizing and predicting transporter-mediated DDIs and the complex DDIs involving transporter-enzyme interplay.

  16. 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.

  17. 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.

  18. Pharmacogenomics of the human ABC transporter ABCG2: from functional evaluation to drug molecular design

    Science.gov (United States)

    Ishikawa, Toshihisa; Tamura, Ai; Saito, Hikaru; Wakabayashi, Kanako; Nakagawa, Hiroshi

    2005-10-01

    In the post-genome-sequencing era, emerging genomic technologies are shifting the paradigm for drug discovery and development. Nevertheless, drug discovery and development still remain high-risk and high-stakes ventures with long and costly timelines. Indeed, the attrition of drug candidates in preclinical and development stages is a major problem in drug design. For at least 30% of the candidates, this attrition is due to poor pharmacokinetics and toxicity. Thus, pharmaceutical companies have begun to seriously re-evaluate their current strategies of drug discovery and development. In that light, we propose that a transport mechanism-based design might help to create new, pharmacokinetically advantageous drugs, and as such should be considered an important component of drug design strategy. Performing enzyme- and/or cell-based drug transporter, interaction tests may greatly facilitate drug development and allow the prediction of drug-drug interactions. We recently developed methods for high-speed functional screening and quantitative structure-activity relationship analysis to study the substrate specificity of ABC transporters and to evaluate the effect of genetic polymorphisms on their function. These methods would provide a practical tool to screen synthetic and natural compounds, and these data can be applied to the molecular design of new drugs. In this review article, we present an overview on the genetic polymorphisms of human ABC transporter ABCG2 and new camptothecin analogues that can circumvent AGCG2-associated multidrug resistance of cancer.

  19. Pharmacogenetics of drug-induced birth defects : the role of polymorphisms of placental transporter proteins

    NARCIS (Netherlands)

    Daud, Aizati N. A.; Bergman, Jorieke E. H.; Bakker, Marian K.; Wang, Hao; de Walle, Hermien E. K.; Plosch, Torsten; Wilffert, Bob

    2014-01-01

    One of the ongoing issues in perinatal medicine is the risk of birth defects associated with maternal drug use. The teratogenic effect of a drug depends, apart from other factors, on the exposition of the fetus to the drug. Transporter proteins are known to be involved in the pharmacokinetics of dru

  20. Effect of respiratory acidosis and respiratory alkalosis on renal transport enzymes.

    Science.gov (United States)

    Eiam-ong, S; Laski, M E; Kurtzman, N A; Sabatini, S

    1994-09-01

    We studied the effect of respiratory acidosis and respiratory alkalosis on acid-base composition and on microdissected renal adenosinetriphosphatase (ATPase) enzymes. Rats were subjected to hypercapnia or hypocapnia of 6, 24, and 72 h duration. After 6 h of hypercapnia, collecting tubule (CT) ATPases were not changed. At 24 h, plasma bicarbonate was 35 +/- 1 meq/l (P respiratory acidosis stimulates activity of both renal proton ATPases. By contrast, both acute and chronic respiratory alkalosis decrease the two renal proton pumps. The stimulatory effect of hypercapnia and the inhibitory effect of hypocapnia on the renal ATPases appear to be potassium and aldosterone independent. Although the precise mechanisms for these results are not known, a direct effect of PCO2, pH, or changes in bicarbonate delivery may be involved.

  1. Renal tubular epithelial cell prorenin receptor regulates blood pressure and sodium transport.

    Science.gov (United States)

    Ramkumar, Nirupama; Stuart, Deborah; Mironova, Elena; Bugay, Vladislav; Wang, Shuping; Abraham, Nikita; Ichihara, Atsuhiro; Stockand, James D; Kohan, Donald E

    2016-07-01

    The physiological significance of the renal tubular prorenin receptor (PRR) has been difficult to elucidate due to developmental abnormalities associated with global or renal-specific PRR knockout (KO). We recently developed an inducible renal tubule-wide PRR KO using the Pax8/LC1 transgenes and demonstrated that disruption of renal tubular PRR at 1 mo of age caused no renal histological abnormalities. Here, we examined the role of renal tubular PRR in blood pressure (BP) regulation and Na(+) excretion and investigated the signaling mechanisms by which PRR regulates Na(+) balance. No detectable differences in BP were observed between control and PRR KO mice fed normal- or low-Na(+) diets. However, compared with controls, PRR KO mice had elevated plasma renin concentration and lower cumulative Na(+) balance with normal- and low-Na(+) intake. PRR KO mice had an attenuated hypertensive response and reduced Na(+) retention following angiotensin II (ANG II) infusion. Furthermore, PRR KO mice had significantly lower epithelial Na(+) channel (ENaC-α) expression. Treatment with mouse prorenin increased, while PRR antagonism decreased, ENaC activity in isolated split-open collecting ducts (CD). The prorenin effect was prevented by protein kinase A and Akt inhibition, but unaffected by blockade of AT1, ERK1/2, or p38 MAPK pathways. Taken together, these data indicate that renal tubular PRR, likely via direct prorenin/renin stimulation of PKA/Akt-dependent pathways, stimulates CD ENaC activity. Absence of renal tubular PRR promotes Na(+) wasting and reduces the hypertensive response to ANG II.

  2. Assessment of drug metabolism enzyme and transporter pharmacogenetics in drug discovery and early development: perspectives of the I-PWG.

    Science.gov (United States)

    Brian, William; Tremaine, Larry M; Arefayene, Million; de Kanter, Ruben; Evers, Raymond; Guo, Yingying; Kalabus, James; Lin, Wen; Loi, Cho-Ming; Xiao, Guangqing

    2016-04-01

    Genetic variants of drug metabolism enzymes and transporters can result in high pharmacokinetic and pharmacodynamic variability, unwanted characteristics of efficacious and safe drugs. Ideally, the contributions of these enzymes and transporters to drug disposition can be predicted from in vitro experiments and in silico modeling in discovery or early development, and then be utilized during clinical development. Recently, regulatory agencies have provided guidance on the preclinical investigation of pharmacogenetics, for application to clinical drug development. This white paper summarizes the results of an industry survey conducted by the Industry Pharmacogenomics Working Group on current practice and challenges with using in vitro systems and in silico models to understand pharmacogenetic causes of variability in drug disposition.

  3. Mathematical modeling of coupled drug and drug-encapsulated nanoparticle transport in patient-specific coronary artery walls

    KAUST Repository

    Hossain, Shaolie S.

    2011-08-20

    The majority of heart attacks occur when there is a sudden rupture of atherosclerotic plaque, exposing prothrombotic emboli to coronary blood flow, forming clots that can cause blockages of the arterial lumen. Diseased arteries can be treated with drugs delivered locally to vulnerable plaques. The objective of this work was to develop a computational tool-set to support the design and analysis of a catheter-based nanoparticulate drug delivery system to treat vulnerable plaques and diffuse atherosclerosis. A threedimensional mathematical model of coupled mass transport of drug and drug-encapsulated nanoparticles was developed and solved numerically utilizing isogeometric finite element analysis. Simulations were run on a patient-specific multilayered coronary artery wall segment with a vulnerable plaque and the effect of artery and plaque inhomogeneity was analyzed. The method captured trends observed in local drug delivery and demonstrated potential for optimizing drug design parameters, including delivery location, nanoparticle surface properties, and drug release rate. © Springer-Verlag 2011.

  4. Mathematical modeling of coupled drug and drug-encapsulated nanoparticle transport in patient-specific coronary artery walls

    Science.gov (United States)

    Hossain, Shaolie S.; Hossainy, Syed F. A.; Bazilevs, Yuri; Calo, Victor M.; Hughes, Thomas J. R.

    2012-02-01

    The majority of heart attacks occur when there is a sudden rupture of atherosclerotic plaque, exposing prothrombotic emboli to coronary blood flow, forming clots that can cause blockages of the arterial lumen. Diseased arteries can be treated with drugs delivered locally to vulnerable plaques. The objective of this work was to develop a computational tool-set to support the design and analysis of a catheter-based nanoparticulate drug delivery system to treat vulnerable plaques and diffuse atherosclerosis. A three-dimensional mathematical model of coupled mass transport of drug and drug-encapsulated nanoparticles was developed and solved numerically utilizing isogeometric finite element analysis. Simulations were run on a patient-specific multilayered coronary artery wall segment with a vulnerable plaque and the effect of artery and plaque inhomogeneity was analyzed. The method captured trends observed in local drug delivery and demonstrated potential for optimizing drug design parameters, including delivery location, nanoparticle surface properties, and drug release rate.

  5. Induction of Drug Transporters Alters Disposition of Risperidone - A Study in Mice

    Directory of Open Access Journals (Sweden)

    David Holthoewer

    2010-06-01

    Full Text Available Pharmacokinetic interactions, e.g. modulation of drug transporters like P-glycoprotein at the blood-brain barrier, can be a reason for treatment non-response. This study focuses on the influence of induction of drug transporters on the disposition of the antipsychotic drugs risperidone and 9-hydroxyrisperidone. Brain and serum concentrations of risperidone and its active metabolite 9-hydroxyrisperidone, which are known P-glycoprotein substrates, were measured after drug transporter induction with rifampicin, dexamethasone or 5-pregnene-3beta-ol-20-on-16alpha-carbonitrile using high performance liquid chromatography. Disposition of risperidone and 9-hydroxyrisperidone was dramatically decreased in mouse brain and serum after drug transporter induction. The metabolism of risperidone was also affected.

  6. Copper transporters regulate the cellular pharmacology and sensitivity to Pt drugs.

    Science.gov (United States)

    Safaei, Roohangiz; Howell, Stephen B

    2005-01-01

    Recent studies have demonstrated that the major Cu influx transporter CTR1 regulates tumor cell uptake of cisplatin (DDP), carboplatin (CBDCA) and oxaliplatin (L-OHP), and that the two Cu efflux transporters ATP7A and ATP7B regulate the efflux of these drugs. Evidence for the concept that these platinum (Pt) drugs enter cells and are distributed to various subcellular compartments via transporters that have evolved to manage Cu homeostasis includes the demonstration of: (1) bidirectional cross-resistance between cells selected for resistance to either the Pt drugs or Cu; (2) parallel changes in the transport of Pt and Cu drugs in resistant cells; (3) altered cytotoxic sensitivity and Pt drug accumulation in cells transfected with Cu transporters; and (4) altered expression of Cu transporters in Pt drug-resistant tumors. Appreciation of the role of the Cu transporters in the development of resistance to DDP, CBDCA, and L-OHP offers novel insights into strategies for preventing or reversing resistance to this very important family of anticancer drugs.

  7. Application of Physiologically-Based Pharmacokinetic Modeling to Explore the Role of Kidney Transporters in Renal Reabsorption of Perfluorooctanoic Acid in the Rat

    Science.gov (United States)

    Worley, Rachel Rogers; Fisher, Jeffrey

    2015-01-01

    Renal elimination and the resulting clearance of perfluorooctanoic acid (PFOA) from the serum exhibit pronounced sex differences in the adult rat. The literature suggests that this is largely due to hormonally regulated expression of organic anion transporters (OATs) on the apical and basolateral membranes of the proximal tubule cells that facilitate excretion and reabsorption of PFOA from the filtrate into the blood. Previously developed PBPK models of PFOA exposure in the rat have not been parameterized to specifically account for transporter-mediated renal elimination. We developed a PBPK model for PFOA in the male and female rat to explore the role of Oat1, Oat3, and Oatp1a1 in sex-specific renal reabsorption and excretion of PFOA. Descriptions of the kinetic behavior of these transporters were extrapolated from in vitro studies and the model was used to simulate time-course serum, liver, and urine data for intravenous (IV) and oral exposures in both sexes. Model predicted concentrations of PFOA in the liver, serum, and urine showed good agreement with experimental data for both the male and female rat indicating that in vitro derived physiological descriptions of transporter-mediated renal reabsorption can successfully predict sex-dependent excretion of PFOA in the rat. This study supports the hypothesis that sex-specific serum half-lives for PFOA are largely driven by expression of transporters in the kidney and contributes to the development of PBPK modeling as a tool for evaluating the role of transporters in renal clearance. PMID:26522833

  8. Investigating the enteroenteric recirculation of apixaban, a factor Xa inhibitor: administration of activated charcoal to bile duct-cannulated rats and dogs receiving an intravenous dose and use of drug transporter knockout rats.

    Science.gov (United States)

    Zhang, Donglu; Frost, Charles E; He, Kan; Rodrigues, A David; Wang, Xiaoli; Wang, Lifei; Goosen, Theunis C; Humphreys, W Griffith

    2013-04-01

    The study described here investigated the impact of intestinal excretion (IE; excretion of drug directly from circulation to intestinal lumen), enteroenteric recirculation (EER), and renal tubule recirculation (RTR) on apixaban pharmacokinetics and disposition. The experimental approaches involve integrating apixaban elimination pathways with pharmacokinetic profiles obtained from bile duct-cannulated (BDC) rats and dogs receiving i.v. doses together with oral administration of activated charcoal (AC). Additionally, the role of P-gp (P-glycoprotein; abcb1) and BCRP (breast cancer resistance protein; abcg2) in apixaban disposition was evaluated in experiments using transporter inhibitors and transporter knockout (KO) rats. Approximately 20-50% of an apixaban i.v. dose was found in feces of BDC rats and dogs, suggesting IE leading to fecal elimination and intestinal clearance (IC). The fecal elimination, IC, and systemic clearance of apixaban were increased upon AC administration in both BDC rats and dogs and were decreased in BDC rats dosed with GF-120918, a dual BCRP and P-gp inhibitor). BCRP appeared to play a more important role for absorption and intestinal and renal elimination of apixaban than P-gp in transporter-KO rats after oral and i.v. dosing, which led to a higher level of active renal excretion in rat than other species. These data demonstrate that apixaban undergoes IE, EER, and RTR that are facilitated by efflux transporters. Intestinal reabsorption of apixaban could be interrupted by AC even at 3 hours post-drug dose in dogs (late charcoal effect). This study demonstrates that the intestine is an organ for direct clearance and redistribution of apixaban. The IE, EER, and RTR contribute to overall pharmacokinetic profiles of apixaban. IE as a clearance pathway, balanced with metabolism and renal excretion, helps decrease the impacts of intrinsic (renal or hepatic impairment) and extrinsic (drug-drug interactions) factors on apixaban disposition.

  9. Treatment of Renal Cell Carcinoma with 2-Stage Total en bloc Spondylectomy after Marked Response to Molecular Target Drugs

    Directory of Open Access Journals (Sweden)

    Yasuhiro Inoue

    2013-01-01

    Full Text Available Metastatic renal cell carcinoma of the bone occurs at a high rate, and the prognosis is poor. In general, total en bloc spondylectomy is considered when there is only one vertebral metastasis and the primary disease is treated. However, palliative surgery is selected when the primary disease is not being treated or metastasis occurs to an important organ. We encountered a patient in whom lung and vertebra metastases were already present at the time of the first examination at our department and the prognosis was considered poor. However, molecular targeted therapy was markedly effective and enabled 2-stage total en bloc spondylectomy. As of one year after total en bloc spondylectomy, the condition has improved to cane gait, and surgery for lung metastasis is planned. Molecular target drugs might markedly change the current therapeutic strategy for renal cell carcinoma.

  10. Drug and Acute Renal Failure%药物与急性肾功能衰竭

    Institute of Scientific and Technical Information of China (English)

    黄颂敏

    2007-01-01

    @@ 药物中毒引起的急性肾功能衰竭(acute renal failure,ARF)又称为肾毒性急性肾功衰竭(Nephrotoxic acute renal failure),指用药后数天至数周后肾功能的恶化.此类ARF多非少尿型,常常表现为无症状的尿素氮、血肌酐升高.

  11. A CASE OF CHRONIC RENAL VEIN THROMBOSIS TREATED WITH THROMBOLYTIC DRUGS

    Directory of Open Access Journals (Sweden)

    S. H. Mousavi Bahar

    2006-05-01

    Full Text Available Renal vein thrombosis (RVT is the most frequent vascular abnormality in newborns, but rarely seen in adults. RVT is an acute problem, and diagnostic and therapeutic approaches should be done immediately. Surgical thrombectomy is not a rational approach and the treatment of choice is conservative management and thrombolytic therapy. We present a 45 years old male patient with chronic renal vein thrombosis who was treated with thrombolytic therapy successfully.

  12. Di/tri-peptide transporters as drug delivery targets

    DEFF Research Database (Denmark)

    Nielsen, C U; Brodin, Birger

    2003-01-01

    . PepT1-mediated transport is up-regulated by short-term exposure to receptor agonists such as EGF, insulin, leptin, and clonidine, and down-regulated by VIP. Overall, the regulation of di/tri-peptide transport may be contributed to 1) changes in apical proton-motive force 2) recruitment of di...

  13. Male-dominant activation of rat renal organic anion transporter 1 (Oat1 and 3 (Oat3 expression by transcription factor BCL6.

    Directory of Open Access Journals (Sweden)

    Waja Wegner

    Full Text Available BACKGROUND: Organic anion transporters 1 (Oat1 and 3 (Oat3 mediate the transport of organic anions, including frequently prescribed drugs, across cell membranes in kidney proximal tubule cells. In rats, these transporters are known to be male-dominant and testosterone-dependently expressed. The molecular mechanisms that are involved in the sex-dependent expression are unknown. Our aim was to identify genes that show a sex-dependent expression and could be involved in male-dominant regulation of Oat1 and Oat3. METHODOLOGY/PRINCIPAL FINDINGS: Promoter activities of Oat1 and Oat3 were analyzed using luciferase assays. Expression profiling was done using a SurePrint G3 rat GE 8 × 60K microarray. RNA was isolated from renal cortical slices of four adult rats per sex. To filter the achieved microarray data for genes expressed in proximal tubule cells, transcription database alignment was carried out. We demonstrate that predicted androgen response elements in the promoters of Oat1 and Oat3 are not functional when the promoters were expressed in OK cells. Using microarray analyses we analyzed 17,406 different genes. Out of these genes, 56 exhibit a sex-dependent expression in rat proximal tubule cells. As genes potentially involved in the regulation of Oat1 and Oat3 expression, we identified, amongst others, the male-dominant hydroxysteroid (17-beta dehydrogenase 1 (Hsd17b1, B-cell CLL/lymphoma 6 (BCL6, and polymerase (RNA III (DNA directed polypeptide G (Polr3g. Moreover, our results revealed that the transcription factor BCL6 activates promoter constructs of Oat1 and Oat3. CONCLUSION: The results indicate that the male-dominant expression of both transporters, Oat1 and Oat3, is possibly not directly regulated by the classical androgen receptor mediated transcriptional pathway but appears to be regulated by the transcription factor BCL6.

  14. 76 FR 59574 - Procedures for Transportation Workplace Drug and Alcohol Testing Programs: Federal Drug Testing...

    Science.gov (United States)

    2011-09-27

    ... Alcohol Testing Programs: Federal Drug Testing Custody and Control Form; Technical Amendment AGENCY... of a new Federal Drug Testing Custody and Control Form (CCF) in its drug testing program. Use of the... amendment to its drug testing procedures by amending a provision of the rule which was inadvertently omitted...

  15. Polyester-Based, Biodegradable Core-Multishell Nanocarriers for the Transport of Hydrophobic Drugs

    Directory of Open Access Journals (Sweden)

    Karolina A. Walker

    2016-05-01

    Full Text Available A water-soluble, core-multishell (CMS nanocarrier based on a new hyperbranched polyester core building block was synthesized and characterized towards drug transport and degradation of the nanocarrier. The hydrophobic drug dexamethasone was encapsulated and the enzyme-mediated biodegradability was investigated by NMR spectroscopy. The new CMS nanocarrier can transport one molecule of dexamethasone and degrades within five days at a skin temperature of 32 °C to biocompatible fragments.

  16. Coordinated control of renal Ca(2+) transport proteins by parathyroid hormone.

    NARCIS (Netherlands)

    Abel, M. van; Hoenderop, J.G.J.; Kemp, J.W.C.M. van der; Friedlaender, M.M.; Leeuwen, J.P.P.M. van; Bindels, R.J.M.

    2005-01-01

    BACKGROUND: The kidney is one of the affected organs involved in the clinical symptoms of parathyroid hormone (PTH)-related disorders, like primary hyperparathyroidism and familial hypocalciuric hypercalcemia. The molecular mechanism(s) underlying alterations in renal Ca(2+) handling in these disord

  17. Excitatory amino acid transporters as potential drug targets

    DEFF Research Database (Denmark)

    Bunch, Lennart; Erichsen, Mette Navy; Jensen, Anders Asbjørn

    2009-01-01

    BACKGROUND: Excitatory amino acid transporters (EAATs) are transmembrane proteins responsible for the uptake of (S)-glutamate (Glu) from the synaptic cleft, thereby terminating the glutamatergic neurotransmitter signal. Today five subtypes have been identified. Except for EAAT2, their individual...

  18. Elucidation of common pharmacophores from analysis of targeted metabolites transported by the multispecific drug transporter-Organic anion transporter1 (Oat1).

    Science.gov (United States)

    Kouznetsova, Valentina L; Tsigelny, Igor F; Nagle, Megha A; Nigam, Sanjay K

    2011-06-01

    Organic anion transporter 1 (Oat1), first identified as NKT, is a multispecific transporter responsible for the handling of drugs and toxins in the kidney and choroid plexus, but its normal physiological role appears to be in small molecule metabolite regulation. Metabolites transported by Oat1 and which are altered in the blood and urine of the murine Oat1 knockout, may serve as templates for further drug design. This may lead to better tissue targeting of drugs or design of Oat1 inhibitors that prolong the half-life of current drugs. Due to the multispecificity of the transporter, 19 of known targeted metabolites have different chemical structures and properties that make constructing a common pharmacophore model difficult. Here we propose an approach that clustered the metabolites into four distinct groups which allowed for the construction of a consensus pharmacophore for each cluster. The screening of commercial molecular databases determined the top candidates whose interaction with Oat1 was confirmed in an experimental model of organic anion transport. Thus, these candidate selections represent potential molecules for further drug design.

  19. Assembly & Transport Mechanism of Tripartite Drug Efflux Systems

    OpenAIRE

    Misra, Rajeev; Bavro, Vassiliy N.

    2009-01-01

    Multidrug efflux (MDR) pumps remove a variety of compounds from the cell into the external environment. There are five different classes of MDR pumps in bacteria, and quite often a single bacterial species expresses multiple classes of pumps. Although under normal circumstances MDR pumps confer low-level intrinsic resistance to drugs, the presence of drugs and mutations in regulatory genes lead to high level expression of MDR pumps that can pose problems with therapeutic treatments. This revi...

  20. 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

  1. Drug trafficking in mice: In vivo functions of OATP uptake and ABC efflux transporters

    NARCIS (Netherlands)

    Iusuf, D.

    2013-01-01

    In recent years, there has been increasing attention for drug uptake transporters of the Organic Anion-Transporting Polypeptide (human OATP, mouse Oatp, gene names SLCO, Slco) superfamily. Especially the OATP1A and OATP1B subfamilies turn out to have important physiological and pharmacological

  2. Drugs, ionophoric peptides, and steroids as substrates of the yeast multidrug transporter Pdr5p

    NARCIS (Netherlands)

    Kolaczkowski, M; vanderRest, M; CybularzKolaczkowska, A; Soumillion, JP; Konings, WN; Goffeau, A

    1996-01-01

    Pdr5p is the yeast Saccharomyces cerevisiae ATP-binding cassette transporter conferring resistance to several unrelated drugs. Its high overproduction in Pdr1p transcription factor mutants allows us to study the molecular mechanism of multidrug transport and substrate specificity. We have developed

  3. Renal (tissue) kallikrein-kinin system in the kidney and novel potential drugs for salt-sensitive hypertension.

    Science.gov (United States)

    Katori, Makoto; Majima, Masataka

    2014-01-01

    A large variety of antihypertensive drugs, such as angiotensin converting enzyme inhibitors, diuretics, and others, are prescribed to hypertensive patients, with good control of the condition. In addition, all individuals are generally believed to be salt sensitive and, thus, severe restriction of salt intake is recommended to all. Nevertheless, the physiological defense mechanisms in the kidney against excess salt intake have not been well clarified. The present review article demonstrated that the renal (tissue) kallikrein-kinin system (KKS) is ideally situated within the nephrons of the kidney, where it functions to inhibit the reabsorption of NaCl through the activation of bradykinin (BK)-B2 receptors localized along the epithelial cells of the collecting ducts (CD). Kinins generated in the CD are immediately inactivated by two kidney-specific kinin-inactivating enzymes (kininases), carboxypeptidase Y-like exopeptidase (CPY), and neutral endopeptidase (NEP). Our work demonstrated that ebelactone B and poststatin are selective inhibitors of these kininases. The reduced secretion of the urinary kallikrein is linked to the development of salt-sensitive hypertension, whereas potassium ions and ATP-sensitive potassium channel blockers ameliorate salt-sensitive hypertension by accelerating the release of renal kallikrein. On the other hand, ebelactone B and poststatin prolong the life of kinins in the CD after excess salt intake, thereby leading to the augmentation of natriuresis and diuresis, and the ensuing suppression of salt-sensitive hypertension. In conclusion, accelerators of the renal kallikrein release and selective renal kininase inhibitors are both novel types of antihypertensive agents that may be useful for treatment of salt-sensitive hypertension.

  4. 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 me

  5. Beauvericin counteracted multi-drug resistant Candida albicans by blocking ABC transporters

    DEFF Research Database (Denmark)

    Tong, Yaojun; Liu, Mei; Zhang, Yu

    2016-01-01

    screening and whole-cell based mechanism study, identified a natural product, beauvericin (BEA) as a drug efflux pump modulator, which can reverse the multi-drug resistant phenotype of Candida albicans by specifically blocking the ATP-binding cassette (ABC) transporters; meantime, BEA alone has fungicidal...

  6. Pharmacogenetics of drug-induced birth defects: the role of polymorphisms of placental transporter proteins.

    Science.gov (United States)

    Daud, Aizati N A; Bergman, Jorieke E H; Bakker, Marian K; Wang, Hao; de Walle, Hermien E K; Plösch, Torsten; Wilffert, Bob

    2014-05-01

    One of the ongoing issues in perinatal medicine is the risk of birth defects associated with maternal drug use. The teratogenic effect of a drug depends, apart from other factors, on the exposition of the fetus to the drug. Transporter proteins are known to be involved in the pharmacokinetics of drugs and have an effect on drug level and fetal drug exposure. This condition may subsequently alter the risk of teratogenicity, which occurs in a dose-dependent manner. This review focuses on the clinically important polymorphisms of transporter proteins and their effects on the mRNA and protein expression in placental tissue. We also propose a novel approach on how the different genotypes of the polymorphism can be translated into phenotypes to facilitate genetic association studies. The last section looks into the recent studies exploring the association between P-glycoprotein polymorphisms and the risk of fetal birth defects associated with medication use during pregnancy.

  7. Protonation of a Glutamate Residue Modulates the Dynamics of the Drug Transporter EmrE

    OpenAIRE

    Gayen, Anindita; Leninger, Maureen; Traaseth, Nathaniel J.

    2016-01-01

    Secondary active transport proteins play a central role in conferring bacterial multidrug resistance. In this work, we investigated the proton-coupled transport mechanism for the Escherichia coli drug efflux pump EmrE using nuclear magnetic resonance (NMR) spectroscopy. Our results show that the global conformational motions necessary for transport are modulated in an allosteric fashion by the protonation state of a membrane-embedded glutamate residue. These observations directly correlate wi...

  8. Protonation of a Glutamate Residue Modulates the Dynamics of the Drug Transporter EmrE

    OpenAIRE

    Gayen, Anindita; Leninger, Maureen; Traaseth, Nathaniel J.

    2016-01-01

    Secondary active transport proteins play a central role in conferring bacterial multidrug resistance. In this work, we investigated the proton-coupled transport mechanism for the Escherichia coli drug efflux pump EmrE using nuclear magnetic resonance (NMR) spectroscopy. Our results show that the global conformational motions necessary for transport are modulated in an allosteric fashion by the protonation state of a membrane-embedded glutamate residue. These observations directly correlate wi...

  9. Binding and inhibition of drug transport proteins by heparin: a potential drug transporter modulator capable of reducing multidrug resistance in human cancer cells.

    Science.gov (United States)

    Chen, Yunliang; Scully, Michael; Petralia, Gloria; Kakkar, Ajay

    2014-01-01

    A major problem in cancer treatment is the development of resistance to chemotherapeutic agents, multidrug resistance (MDR), associated with increased activity of transmembrane drug transporter proteins which impair cytotoxic treatment by rapidly removing the drugs from the targeted cells. Previously, it has been shown that heparin treatment of cancer patients undergoing chemotherapy increases survival. In order to determine whether heparin is capable reducing MDR and increasing the potency of chemotherapeutic drugs, the cytoxicity of a number of agents toward four cancer cell lines (a human enriched breast cancer stem cell line, two human breast cancer cell lines, MCF-7 and MDA-MB-231, and a human lung cancer cell line A549) was tested in the presence or absence of heparin. Results demonstrated that heparin increased the cytotoxicity of a range of chemotherapeutic agents. This effect was associated with the ability of heparin to bind to several of the drug transport proteins of the ABC and non ABC transporter systems. Among the ABC system, heparin treatment caused significant inhibition of the ATPase activity of ABCG2 and ABCC1, and of the efflux function observed as enhanced intracellular accumulation of specific substrates. Doxorubicin cytoxicity, which was enhanced by heparin treatment of MCF-7 cells, was found to be under the control of one of the major non-ABC transporter proteins, lung resistance protein (LRP). LRP was also shown to be a heparin-binding protein. These findings indicate that heparin has a potential role in the clinic as a drug transporter modulator to reduce multidrug resistance in cancer patients.

  10. Adjusted drug treatment is superior to renal sympathetic denervation in patients with true treatment-resistant hypertension.

    Science.gov (United States)

    Fadl Elmula, Fadl Elmula M; Hoffmann, Pavel; Larstorp, Anne C; Fossum, Eigil; Brekke, Magne; Kjeldsen, Sverre E; Gjønnæss, Eyvind; Hjørnholm, Ulla; Kjaer, Vibeke N; Rostrup, Morten; Os, Ingrid; Stenehjem, Aud; Høieggen, Aud

    2014-05-01

    We aimed to investigate for the first time the blood pressure (BP)-lowering effect of renal sympathetic denervation (RDN) versus clinically adjusted drug treatment in true treatment-resistant hypertension (TRH) after excluding patients with confounding poor drug adherence. Patients with apparent TRH (n=65) were referred for RDN, and those with secondary and spurious hypertension (n=26) were excluded. TRH was defined as office systolic BP (SBP) >140 mm Hg, despite maximally tolerated doses of ≥3 antihypertensive drugs including a diuretic. In addition, ambulatory daytime SBP >135 mm Hg after witnessed intake of antihypertensive drugs was required, after which 20 patients had normalized BP and were excluded. Patients with true TRH were randomized and underwent RDN (n=9) performed with Symplicity Catheter System versus clinically adjusted drug treatment (n=10). The study was stopped early for ethical reasons because RDN had uncertain BP-lowering effect. Office SBP and diastolic BP in the drug-adjusted group changed from 160±14/88±13 mm Hg (±SD) at baseline to 132±10/77±8 mm Hg at 6 months (Pdrug-adjusted group at 6 months (P=0.002 and P=0.004, respectively), and absolute changes in SBP were larger in the drug-adjusted group (P=0.008). Ambulatory BPs changed in parallel to office BPs. Our data suggest that adjusted drug treatment has superior BP lowering effects compared with RDN in patients with true TRH. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT01673516.

  11. 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

  12. Anticancer Drug 2-Methoxyestradiol Protects against Renal Ischemia/Reperfusion Injury by Reducing Inflammatory Cytokines Expression

    Directory of Open Access Journals (Sweden)

    Ying-Yin Chen

    2014-01-01

    Full Text Available Background. Ischemia/reperfusion (I/R injury is a major cause of acute renal failure and allograft dysfunction in kidney transplantation. ROS/inflammatory cytokines are involved in I/R injury. 2-Methoxyestradiol (2ME2, an endogenous metabolite of estradiol, inhibits inflammatory cytokine expression and is an antiangiogenic and antitumor agent. We investigated the inhibitory effect of 2ME2 on renal I/R injury and possible molecular actions. Methods. BALB/c mice were intraperitoneally injected with 2ME2 (10 or 20 mg/kg or vehicle 12 h before and immediately after renal I/R experiments. The kidney weight, renal function, tubular damages, and apoptotic response were examined 24 h after I/R injury. The expression of mRNA of interleukin-1β, tumor necrosis factor- (TNF α, caspase-3, hypoxia inducible factor- (HIF 1α, and proapoptotic Bcl-2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3 in kidney tissue was determined using RT-PCR, while the expression of nuclear factor κB (NF-κB, BCL-2, and BCL-xL, activated caspase-9, and HIF-1α was determined using immunoblotting. In vitro, we determined the effect of 2ME2 on reactive oxygen species (ROS production and cell viability in antimycin-A-treated renal mesangial (RMC and tubular (NRK52E cells. Results. Serum creatinine and blood urea nitrogen were significantly higher in mice with renal I/R injury than in sham control and in I/R+2ME2-treated mice. Survival in I/R+2ME2-treated mice was higher than in I/R mice. Histological examination showed that 2ME2 attenuated tubular damage in I/R mice, which was associated with lower expression TNF-α, IL-1β, caspase-9, HIF-1α, and BNIP3 mRNA in kidney tissue. Western blotting showed that 2ME2 treatment substantially decreased the expression of activated caspase-9, NF-κB, and HIF-1α but increased the antiapoptotic proteins BCL-2 and BCL-xL in kidney of I/R injury. In vitro, 2MR2 decreased ROS production and increased cell viability in antimycin

  13. Overcoming ABC transporter-mediated multidrug resistance: Molecular mechanisms and novel therapeutic drug strategies.

    Science.gov (United States)

    Li, Wen; Zhang, Han; Assaraf, Yehuda G; Zhao, Kun; Xu, Xiaojun; Xie, Jinbing; Yang, Dong-Hua; Chen, Zhe-Sheng

    2016-07-01

    Multidrug resistance is a key determinant of cancer chemotherapy failure. One of the major causes of multidrug resistance is the enhanced efflux of drugs by membrane ABC transporters. Targeting ABC transporters projects a promising approach to eliminating or suppressing drug resistance in cancer treatment. To reveal the functional mechanisms of ABC transporters in drug resistance, extensive studies have been conducted from identifying drug binding sites to elucidating structural dynamics. In this review article, we examined the recent crystal structures of ABC proteins to depict the functionally important structural elements, such as domains, conserved motifs, and critical amino acids that are involved in ATP-binding and drug efflux. We inspected the drug-binding sites on ABC proteins and the molecular mechanisms of various substrate interactions with the drug binding pocket. While our continuous battle against drug resistance is far from over, new approaches and technologies have emerged to push forward our frontier. Most recent developments in anti-MDR strategies include P-gp inhibitors, RNA-interference, nano-medicines, and delivering combination strategies. With the advent of the 'Omics' era - genomics, epigenomics, transcriptomics, proteomics, and metabolomics - these disciplines play an important role in fighting the battle against chemoresistance by further unraveling the molecular mechanisms of drug resistance and shed light on medical therapies that specifically target MDR. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Photoactivatable Drug-Caged Fluorophore Conjugate Allows Direct Quantification of Intracellular Drug Transport

    Science.gov (United States)

    Kohler, Rainer H.; Weissleder, Ralph

    2013-01-01

    We report here a method that utilizes photoactivatable drug-caged fluorophore conjugate to quantify intracellular drug trafficking processes at single cell resolution. Photoactivation is performed in labeled cellular compartments to visualize intracellular drug exchange at physiologic conditions, without the need for washing, facilitating its translation to in vivo cancer models. PMID:24135896

  15. Interaction Potential of the Multitargeted Receptor Tyrosine Kinase Inhibitor Dovitinib with Drug Transporters and Drug Metabolising Enzymes Assessed in Vitro

    Directory of Open Access Journals (Sweden)

    Johanna Weiss

    2014-12-01

    Full Text Available Dovitinib (TKI-258 is under development for the treatment of diverse cancer entities. No published information on its pharmacokinetic drug interaction potential is available. Thus, we assessed its interaction with important drug metabolising enzymes and drug transporters and its efficacy in multidrug resistant cells in vitro. P-glycoprotein (P-gp, MDR1, ABCB1 inhibition was evaluated by calcein assay, inhibition of breast cancer resistance protein (BCRP, ABCG2 by pheophorbide A efflux, and inhibition of organic anion transporting polypeptides (OATPs by 8-fluorescein-cAMP uptake. Inhibition of cytochrome P450 3A4, 2C19, and 2D6 was assessed by using commercial kits. Induction of transporters and enzymes was quantified by real-time RT-PCR. Possible aryl hydrocarbon receptor (AhR activating properties were assessed by a reporter gene assay. Substrate characteristics were evaluated by growth inhibition assays in cells over-expressing P-gp or BCRP. Dovitinib weakly inhibited CYP2C19, CYP3A4, P-gp and OATPs. The strongest inhibition was observed for BCRP (IC50 = 10.3 ± 4.5 μM. Among the genes investigated, dovitinib only induced mRNA expression of CYP1A1, CYP1A2, ABCC3 (coding for multidrug resistance-associated protein 3, and ABCG2 and suppressed mRNA expression of some transporters and drug metabolising enzymes. AhR reporter gene assay demonstrated that dovitinib is an activator of this nuclear receptor. Dovitinib retained its efficacy in cell lines over-expressing P-gp or BCRP. Our analysis indicates that dovitinib will most likely retain its efficacy in tumours over-expressing P-gp or BCRP and gives first evidence that dovitinib might act as a perpetrator drug in pharmacokinetic drug–drug interactions.

  16. Assessment of drug-drug interactions among renal failure patients of nephrology ward in a south Indian tertiary care hospital

    Directory of Open Access Journals (Sweden)

    Mylapuram Rama

    2012-01-01

    Full Text Available Polypharmacy is common in drug prescriptions of chronic kidney disease patients. A study of the prescription patterns of drugs with potential interactions would be of interest to prevent drug related adverse events. A prospective observational study of six months (Dec 2009-May 2010 was carried out among the chronic kidney disease patients admitted to the nephrology ward of a South Indian tertiary care hospital. The pattern and rates of drug-drug interactions seen in the prescriptions of these patients was studied. Among the 205 prescriptions included, a total of 474 interactions were reported, making 2.7 interactions per prescription with incidence rates of 76.09%. Around 19.62% of interactions were of major severity. Most common interactions were found between ascorbic acid and cyanocobalamine (12.45%, clonidine and metoprolol (3.80% respectively. Hypo or hypertension (31.65%, decreased drug efficacy (29.11% and hypo or hyperglycemia (14.14%, were the most commonly reported clinical outcomes of the drug interactions. Cardiovascular drugs (calcium channel blockers and beta blockers; 52% constitute the major class of drugs involved in interactions. As most of the interactions had a delayed onset, long term follow-up is essential to predict the clinically significant outcomes of these interactions. Hence, drug interactions are commonly seen in the prescriptions of chronic kidney disease patients which can lead to serious adverse events if not detected early. Need for collaboration with a clinical pharmacist and electronic surveillance, which are absent in developing countries like India, is emphatic.

  17. In vitro drug-drug interactions of budesonide: inhibition and induction of transporters and cytochrome P450 enzymes.

    Science.gov (United States)

    Chen, Nancy; Cui, Donghui; Wang, Qing; Wen, Zhiming; Finkelman, Richard D; Welty, Devin

    2017-07-21

    1. Budesonide is a glucocorticoid used in the treatment of several respiratory and gastrointestinal inflammatory diseases. Glucocorticoids have been demonstrated to induce cytochrome P450 (CYP) 3A and the efflux transporter P-glycoprotein (P-gp). This study aimed to evaluate the potential of budesonide to act as a perpetrator or a victim of transporter- or CYP-mediated drug-drug interactions (DDIs). 2. In vitro studies were conducted for P-gp, breast cancer resistance protein and organic anion and cation transporters (OATP1B1, OATP1B3, OAT1, OAT3, OCT2) in transporter-transfected cells. Changes in mRNA expression in human hepatocytes and enzyme activity in human liver microsomes by budesonide were determined for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A. 3. The data indicated that budesonide is a substrate of P-gp but is not a substrate or an inhibitor of the other transporters investigated. Budesonide is neither an inducer nor an inhibitor of major CYP enzymes. The effect of P-gp on budesonide disposition is anticipated to be low owing to CYP3A-mediated clearance. 4. Collectively, our data indicate there is a low risk of budesonide perpetrating clinical DDIs mediated by the transporters or CYPs studied.

  18. Nano carriers for drug transport across the blood-brain barrier.

    Science.gov (United States)

    Li, Xinming; Tsibouklis, John; Weng, Tingting; Zhang, Buning; Yin, Guoqiang; Feng, Guangzhu; Cui, Yingde; Savina, Irina N; Mikhalovska, Lyuba I; Sandeman, Susan R; Howel, Carol A; Mikhalovsky, Sergey V

    2017-01-01

    Effective therapy lies in achieving a therapeutic amount of drug to the proper site in the body and then maintaining the desired drug concentration for a sufficient time interval to be clinically effective for treatment. The blood-brain barrier (BBB) hinders most drugs from entering the central nervous system (CNS) from the blood stream, leading to the difficulty of delivering drugs to the brain via the circulatory system for the treatment, diagnosis and prevention of brain diseases. Several brain drug delivery approaches have been developed, such as intracerebral and intracerebroventricular administration, intranasal delivery and blood-to-brain delivery, as a result of transient BBB disruption induced by biological, chemical or physical stimuli such as zonula occludens toxin, mannitol, magnetic heating and ultrasound, but these approaches showed disadvantages of being dangerous, high cost and unsuitability for most brain diseases and drugs. The strategy of vector-mediated blood-to-brain delivery, which involves improving BBB permeability of the drug-carrier conjugate, can minimize side effects, such as being submicrometre objects that behave as a whole unit in terms of their transport and properties, nanomaterials, are promising carrier vehicles for direct drug transport across the intact BBB as a result of their potential to enter the brain capillary endothelial cells by means of normal endocytosis and transcytosis due to their small size, as well as their possibility of being functionalized with multiple copies of the drug molecule of interest. This review provids a concise discussion of nano carriers for drug transport across the intact BBB, various forms of nanomaterials including inorganic/solid lipid/polymeric nanoparticles, nanoemulsions, quantum dots, nanogels, liposomes, micelles, dendrimers, polymersomes and exosomes are critically evaluated, their mechanisms for drug transport across the BBB are reviewed, and the future directions of this area are fully

  19. Influence of excipients on drug absorption via modulation of intestinal transporters activity

    Directory of Open Access Journals (Sweden)

    Hetal P Thakkar

    2015-01-01

    Full Text Available One of the major factors affecting oral drug bioavailability is the activity of intestinal transport proteins, particularly for the drugs that undergo absorption by active transport mechanism. Many of the active pharmacological agents and the excipients used in their formulation are reported to modulate the activity of these transporters thereby either enhancing or decreasing the drug absorption and its systemic availability. These excipients are considered pharmacologically "inert" and have been used since years in pharmaceutical formulations. Appreciable interest is developing on the data demonstrating the role of excipients in altering the drug absorption across the intestine. Careful selection of the excipients thus is very important. A correctly chosen excipient can enhance the drug bioavailability and thus its therapeutic efficacy without increasing its dose. For locally acting drugs having systemic side effects, a proper excipient could lead to a decrease in its systemic absorption, thus reducing its side effects. This review focuses on the current findings of the excipients identified to modulate the activity of transporters, their mechanism of modulating the transporter′s activity and various formulation strategies using these excipients to enhance drug absorption.

  20. Tri-partite complex for axonal transport drug delivery achieves pharmacological effect

    Directory of Open Access Journals (Sweden)

    Frederickson Martyn

    2010-01-01

    Full Text Available Abstract Background Targeted delivery of pharmaceutical agents into selected populations of CNS (Central Nervous System neurons is an extremely compelling goal. Currently, systemic methods are generally used for delivery of pain medications, anti-virals for treatment of dermatomal infections, anti-spasmodics, and neuroprotectants. Systemic side effects or undesirable effects on parts of the CNS that are not involved in the pathology limit efficacy and limit clinical utility for many classes of pharmaceuticals. Axonal transport from the periphery offers a possible selective route, but there has been little progress towards design of agents that can accomplish targeted delivery via this intraneural route. To achieve this goal, we developed a tripartite molecular construction concept involving an axonal transport facilitator molecule, a polymer linker, and a large number of drug molecules conjugated to the linker, then sought to evaluate its neurobiology and pharmacological behavior. Results We developed chemical synthesis methodologies for assembling these tripartite complexes using a variety of axonal transport facilitators including nerve growth factor, wheat germ agglutinin, and synthetic facilitators derived from phage display work. Loading of up to 100 drug molecules per complex was achieved. Conjugation methods were used that allowed the drugs to be released in active form inside the cell body after transport. Intramuscular and intradermal injection proved effective for introducing pharmacologically effective doses into selected populations of CNS neurons. Pharmacological efficacy with gabapentin in a paw withdrawal latency model revealed a ten fold increase in half life and a 300 fold decrease in necessary dose relative to systemic administration for gabapentin when the drug was delivered by axonal transport using the tripartite vehicle. Conclusion Specific targeting of selected subpopulations of CNS neurons for drug delivery by axonal

  1. The role of the erythrocyte in antitumour drug transport

    NARCIS (Netherlands)

    Dumez, Herlinde

    2005-01-01

    The area of research on the substance-carrier capacity of the erythrocyte is rather limited and it remains difficult to estimate the impact of erythrocyte drug level monitoring in the clinic. Although equilibrium between blood and tissues based on the dissolution of compounds in the plasma water

  2. Drug release from hydrogel: a new understanding of transport phenomena.

    Science.gov (United States)

    Perale, G; Rossi, F; Santoro, M; Marchetti, P; Mele, A; Castiglione, F; Raffa, E; Masi, M

    2011-06-01

    In tissue engineering, i.e., in combined advanced technologies to replace damaged or missing parts of living tissues, emerging strategies strongly point toward the use of hydrogels also for their ability of being vehicles for local controlled drug delivery. The investigation of drug release mechanisms in such matrices thus plays a key role in the design of smart system but literature is still very controversial on theoretical interpretations and understanding of available data. In this framework we used the new HRMAS-NMR DOSY technique to study the diffusive motions of sodium fluorescein, a drug mimetic small chromophoric molecule, loaded in a promising hydrogel developed for tissue engineering. While fluorescein behavior in water was as expected, also showing aggregation from mid concentrations, data collected within hydrogel samples surprisingly showed no aggregation and diffusion coefficients were always higher with respect to aqueous solution. Furthermore, the promotion of diffusion increased along with fluorescein concentration. The proportion of this effect was directly linked to hydrogel mesh size, thus carrying intrinsic novelty, but also complexity, and suggesting that not only strictly hydrodynamic effects should be considered but also electrostatic interactions between polymer chains and drug molecules might be key players in avoiding fluorescein aggregation and also affecting diffusivity.

  3. Several hPepT1-transported drugs are substrates of the Escherichia coli proton-coupled oligopeptide transporter YdgR

    DEFF Research Database (Denmark)

    Prabhala, Bala K; Aduri, Nanda G; Iqbal, Mazhar

    2017-01-01

    transported by hPepT1. The transport of these drugs was evaluated using the prototypical POT YdgR from E. coli. The transport studies were pursued through combining cell-based assays with liquid chromatography-tandem mass spectrometric (LC-MS/MS) analysis. These investigations revealed that YdgR from E. coli...... is able to transport five (sulpiride, bestatin, valacyclovir, ampicillin and oseltamivir) drugs. Furthermore, cells not overexpressing YdgR were also able to transport these drugs in a POT-like manner. Orthologues of YdgR are found in several species in the gut microbiome; hence, our findings could have...

  4. In silico methods for predicting drug-drug interactions with cytochrome P-450s, transporters and beyond.

    Science.gov (United States)

    Ai, Ni; Fan, Xiaohui; Ekins, Sean

    2015-06-23

    Drug-drug interactions (DDIs) are associated with severe adverse effects that may lead to the patient requiring alternative therapeutics and could ultimately lead to drug withdrawal from the market if they are severe. To prevent the occurrence of DDI in the clinic, experimental systems to evaluate drug interaction have been integrated into the various stages of the drug discovery and development process. A large body of knowledge about DDI has also accumulated through these studies and pharmacovigillence systems. Much of this work to date has focused on the drug metabolizing enzymes such as cytochrome P-450s as well as drug transporters, ion channels and occasionally other proteins. This combined knowledge provides a foundation for a hypothesis-driven in silico approach, using either cheminformatics or physiologically based pharmacokinetics (PK) modeling methods to assess DDI potential. Here we review recent advances in these approaches with emphasis on hypothesis-driven mechanistic models for important protein targets involved in PK-based DDI. Recent efforts with other informatics approaches to detect DDI are highlighted. Besides DDI, we also briefly introduce drug interactions with other substances, such as Traditional Chinese Medicines to illustrate how in silico modeling can be useful in this domain. We also summarize valuable data sources and web-based tools that are available for DDI prediction. We finally explore the challenges we see faced by in silico approaches for predicting DDI and propose future directions to make these computational models more reliable, accurate, and publically accessible.

  5. Transport of peptidomimetic drugs by the intestinal Di/tri-peptide transporter, PepT1

    DEFF Research Database (Denmark)

    Brodin, Birger; Nielsen, Carsten Uhd; Steffansen, Bente

    2002-01-01

    The apical membrane of small intestinal enterocytes possess an uptake system for di- and tripeptides. The physiological function of the system is to transport small peptides resulting from digestion of dietary protein. Moreover, due to the broad substrate specificity of the system, it is also cap...... an updated introduction to the transport system and discuss the substrate characteristics of the di/tri-peptide transporter system with special emphasis on chemically modified substrates and prodrugs....

  6. Inhibition of Human Drug Transporter Activities by the Pyrethroid Pesticides Allethrin and Tetramethrin.

    Science.gov (United States)

    Chedik, Lisa; Bruyere, Arnaud; Le Vee, Marc; Stieger, Bruno; Denizot, Claire; Parmentier, Yannick; Potin, Sophie; Fardel, Olivier

    2017-01-01

    Pyrethroids are widely-used chemical insecticides, to which humans are commonly exposed, and known to alter functional expression of drug metabolizing enzymes. Limited data have additionally suggested that drug transporters, that constitute key-actors of the drug detoxification system, may also be targeted by pyrethroids. The present study was therefore designed to analyze the potential regulatory effects of these pesticides towards activities of main ATP-binding cassette (ABC) and solute carrier (SLC) drug transporters, using transporter-overexpressing cells. The pyrethroids allethrin and tetramethrin were found to inhibit various ABC and SLC drug transporters, including multidrug resistance-associated protein (MRP) 2, breast cancer resistance protein (BCRP), organic anion transporter polypeptide (OATP) 1B1, organic anion transporter (OAT) 3, multidrug and toxin extrusion transporter (MATE) 1, organic cation transporter (OCT) 1 and OCT2, with IC50 values however ranging from 2.6 μM (OCT1 inhibition by allethrin) to 77.6 μM (OAT3 inhibition by tetramethrin) and thus much higher than pyrethroid concentrations (in the nM range) reached in environmentally pyrethroid-exposed humans. By contrast, allethrin and tetramethrin cis-stimulated OATP2B1 activity and failed to alter activities of OATP1B3, OAT1 and MATE2-K, whereas P-glycoprotein activity was additionally moderately inhibited. Twelve other pyrethoids used at 100 μM did not block activities of the various investigated transporters, or only moderately inhibited some of them (inhibition by less than 50%). In silico analysis of structure-activity relationships next revealed that molecular parameters, including molecular weight and lipophilicity, are associated with transporter inhibition by allethrin/tetramethrin and successfully predicted transporter inhibition by the pyrethroids imiprothrin and prallethrin. Taken together, these data fully demonstrated that two pyrethoids, i.e., allethrin and tetramethrin, can

  7. Inhibition of Human Drug Transporter Activities by the Pyrethroid Pesticides Allethrin and Tetramethrin

    Science.gov (United States)

    Chedik, Lisa; Bruyere, Arnaud; Le Vee, Marc; Stieger, Bruno; Denizot, Claire; Parmentier, Yannick; Potin, Sophie; Fardel, Olivier

    2017-01-01

    Pyrethroids are widely-used chemical insecticides, to which humans are commonly exposed, and known to alter functional expression of drug metabolizing enzymes. Limited data have additionally suggested that drug transporters, that constitute key-actors of the drug detoxification system, may also be targeted by pyrethroids. The present study was therefore designed to analyze the potential regulatory effects of these pesticides towards activities of main ATP-binding cassette (ABC) and solute carrier (SLC) drug transporters, using transporter-overexpressing cells. The pyrethroids allethrin and tetramethrin were found to inhibit various ABC and SLC drug transporters, including multidrug resistance-associated protein (MRP) 2, breast cancer resistance protein (BCRP), organic anion transporter polypeptide (OATP) 1B1, organic anion transporter (OAT) 3, multidrug and toxin extrusion transporter (MATE) 1, organic cation transporter (OCT) 1 and OCT2, with IC50 values however ranging from 2.6 μM (OCT1 inhibition by allethrin) to 77.6 μM (OAT3 inhibition by tetramethrin) and thus much higher than pyrethroid concentrations (in the nM range) reached in environmentally pyrethroid-exposed humans. By contrast, allethrin and tetramethrin cis-stimulated OATP2B1 activity and failed to alter activities of OATP1B3, OAT1 and MATE2-K, whereas P-glycoprotein activity was additionally moderately inhibited. Twelve other pyrethoids used at 100 μM did not block activities of the various investigated transporters, or only moderately inhibited some of them (inhibition by less than 50%). In silico analysis of structure-activity relationships next revealed that molecular parameters, including molecular weight and lipophilicity, are associated with transporter inhibition by allethrin/tetramethrin and successfully predicted transporter inhibition by the pyrethroids imiprothrin and prallethrin. Taken together, these data fully demonstrated that two pyrethoids, i.e., allethrin and tetramethrin, can

  8. Non-steroidal anti-inflammatory drugs and renal response to exercise

    DEFF Research Database (Denmark)

    Olsen, Niels Vidiendal; Jensen, N G; Hansen, J M

    1999-01-01

    at baseline, during graded 20-min exercise sessions at 25%, 50% and 75% of the maximal oxygen uptake rate, and subsequently during two 1-h recovery periods. Heart rate, arterial blood pressure, cardiac output and plasma catecholamines at rest and during exercise were not altered by indomethacin or nabumetone....... Indomethacin decreased urinary rates of excretion of 6-oxo-prostaglandin F(1alpha) (6-oxo-PGF(1alpha)) and thromboxane B(2) in all study periods. Nabumetone decreased 6-oxo-PGF(1alpha) excretion during and after exercise. Excretion rates for PGE(2) did not change. Neither indomethacin nor nabumetone changed...... baseline values or exercise-induced decreases in renal plasma flow or glomerular filtration rate. Indomethacin, but not nabumetone, decreased sodium excretion, urine flow rate and free water clearance. The renal response to exercise, however, remained unchanged. In contrast with nabumatone, indomethacin...

  9. Deafness and renal tubular acidosis in mice lacking the K-Cl co-transporter Kcc4.

    Science.gov (United States)

    Boettger, Thomas; Hübner, Christian A; Maier, Hannes; Rust, Marco B; Beck, Franz X; Jentsch, Thomas J

    2002-04-25

    Hearing depends on a high K(+) concentration bathing the apical membranes of sensory hair cells. K(+) that has entered hair cells through apical mechanosensitive channels is transported to the stria vascularis for re-secretion into the scala media(). K(+) probably exits outer hair cells by KCNQ4 K(+) channels(), and is then transported by means of a gap junction system connecting supporting Deiters' cells and fibrocytes() back to the stria vascularis. We show here that mice lacking the K(+)/Cl(-) (K-Cl) co-transporter Kcc4 (coded for by Slc12a7) are deaf because their hair cells degenerate rapidly after the beginning of hearing. In the mature organ of Corti, Kcc4 is restricted to supporting cells of outer and inner hair cells. Our data suggest that Kcc4 is important for K(+) recycling() by siphoning K(+) ions after their exit from outer hair cells into supporting Deiters' cells, where K(+) enters the gap junction pathway. Similar to some human genetic syndromes(), deafness in Kcc4-deficient mice is associated with renal tubular acidosis. It probably results from an impairment of Cl(-) recycling across the basolateral membrane of acid-secreting alpha-intercalated cells of the distal nephron.

  10. The Role of Folate Transport in Antifolate Drug Action in Trypanosoma brucei*

    Science.gov (United States)

    Dewar, Simon; Sienkiewicz, Natasha; Ong, Han B.; Wall, Richard J.; Horn, David

    2016-01-01

    The aim of this study was to identify and characterize mechanisms of resistance to antifolate drugs in African trypanosomes. Genome-wide RNAi library screens were undertaken in bloodstream form Trypanosoma brucei exposed to the antifolates methotrexate and raltitrexed. In conjunction with drug susceptibility and folate transport studies, RNAi knockdown was used to validate the functions of the putative folate transporters. The transport kinetics of folate and methotrexate were further characterized in whole cells. RNA interference target sequencing experiments identified a tandem array of genes encoding a folate transporter family, TbFT1–3, as major contributors to antifolate drug uptake. RNAi knockdown of TbFT1–3 substantially reduced folate transport into trypanosomes and reduced the parasite's susceptibly to the classical antifolates methotrexate and raltitrexed. In contrast, knockdown of TbFT1–3 increased susceptibly to the non-classical antifolates pyrimethamine and nolatrexed. Both folate and methotrexate transport were inhibited by classical antifolates but not by non-classical antifolates or biopterin. Thus, TbFT1–3 mediates the uptake of folate and classical antifolates in trypanosomes, and TbFT1–3 loss-of-function is a mechanism of antifolate drug resistance. PMID:27703008

  11. SGLT2 inhibitor lowers serum uric acid through alteration of uric acid transport activity in renal tubule by increased glycosuria

    Science.gov (United States)

    Chino, Yukihiro; Samukawa, Yoshishige; Sakai, Soichi; Nakai, Yasuhiro; Yamaguchi, Jun-ichi; Nakanishi, Takeo; Tamai, Ikumi

    2014-01-01

    Sodium glucose cotransporter 2 (SGLT2) inhibitors have been reported to lower the serum uric acid (SUA) level. To elucidate the mechanism responsible for this reduction, SUA and the urinary excretion rate of uric acid (UEUA) were analysed after the oral administration of luseogliflozin, a SGLT2 inhibitor, to healthy subjects. After dosing, SUA decreased, and a negative correlation was observed between the SUA level and the UEUA, suggesting that SUA decreased as a result of the increase in the UEUA. The increase in UEUA was correlated with an increase in urinary d-glucose excretion, but not with the plasma luseogliflozin concentration. Additionally, in vitro transport experiments showed that luseogliflozin had no direct effect on the transporters involved in renal UA reabsorption. To explain that the increase in UEUA is likely due to glycosuria, the study focused on the facilitative glucose transporter 9 isoform 2 (GLUT9ΔN, SLC2A9b), which is expressed at the apical membrane of the kidney tubular cells and transports both UA and d-glucose. It was observed that the efflux of [14C]UA in Xenopus oocytes expressing the GLUT9 isoform 2 was trans-stimulated by 10 mm d-glucose, a high concentration of glucose that existed under SGLT2 inhibition. On the other hand, the uptake of [14C]UA by oocytes was cis-inhibited by 100 mm d-glucose, a concentration assumed to exist in collecting ducts. In conclusion, it was demonstrated that the UEUA could potentially be increased by luseogliflozin-induced glycosuria, with alterations of UA transport activity because of urinary glucose. PMID:25044127

  12. Glycemic control and antidiabetic drugs in type 2 diabetes mellitus patients with renal complications

    Directory of Open Access Journals (Sweden)

    Huri HZ

    2015-08-01

    Full Text Available Hasniza Zaman Huri,1,2 Lay Peng Lim,1 Soo Kun Lim3 1Department of Pharmacy, Faculty of Medicine, University of Malaya, 2Clinical Investigation Centre, University Malaya Medical Centre, 3Renal Unit, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia Background: Good glycemic control can delay the progression of kidney diseases in type 2 diabetes mellitus (T2DM patients with renal complications. To date, the association between antidiabetic agents and glycemic control in this specific patient population is not well established.Purpose: This study aimed to identify antidiabetic regimens as well as other factors that associated with glycemic control in T2DM patients with different stages of chronic kidney disease (CKD.Patients and methods: This retrospective, cross-sectional study involved 242 T2DM inpatients and outpatients with renal complications from January 2009 to March 2014 and was conducted in a tertiary teaching hospital in Malaysia. Glycated hemoglobin (A1C was used as main parameter to assess patients’ glycemic status. Patients were classified to have good (A1C <7% or poor glycemic control (A1C ≥7% based on the recommendations of the American Diabetes Association.Results: Majority of the patients presented with CKD stage 4 (43.4%. Approximately 55.4% of patients were categorized to have poor glycemic control. Insulin (57.9% was the most commonly prescribed antidiabetic medication, followed by sulfonylureas (43%. Of all antidiabetic regimens, sulfonylureas monotherapy (P<0.001, insulin therapy (P=0.005, and combination of biguanides with insulin (P=0.038 were found to be significantly associated with glycemic control. Other factors including duration of T2DM (P=0.004, comorbidities such as anemia (P=0.024 and retinopathy (P=0.033, concurrent medications such as erythropoietin therapy (P=0.047, a-blockers (P=0.033, and antigouts (P=0.003 were also correlated with A1C.Conclusion: Identification of

  13. Norepinephrine transporter function and desipramine: residual drug effects versus short-term regulation.

    Science.gov (United States)

    Ordway, Gregory A; Jia, Weihong; Li, Jing; Zhu, Meng-Yang; Mandela, Prashant; Pan, Jun

    2005-04-30

    Previous research has shown that exposure of norepinephrine transporter (NET)-expressing cells to desipramine (DMI) downregulates the norepinephrine transporter, although changes in the several transporter parameters do not demonstrate the same time course. Exposures to desipramine for effects of residual desipramine on norepinephrine transporter binding and uptake were re-evaluated following exposures of PC12 cells to desipramine using different methods to remove residual drug. Using a method that minimizes residual drug, exposure of intact PC12 cells to desipramine for 4h had no effect on uptake capacity or [(3)H]nisoxetine binding to the norepinephrine transporter, while exposures for > or =16 h reduced uptake capacity. Desipramine-induced reductions in binding to the transporter required >24 h or greater periods of desipramine exposure. This study confirms that uptake capacity of the norepinephrine transporter is reduced earlier than changes in radioligand binding, but with a different time course than originally shown. Special pre-incubation procedures are required to abolish effects of residual transporter inhibitor when studying inhibitor-induced transporter regulation.

  14. Effects of potassium on expression of renal sodium transporters in salt-sensitive hypertensive rats induced by uninephrectomy.

    Science.gov (United States)

    Jung, Ji Yong; Kim, Sejoong; Lee, Jay Wook; Jung, Eun Sook; Heo, Nam Ju; Son, Min-Jeong; Oh, Yun Kyu; Na, Ki Young; Han, Jin Suk; Joo, Kwon Wook

    2011-06-01

    Dietary potassium is an important modulator of systemic blood pressure (BP). The purpose of this study was to determine whether dietary potassium is associated with an altered abundance of major renal sodium transporters that may contribute to the modulation of systemic BP. A unilateral nephrectomy (uNx) was performed in male Sprague-Dawley rats, and the rats were fed a normal-salt diet (0.3% NaCl) for 4 wk. Thereafter, the rats were fed a high-salt (HS) diet (3% NaCl) for the entire experimental period. The potassium-repleted (HS+KCl) group was given a mixed solution of 1% KCl as a substitute for drinking water. We examined the changes in the abundance of major renal sodium transporters and the expression of mRNA of With-No-Lysine (WNK) kinases sequentially at 1 and 3 wk. The systolic BP of the HS+KCl group was decreased compared with the HS group (140.3 ± 2.97 vs. 150.9 ± 4.04 mmHg at 1 wk; 180.3 ± 1.76 vs. 207.7 ± 6.21 mmHg at 3 wk). The protein abundances of type 3 Na(+)/H(+) exchanger (NHE3) and Na(+)-Cl(-) cotransporter (NCC) in the HS+KCl group were significantly decreased (53 and 45% of the HS group at 1 wk, respectively; 19 and 8% of HS group at 3 wk). WNK4 mRNA expression was significantly increased in the HS+KCl group (1.4-fold of control at 1 wk and 1.9-fold of control at 3 wk). The downregulation of NHE3 and NCC may contribute to the BP-attenuating effect of dietary potassium associated with increased urinary sodium excretion.

  15. A four-drug combination therapy consisting of low-dose tacrolimus, low-dose mycophenolate mofetil, corticosteroids, and mizoribine in living donor renal transplantation: A randomized study

    Directory of Open Access Journals (Sweden)

    Tian-zhong Yan

    2016-05-01

    Full Text Available Objective: We compared a three-drug combination therapy (control group consisting of tacrolimus, mycophenolate mofetil, and corticosteroids in living donor renal transplantation with a four-drug combination therapy (study group, in which the doses of tacrolimus and mycophenolate mofetil were halved and the immunosuppressive drug mizoribine was added, in order to determine whether the incidence rates of acute rejection after transplantation between the study group and the control group are similar, whether the study group regimen prevents the occurrence of calcineurin inhibitor–induced renal damage, and whether the study group regimen prevents adverse effects such as diarrhea caused by mycophenolate mofetil. Methods: We investigated the incidence of acute rejection, serum creatinine levels, and estimated glomerular filtration rate and the incidence of adverse effects such as diarrhea. Results: There was no significant difference between the two groups in the incidence of acute rejection. Renal function (estimated glomerular filtration rate and serum creatinine was maintained in the control group whereas in the study group renal function gradually improved, with a statistical difference observed at 12 months. The incidence of gastrointestinal symptoms including diarrhea was significantly higher in the control group than in the study group. There was no significant difference in the incidence of cytomegalovirus infection and other adverse effects. Conclusion: These results suggest the study group therapy is an effective regimen in preventing acute rejection and the deterioration of renal function. These results also show this therapy can reduce the incidence of adverse effects such as gastrointestinal symptoms.

  16. Regulation of human hepatic drug transporter activity and expression by diesel exhaust particle extract.

    Directory of Open Access Journals (Sweden)

    Marc Le Vee

    Full Text Available Diesel exhaust particles (DEPs are common environmental air pollutants primarily affecting the lung. DEPs or chemicals adsorbed on DEPs also exert extra-pulmonary effects, including alteration of hepatic drug detoxifying enzyme expression. The present study was designed to determine whether organic DEP extract (DEPe may target hepatic drug transporters that contribute in a major way to drug detoxification. Using primary human hepatocytes and transporter-overexpressing cells, DEPe was first shown to strongly inhibit activities of the sinusoidal solute carrier (SLC uptake transporters organic anion-transporting polypeptides (OATP 1B1, 1B3 and 2B1 and of the canalicular ATP-binding cassette (ABC efflux pump multidrug resistance-associated protein 2, with IC50 values ranging from approximately 1 to 20 μg/mL and relevant to environmental exposure situations. By contrast, 25 μg/mL DEPe failed to alter activities of the SLC transporter organic cation transporter (OCT 1 and of the ABC efflux pumps P-glycoprotein and bile salt export pump (BSEP, whereas it only moderately inhibited those of sodium taurocholate co-transporting polypeptide and of breast cancer resistance protein (BCRP. Treatment by 25 μg/mL DEPe was next demonstrated to induce expression of BCRP at both mRNA and protein level in cultured human hepatic cells, whereas it concomitantly repressed mRNA expression of various transporters, including OATP1B3, OATP2B1, OCT1 and BSEP. Such changes in transporter expression were found to be highly correlated to those caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, a reference activator of the aryl hydrocarbon receptor (AhR pathway. This suggests that DEPe, which is enriched in known ligands of AhR like polycyclic aromatic hydrocarbons, alters drug transporter expression via activation of the AhR cascade. Taken together, these data established human hepatic transporters as targets of organic chemicals containing in DEPs, which may contribute

  17. Mechanism of coupling drug transport reactions located in two different membranes

    Directory of Open Access Journals (Sweden)

    Helen I. Zgurskaya

    2015-02-01

    Full Text Available Gram- negative bacteria utilize a diverse array of multidrug transporters to pump toxic compounds out of cells. Some transporters together with periplasmic membrane fusion proteins (MFPs and outer membrane channels assemble trans-envelope complexes that expel multiple antibiotics across outer membranes of Gram-negative bacteria and into the external medium. Others further potentiate this efflux by pumping drugs across the inner membrane into the periplasm. Together these transporters create a powerful network of efflux that protect bacteria against a broad range of antimicrobial agents. This review is focused on the mechanism of coupling transport reactions located in two different membranes of Gram-negative bacteria. Using a combination of biochemical, genetic and biophysical approaches we have reconstructed the sequence of events leading to the assembly of trans-envelope drug efflux complexes and characterized the roles of periplasmic and outer membrane proteins in this process. Our recent data suggest a critical step in the activation of intermembrane efflux pumps, which is controlled by MFPs. We propose that the reaction cycles of transporters are tightly coupled to the assembly of the trans-envelope complexes. Transporters and MFPs exist in the inner membrane as dormant complexes. The activation of complexes is triggered by MFP binding to the outer membrane channel, which leads to a conformational change in the membrane proximal domain of MFP needed for stimulation of transporters. The activated MFP-transporter complex engages the outer membrane channel to expel substrates across the outer membrane. The recruitment of the channel is likely triggered by binding of effectors (substrates to MFP or MFP-transporter complexes. This model together with recent structural and functional advances in the field of drug efflux provides a fairly detailed understanding of the mechanism of drug efflux across the two membranes.

  18. Pharmacogenomics of Drug Metabolizing Enzymes and Transporters:Relevance to Precision Medicine

    Institute of Scientific and Technical Information of China (English)

    Shabbir Ahmed; Zhan Zhou; Jie Zhou; Shu-Qing Chen

    2016-01-01

    The interindividual genetic variations in drug metabolizing enzymes and transporters influence the efficacy and toxicity of numerous drugs. As a fundamental element in precision med-icine, pharmacogenomics, the study of responses of individuals to medication based on their genomic information, enables the evaluation of some specific genetic variants responsible for an individual’s particular drug response. In this article, we review the contributions of genetic polymorphisms to major individual variations in drug pharmacotherapy, focusing specifically on the pharmacoge-nomics of phase-I drug metabolizing enzymes and transporters. Substantial frequency differences in key variants of drug metabolizing enzymes and transporters, as well as their possible functional consequences, have also been discussed across geographic regions. The current effort illustrates the common presence of variability in drug responses among individuals and across all geographic regions. This information will aid health-care professionals in prescribing the most appropriate treatment aimed at achieving the best possible beneficial outcomes while avoiding unwanted effects for a particular patient.

  19. Transport of diclofenac by breast cancer resistance protein (ABCG2) and stimulation of multidrug resistance protein 2 (ABCC2)-mediated drug transport by diclofenac and benzbromarone.

    Science.gov (United States)

    Lagas, Jurjen S; van der Kruijssen, Cornelia M M; van de Wetering, Koen; Beijnen, Jos H; Schinkel, Alfred H

    2009-01-01

    Diclofenac is an important analgesic and anti-inflammatory drug, widely used for treatment of postoperative pain, rheumatoid arthritis, and chronic pain associated with cancer. Consequently, diclofenac is often used in combination regimens and undesirable drug-drug interactions may occur. Because many drug-drug interactions may occur at the level of drug transporting proteins, we studied interactions of diclofenac with apical ATP-binding cassette (ABC) multidrug efflux transporters. Using Madin-Darby canine kidney (MDCK)-II cells transfected with human P-glycoprotein (P-gp; MDR1/ABCB1), multidrug resistance protein 2 (MRP2/ABCC2), and breast cancer resistance protein (BCRP/ABCG2) and murine Bcrp1, we found that diclofenac was efficiently transported by murine Bcrp1 and moderately by human BCRP but not by P-gp or MRP2. Furthermore, in Sf9-BCRP membrane vesicles diclofenac inhibited transport of methotrexate in a concentration-dependent manner. We next used MDCK-II-MRP2 cells to study interactions of diclofenac with MRP2-mediated drug transport. Diclofenac stimulated paclitaxel, docetaxel, and saquinavir transport at only 50 microM. We further found that the uricosuric drug benzbromarone stimulated MRP2 at an even lower concentration, having maximal stimulatory activity at only 2 microM. Diclofenac and benzbromarone stimulated MRP2-mediated transport of amphipathic lipophilic drugs at 10- and 250-fold lower concentrations, respectively, than reported for other MRP2 stimulators. Because these concentrations are readily achieved in patients, adverse drug-drug interactions may occur, for example, during cancer therapy, in which drug concentrations are often critical and stimulation of elimination via MRP2 may result in suboptimal chemotherapeutic drug concentrations. Moreover, stimulation of MRP2 activity in tumors may lead to increased efflux of chemotherapeutic drugs and thereby drug resistance.

  20. Effect of chronic antioxidant therapy with superoxide dismutase-mimetic drug, tempol, on progression of renal disease in rats with renal mass reduction.

    Science.gov (United States)

    Quiroz, Yasmir; Ferrebuz, Atilio; Vaziri, Nosratola D; Rodriguez-Iturbe, Bernardo

    2009-01-01

    Oxidative stress and inflammation play a major role in the progression of renal damage and antioxidants are potentially useful therapeutic options in chronic renal disease. We investigated if treatment with tempol, a superoxide dismutase mimetic that has beneficial effects in several experimental models of hypertension and acute kidney injury, ameliorates the chronic renal damage resulting in renal mass reduction. Rats with surgical 5/6 nephrectomy were randomly assigned to receive no treatment (CRF group, n = 10) or tempol, 1 mmol/l in the drinking water (CRF-tempol group, n = 10). Sham-operated rats (n = 10) served as controls. All rats were followed for 12 weeks post-nephrectomy. Tempol treatment reduced plasma malondialdehyde (MDA) levels and halved the number of superoxide-positive cells in the remnant kidney; however, the number of hydrogen peroxide-positive cells increased and the overall renal oxidative stress (MDA and nitrotyrosine abundance) and inflammation (interstitial p65 NF-kappaB, macrophage and lymphocyte infiltration) were unchanged. Proteinuria, renal function and glomerular and tubulointerstitial damage in the remnant kidney were similar in the CRF and CRF-tempol groups. In conclusion, tempol administration, at the dose used in these studies, decreased plasma MDA and heightened superoxide dismutation in the kidney, but was incapable of reducing renal oxidative stress or improving renal function or structure in the remnant kidney model.

  1. Optimising drug prescribing and dispensing in subjects at risk for drug errors due to renal impairment : improving drug safety in primary healthcare by low eGFR alerts

    NARCIS (Netherlands)

    Joosten, Hanneke; Drion, Iefke; Boogerd, Kees J.; van der Pijl, Emiel V.; Slingerland, Robbert J.; Slaets, Joris P. J.; Jansen, Tiele J.; Schwantje, Olof; Gans, Reinold O. B.; Bilo, Henk J. G.

    2013-01-01

    Objectives: To assess the risk of medication errors in subjects with renal impairment (defined as an estimated glomerular filtration rate (eGFR) Design: Clinical survey. Setting: The city of Zwolle, The Netherlands, in a primary care setting including 22 community pharmacists and 65 general practiti

  2. Manipulating the drug/proton antiport stoichiometry of the secondary multidrug transporter MdfA.

    Science.gov (United States)

    Tirosh, Osnat; Sigal, Nadejda; Gelman, Amir; Sahar, Nadav; Fluman, Nir; Siemion, Shira; Bibi, Eitan

    2012-07-31

    Multidrug transporters are integral membrane proteins that use cellular energy to actively extrude antibiotics and other toxic compounds from cells. The multidrug/proton antiporter MdfA from Escherichia coli exchanges monovalent cationic substrates for protons with a stoichiometry of 1, meaning that it translocates only one proton per antiport cycle. This may explain why transport of divalent cationic drugs by MdfA is energetically unfavorable. Remarkably, however, we show that MdfA can be easily converted into a divalent cationic drug/≥ 2 proton-antiporter, either by random mutagenesis or by rational design. The results suggest that exchange of divalent cationi c drugs with two (or more) protons requires an additional acidic residue in the multidrug recognition pocket of MdfA. This outcome further illustrates the exceptional promiscuous capabilities of multidrug transporters.

  3. Potential role of serine proteases in modulating renal sodium transport in vivo.

    Science.gov (United States)

    Jacquillet, G; Rubera, I; Unwin, R J

    2011-01-01

    The maintenance of sodium (Na+) homeostasis is an essential function of the kidney. It is achieved by a variety of transport processes localized all along the highly specialised segments of the nephron. Impairment of these transport mechanisms, and thereby Na+ handling, is associated with disturbed Na+ and water balance, leading to hypertension and oedema. This review focuses on the novel regulation of sodium reabsorption by serine proteases acting along the entire nephron.

  4. Protonation of a glutamate residue modulates the dynamics of the drug transporter EmrE.

    Science.gov (United States)

    Gayen, Anindita; Leninger, Maureen; Traaseth, Nathaniel J

    2016-03-01

    Secondary active transport proteins play a central role in conferring bacterial multidrug resistance. In this work, we investigated the proton-coupled transport mechanism for the Escherichia coli drug efflux pump EmrE using NMR spectroscopy. Our results show that the global conformational motions necessary for transport are modulated in an allosteric fashion by the protonation state of a membrane-embedded glutamate residue. These observations directly correlate with the resistance phenotype for wild-type EmrE and the E14D mutant as a function of pH. Furthermore, our results support a model in which the pH gradient across the inner membrane of E. coli may be used on a mechanistic level to shift the equilibrium of the transporter in favor of an inward-open resting conformation poised for drug binding.

  5. Multifunctional superparamagnetic nanoparticles for enhanced drug transport in cystic fibrosis

    Science.gov (United States)

    Armijo, Leisha M.; Brandt, Yekaterina I.; Rivera, Antonio C.; Cook, Nathaniel C.; Plumley, John B.; Withers, Nathan J.; Kopciuch, Michael; Smolyakov, Gennady A.; Huber, Dale L.; Smyth, Hugh D.; Osinski, Marek

    2012-10-01

    Iron oxide colloidal nanoparticles (ferrofluids) are investigated for application in the treatment of cystic fibrosis lung infections, the leading cause of mortality in cystic fibrosis patients. We investigate the use of iron oxide nanoparticles to increase the effectiveness of administering antibiotics through aerosol inhalation using two mechanisms: directed particle movement in the presence of an inhomogeneous static external magnetic field and magnetic hyperthermia. Magnetic hyperthermia is an effective method for decreasing the viscosity of the mucus and biofilm, thereby enhancing drug, immune cell, and antibody penetration to the affected area. Iron oxide nanoparticles of various sizes and morphologies were synthesized and tested for specific losses (heating power). Nanoparticles in the superparamagnetic to ferromagnetic size range exhibited excellent heating power. Additionally, iron oxide / zinc selenide core/shell nanoparticles were prepared, in order to enable imaging of the iron oxide nanoparticles. We also report on synthesis and characterization of MnSe/ZnSeS alloyed quantum dots.

  6. Stereocomplex micelle from nonlinear enantiomeric copolymers efficiently transports antineoplastic drug

    Science.gov (United States)

    Wang, Jixue; Shen, Kexin; Xu, Weiguo; Ding, Jianxun; Wang, Xiaoqing; Liu, Tongjun; Wang, Chunxi; Chen, Xuesi

    2015-05-01

    Nanoscale polymeric micelles have attracted more and more attention as a promising nanocarrier for controlled delivery of antineoplastic drugs. Herein, the doxorubicin (DOX)-loaded poly(D-lactide)-based micelle (PDM/DOX), poly(L-lactide)-based micelle (PLM/DOX), and stereocomplex micelle (SCM/DOX) from the equimolar mixture of the enantiomeric four-armed poly(ethylene glycol)-polylactide (PEG-PLA) copolymers were successfully fabricated. In phosphate-buffered saline (PBS) at pH 7.4, SCM/DOX exhibited the smallest hydrodynamic diameter ( D h) of 90 ± 4.2 nm and the slowest DOX release compared with PDM/DOX and PLM/DOX. Moreover, PDM/DOX, PLM/DOX, and SCM/DOX exhibited almost stable D hs of around 115, 105, and 90 nm at above normal physiological condition, respectively, which endowed them with great potential in controlled drug delivery. The intracellular DOX fluorescence intensity after the incubation with the laden micelles was different degrees weaker than that incubated with free DOX · HCl within 12 h, probably due to the slow DOX release from micelles. As the incubation time reached to 24 h, all the cells incubated with the laden micelles, especially SCM/DOX, demonstrated a stronger intracellular DOX fluorescence intensity than free DOX · HCl-cultured ones. More importantly, all the DOX-loaded micelles, especially SCM/DOX, exhibited potent antineoplastic efficacy in vitro, excellent serum albumin-tolerance stability, and satisfactory hemocompatibility. These encouraging data indicated that the loading micelles from nonlinear enantiomeric copolymers, especially SCM/DOX, might be promising in clinical systemic chemotherapy through intravenous injection.

  7. Echinacea purpurea and P-glycoprotein drug transport in Caco-2 cells.

    Science.gov (United States)

    Hansen, Torstein Schrøder; Nilsen, Odd Georg

    2009-01-01

    Echinacea is widely used as a medical herbal product, but its interaction potential with the drug efflux transporter P-glycoprotein (P-gp) has not yet been evaluated. The interaction potential of Echinacea purpurea towards P-gp mediated drug transport was studied in human intestinal Caco-2 cells. Digoxin (30 nm) was used as a substrate and verapamil as a control inhibitor. Ethanol, 0.8%, needed for herbal extraction and compatibility with the commercial products, inhibited the net digoxin flux by 18%. E. purpurea influenced to a higher degree the B-A transport of digoxin than the A-B transport. A minor increase in net digoxin flux was observed at low concentrations of E. purpurea, an effect anticipated to be allosteric in nature. At higher concentrations, from 0.4 to 6.36 mg dry weight/mL, a statistically significant linear dose-related decrease was observed in the net digoxin flux, indicating a dose dependent E. purpurea inhibition of P-gp. Both Vmax and Km of the net digoxin flux, calculated to 23.7 nmol/cm2/h and 385 microm, respectively, decreased in the presence of E. purpurea in an uncompetitive fashion. Although the effects of Echinacea purpurea on systemic P-gp mediated drug transport are probably limited, an influence on drug bioavailability can not be excluded. Copyright 2008 John Wiley & Sons, Ltd.

  8. Precision-cut kidney slices (PCKS to study development of renal fibrosis and efficacy of drug targeting ex vivo

    Directory of Open Access Journals (Sweden)

    Fariba Poosti

    2015-10-01

    Full Text Available Renal fibrosis is a serious clinical problem resulting in the greatest need for renal replacement therapy. No adequate preventive or curative therapy is available that could be clinically used to target renal fibrosis specifically. The search for new efficacious treatment strategies is therefore warranted. Although in vitro models using homogeneous cell populations have contributed to the understanding of the pathogenetic mechanisms involved in renal fibrosis, these models poorly mimic the complex in vivo milieu. Therefore, we here evaluated a precision-cut kidney slice (PCKS model as a new, multicellular ex vivo model to study the development of fibrosis and its prevention using anti-fibrotic compounds. Precision-cut slices (200-300 μm thickness were prepared from healthy C57BL/6 mouse kidneys using a Krumdieck tissue slicer. To induce changes mimicking the fibrotic process, slices were incubated with TGFβ1 (5 ng/ml for 48 h in the presence or absence of the anti-fibrotic cytokine IFNγ (1 µg/ml or an IFNγ conjugate targeted to PDGFRβ (PPB-PEG-IFNγ. Following culture, tissue viability (ATP-content and expression of α-SMA, fibronectin, collagen I and collagen III were determined using real-time PCR and immunohistochemistry. Slices remained viable up to 72 h of incubation, and no significant effects of TGFβ1 and IFNγ on viability were observed. TGFβ1 markedly increased α-SMA, fibronectin and collagen I mRNA and protein expression levels. IFNγ and PPB-PEG-IFNγ significantly reduced TGFβ1-induced fibronectin, collagen I and collagen III mRNA expression, which was confirmed by immunohistochemistry. The PKCS model is a novel tool to test the pathophysiology of fibrosis and to screen the efficacy of anti-fibrotic drugs ex vivo in a multicellular and pro-fibrotic milieu. A major advantage of the slice model is that it can be used not only for animal but also for (fibrotic human kidney tissue.

  9. Efficacy of anti-pruritis drugs in chronic renal failure: a comparative study

    Directory of Open Access Journals (Sweden)

    "H. Khalili

    2006-07-01

    Full Text Available Background: Pruritus is one of the most common problems in patients suffering chronic renal failure. Twenty five - 35% of predialysis patients and 60-80% of patients during dialysis complain pruritus. The exact pathophysiology of pruritus is unknown; however, some possible interactive factors include: histamine release from mast cells and basophiles, uremic skin, cutaneous mast cells proliferation, adipose cells atrophy, electrolyte imbalance, and accumulation of bile acids. Since histamine is the main proposed mediator in pruritus, the goal of this study was to evaluate the role of antihistamines in controling of pruritus of patients with chronic renal failure. This study was done as a before - after study during one year period in dialysis department of Imam Khomeini hospital. Methods: Thirty patients complied with inclusion criteria were entered in the study. Treatment strategy was: 2 weeks treatment with hydroxyzine 25 mg TDS, followed by one week wash-out period, then 2 weeks ketotifen therapy 1mg BID and finally two weeks treatment with chlorpheniramine 4mg BD following one week washout period after ketotifen therapy. Pruritus severity before and after each treatment period was evaluated with Pruritus Severity Score (PSS chart. Results: The mean PSS reduction by hydroxyzine, ketotifen and chlorpheniramine, were 33%, 4.5% and 20%, respectively. Conclusion: PSS improvement with hydroxyzine and chlorpheniramine was statistically significant (p<0.001. However, ketotifen induced pruritus reduction was not considerably significant.

  10. Cancer drug troglitazone stimulates the growth and response of renal cells to hypoxia inducible factors

    Energy Technology Data Exchange (ETDEWEB)

    Taub, Mary, E-mail: biochtau@buffalo.edu

    2016-03-11

    Troglitazone has been used to suppress the growth of a number of tumors through apoptosis and autophagy. However, previous in vitro studies have employed very high concentrations of troglitazone (≥10{sup −5} M) in order to elicit growth inhibitory effects. In this report, when employing lower concentrations of troglitazone in defined medium, troglitazone was observed to stimulate the growth of primary renal proximal tubule (RPT) cells. Rosiglitazone, like troglitazone, is a thiazolidinedione (TZD) that is known to activate Peroxisome Proliferator Activated Receptor Υ (PPARΥ). Notably, rosiglitazone also stimulates RPT cell growth, as does Υ-linolenic acids, another PPARΥ agonist. The PPARΥ antagonist GW9662 inhibited the growth stimulatory effect of troglitazone. In addition, troglitazone stimulated transcription by a PPAR Response Element/Luciferase construct. These results are consistent with the involvement of PPARΥ as a mediator of the growth stimulatory effect of troglitazone. In a number of tumor cells, the expression of hypoxia inducible factor (HIF) is increased, promoting the expression of HIF inducible genes, and vascularization. Troglitazone was observed to stimulate transcription by a HIF/luciferase construct. These observations indicate that troglitazone not only promotes growth, also the survival of RPT cells under conditions of hypoxia. - Highlights: • Troglitazone and rosiglitazone stimulate renal proximal tubule cell growth. • Troglitazone and linolenic acid stimulate growth via PPARϒ. • Linolenic acid stimulates growth in the presence of fatty acid free serum albumin. • Rosiglitazone stimulates transcription by a HRE luciferase construct.

  11. Long-term bone loss after renal transportation. Comparison of immunosuppressive regimens

    Energy Technology Data Exchange (ETDEWEB)

    Menzies, B.; Rigby, R.; Hawley, CJ.M.; Hardie, I.R. [Princess Alexandra Hospital, Renal Transplant Unit, Woolloongabba (Australia); McIntyre, H.D. [Mater Adult Hospital, Department of Medicine, South Brisbane (Australia); Perry-Keene, D.A. [Royal Brisbane Hospital, Department of Endocrinology, Herston, Queensland (Australia)

    1995-02-01

    Serial measurements of serum and urine markers of bone metabolism and of forearm bone density (BMD) by dual photon absorptiometry were performed in 22 patients undergoing renal transplantation in 1986. Patients were randomised to immunosuppression with (1) cyclosporin alone (CsA group, n = 10), (2) cyclosporin for 3 months followed by azathioprine-prednisone (CsA/AzP group, n = 3) or (3) long-term azathioprine-prednisone (LT AzP group, n = 9). As no reduction in bone mineral density (BMD) was noted in the first 6 months, groups 2 and 3 were considered together (AzP group, n = 12). Mean{+-}SEM BMD fell by 19{+-}2% at 36 months (n = 19,m p<0.01), with similar reductions seen in the CsA and AzP groups. At 60 months, BMD of the AzP group was 25{+-}3% below baseline (p<0.01), while the CsA group were only 5{+-}4% belov baseline (p = NS vs baseline, p<0.05 vs AzP group). The degree of reduction in BMD over 5 years correlated with total glucocorticoid dose (r = 0.63, p<0.05), but not with biochemical markers of bone turnover. Serum alkaline phosphatase fell post-transplant in patients treated with AzP, but not in the CsA group. These results demonstrate significant loss of forearm bone mineral with long-term follow-up after renal transplantation, but suggest that patients treated with cyclosporin monotherapy may be at lower risk of this complication. (au) (15 refs.).

  12. A hybrid cellular automaton model of solid tumor growth and bioreductive drug transport.

    Science.gov (United States)

    Kazmi, Nabila; Hossain, M A; Phillips, Roger M

    2012-01-01

    Bioreductive drugs are a class of hypoxia selective drugs that are designed to eradicate the hypoxic fraction of solid tumors. Their activity depends upon a number of biological and pharmacological factors and we used a mathematical modeling approach to explore the dynamics of tumor growth, infusion, and penetration of the bioreductive drug Tirapazamine (TPZ). An in-silico model is implemented to calculate the tumor mass considering oxygen and glucose as key microenvironmental parameters. The next stage of the model integrated extra cellular matrix (ECM), cell-cell adhesion, and cell movement parameters as growth constraints. The tumor microenvironments strongly influenced tumor morphology and growth rates. Once the growth model was established, a hybrid model was developed to study drug dynamics inside the hypoxic regions of tumors. The model used 10, 50 and 100 \\mu {\\rm M} as TPZ initial concentrations and determined TPZ pharmacokinetic (PK) (transport) and pharmacodynamics (cytotoxicity) properties inside hypoxic regions of solid tumor. The model results showed that diminished drug transport is a reason for TPZ failure and recommend the optimization of the drug transport properties in the emerging TPZ generations. The modeling approach used in this study is novel and can be a step to explore the behavioral dynamics of TPZ.

  13. Leishmania panamensis infection and antimonial drugs modulate expression of macrophage drug transporters and metabolizing enzymes: impact on intracellular parasite survival

    Science.gov (United States)

    Gómez, Maria Adelaida; Navas, Adriana; Márquez, Ricardo; Rojas, Laura Jimena; Vargas, Deninson Alejandro; Blanco, Victor Manuel; Koren, Roni; Zilberstein, Dan; Saravia, Nancy Gore

    2014-01-01

    Objectives Treatment failure is multifactorial. Despite the importance of host cell drug transporters and metabolizing enzymes in the accumulation, distribution and metabolism of drugs targeting intracellular pathogens, their impact on the efficacy of antileishmanials is unknown. We examined the contribution of pharmacologically relevant determinants in human macrophages in the antimony-mediated killing of intracellular Leishmania panamensis and its relationship with the outcome of treatment with meglumine antimoniate. Methods Patients with cutaneous leishmaniasis who failed (n = 8) or responded (n = 8) to treatment were recruited. Gene expression profiling of pharmacological determinants in primary macrophages was evaluated by quantitative RT–PCR and correlated to the drug-mediated intracellular parasite killing. Functional validation was conducted through short hairpin RNA gene knockdown. Results Survival of L. panamensis after exposure to antimonials was significantly higher in macrophages from patients who failed treatment. Sixteen macrophage drug-response genes were modulated by infection and exposure to meglumine antimoniate. Correlation analyses of gene expression and intracellular parasite survival revealed the involvement of host cell metallothionein-2A and ABCB6 in the survival of Leishmania during exposure to antimonials. ABCB6 was functionally validated as a transporter of antimonial compounds localized in both the cell and phagolysosomal membranes of macrophages, revealing a novel mechanism of host cell-mediated regulation of intracellular drug exposure and parasite survival within phagocytes. Conclusions These results provide insight into host cell mechanisms regulating the intracellular exposure of Leishmania to antimonials and variations among individuals that impact parasite survival. Understanding of host cell determinants of intracellular pharmacokinetics/pharmacodynamics opens new avenues to improved drug efficacy for intracellular

  14. Rapid redistribution and inhibition of renal sodium transporters during acute pressure natriuresis

    DEFF Research Database (Denmark)

    Zhang, Y; Mircheff, A K; Hensley, C B

    1996-01-01

    Acute arterial hypertension provokes a rapid decrease in proximal tubule (PT) Na+ reabsorption, increasing flow to the macula densa, the signal for tubuloglomerular feedback. We tested the hypothesis, in rats, that Na+ transport is decreased due to rapid redistribution of apical Na+/H+ exchangers...... natriuretic stimuli, cortex was removed, and membranes were fractionated by density gradient centrifugation. Urine output and endogenous lithium clearance increased threefold in response to either stimuli. Acute hypertension provoked a redistribution of apical Na+/H+ exchanger NHE3, alkaline phosphatase...... is attributed to decreased activity of the transporters. Benzolamide did not alter Na+ transporter activity or distribution, implying that decreasing apical Na+ uptake does not initiate redistribution or inhibition of basolateral Na(+)-K(+)-ATPase. We conclude that PT natriuresis provoked by acute arterial...

  15. Direct effect of methylprednisolone on renal sodium and water transport via the principal cells in the kidney

    DEFF Research Database (Denmark)

    Lauridsen, Thomas G; Vase, Henrik; Bech, Jesper N;

    2010-01-01

    Glucocorticoids influence renal concentrating and diluting ability. We tested the hypothesis that methylprednisolone treatment increased renal water and sodium absorption by increased absorption via the aquaporin-2 (AQP2) water channels and the epithelial sodium channels (ENaCs) respectively....

  16. Regulation of Renal Organic Anion Transporter 3 (SLC22A8 Expression and Function by the Integrity of Lipid Raft Domains and their Associated Cytoskeleton

    Directory of Open Access Journals (Sweden)

    Chutima Srimaroeng

    2013-04-01

    Full Text Available Background/Aims: In humans and rodents, organic anion transporter 3 (Oat3 is highly expressed on the basolateral membrane of renal proximal tubules and mediates the secretion of exogenous and endogenous anions. Regulation of Oat3 expression and function has been observed in both expression system and intact renal epithelia. However, information on the local membrane environment of Oat3 and its role is limited. Lipid raft domains (LRD; cholesterol-rich domains of the plasma membrane play important roles in membrane protein expression, function and targeting. In the present study, we have examined the role of LRD-rich membranes and their associated cytoskeletal proteins on Oat3 expression and function. Methods: LRD-rich membranes were isolated from rat renal cortical tissues and from HEK-293 cells stably expressing human OAT3 (hOAT3 by differential centrifugation with triton X-100 extraction. Western blots were subsequently analyzed to determine protein expression. In addition, the effect of disruption of LRD-rich membranes was examined on functional Oat3 mediated estrone sulfate (ES transport in rat renal cortical slices. Cytoskeleton disruptors were investigated in both hOAT3 expressing HEK-293 cells and rat renal cortical slices. Results: Lipid-enriched membranes from rat renal cortical tissues and hOAT3-expressing HEK-293 cells showed co-expression of rOat3/hOAT3 and several lipid raft-associated proteins, specifically caveolin 1 (Cav1, β-actin and myosin. Moreover, immunohistochemistry in hOAT3-expressing HEK-293 cells demonstrated that these LRD-rich proteins co-localized with hOAT3. Potassium iodide (KI, an inhibitor of protein-cytoskeletal interaction, effectively detached cytoskeleton proteins and hOAT3 from plasma membrane, leading to redistribution of hOAT3 into non-LRD-rich compartments. In addition, inhibition of cytoskeleton integrity and membrane trafficking processes significantly reduced ES uptake mediated by both human and rat

  17. Lansoprazole Exacerbates Pemetrexed-Mediated Hematologic Toxicity by Competitive Inhibition of Renal Basolateral Human Organic Anion Transporter 3.

    Science.gov (United States)

    Ikemura, Kenji; Hamada, Yugo; Kaya, Chinatsu; Enokiya, Tomoyuki; Muraki, Yuichi; Nakahara, Hiroki; Fujimoto, Hajime; Kobayashi, Tetsu; Iwamoto, Takuya; Okuda, Masahiro

    2016-10-01

    Pemetrexed, a multitargeted antifolate, is eliminated by tubular secretion via human organic anion transporter 3 (hOAT3). Although proton pump inhibitors (PPIs) are frequently used in cancer patients, the drug interaction between PPIs and pemetrexed remains to be clarified. In this study, we examined the drug interaction between pemetrexed and PPIs in hOAT3-expressing cultured cells, and retrospectively analyzed the impact of PPIs on the development of hematologic toxicity in 108 patients who received pemetrexed and carboplatin treatment of nonsquamous non-small cell lung cancer for the first time between January 2011 and June 2015. We established that pemetrexed was transported via hOAT3 (Km = 68.3 ± 11.1 µM). Lansoprazole, rabeprazole, pantoprazole, esomeprazole, omeprazole, and vonoprazan inhibited hOAT3-mediated uptake of pemetrexed in a concentration-dependent manner. The inhibitory effect of lansoprazole was much greater than those of other PPIs and the apparent IC50 value of lansoprazole against pemetrexed transport via hOAT3 was 0.57 ± 0.17 µM. The inhibitory type of lansoprazole was competitive. In a retrospective study, multivariate analysis revealed that coadministration of lansoprazole, but not other PPIs, with pemetrexed and carboplatin was an independent risk factor significantly contributing to the development of hematologic toxicity (odds ratio: 10.004, P = 0.005). These findings demonstrated that coadministration of lansoprazole could exacerbate the hematologic toxicity associated with pemetrexed, at least in part, by competitive inhibition of hOAT3. Our results would aid clinicians to make decisions of coadministration drugs to avoid drug interaction-induced side effects for achievement of safe and appropriate chemotherapy with pemetrexed.

  18. Copper transporters and the cellular pharmacology of the platinum-containing cancer drugs.

    Science.gov (United States)

    Howell, Stephen B; Safaei, Roohangiz; Larson, Christopher A; Sailor, Michael J

    2010-06-01

    Multiple lines of evidence indicate that the platinum-containing cancer drugs enter cells, are distributed to various subcellular compartments, and are exported from cells via transporters that evolved to manage copper homeostasis. The cytotoxicity of the platinum drugs is directly related to how much drug enters the cell, and almost all cells that have acquired resistance to the platinum drugs exhibit reduced drug accumulation. The major copper influx transporter, copper transporter 1 (CTR1), has now been shown to control the tumor cell accumulation and cytotoxic effect of cisplatin, carboplatin, and oxaliplatin. There is a good correlation between change in CTR1 expression and acquired cisplatin resistance among ovarian cancer cell lines, and genetic knockout of CTR1 renders cells resistant to cisplatin in vivo. The expression of CTR1 is regulated at the transcriptional level by copper via Sp1 and at the post-translational level by the proteosome. Copper and cisplatin both trigger the down-regulation of CTR1 via a process that involves ubiquitination and proteosomal degradation and requires the copper chaperone antioxidant protein 1 (ATOX1). The cisplatin-induced degradation of CTR1 can be blocked with the proteosome inhibitor bortezomib, and this increases the cellular uptake and the cytotoxicity of cisplatin in a synergistic manner. Copper and platinum(II) have similar sulfur binding characteristics, and the presence of stacked rings of methionines and cysteines in the CTR1 trimer suggest a mechanism by which CTR1 selectively transports copper and the platinum-containing drugs via sequential transchelation reactions similar to the manner in which copper is passed from ATOX1 to the copper efflux transporters.

  19. 透析患者肾性骨病的药物治疗进展%Progress on drug therapy against renal osteopathy in dialysis patients

    Institute of Scientific and Technical Information of China (English)

    田寿福; 汪年松

    2011-01-01

    肾性骨病是慢性肾脏病(CKD)透析患者的常见并发症.随着透析技术的发展和普及,终末期肾衰透析患者生存期延长,肾性骨病成为影响透析患者生活质量和生存时间的重要因素.目前已开发的多种新药针对肾性骨病病理生理的多个环节进行干预.本文综述透析患者肾性骨病药物治疗研究进展.%Renal osteopathy is a common complication in dialysis patients with chronic kidney disease (CKD). As the development of dialysis technology and its popular application, the survival time of partients with end stage renal failure is extended. However, the renal osteopathy becomes an important factor affecting the life quality and survival time of dialysis patients. With the research progress on pathogenesis of renal osteopathy, some new drugs have been developed.This review focuses on the drug therapy against renal osteopathy in dialysis patients.

  20. Excessive fructose intake causes 1,25-(OH)(2)D(3)-dependent inhibition of intestinal and renal calcium transport in growing rats.

    Science.gov (United States)

    Douard, Veronique; Sabbagh, Yves; Lee, Jacklyn; Patel, Chirag; Kemp, Francis W; Bogden, John D; Lin, Sheldon; Ferraris, Ronaldo P

    2013-06-15

    We recently discovered that chronic high fructose intake by lactating rats prevented adaptive increases in rates of active intestinal Ca(2+) transport and in levels of 1,25-(OH)2D3, the active form of vitamin D. Since sufficient Ca(2+) absorption is essential for skeletal growth, our discovery may explain findings that excessive consumption of sweeteners compromises bone integrity in children. We tested the hypothesis that 1,25-(OH)2D3 mediates the inhibitory effect of excessive fructose intake on active Ca(2+) transport. First, compared with those fed glucose or starch, growing rats fed fructose for 4 wk had a marked reduction in intestinal Ca(2+) transport rate as well as in expression of intestinal and renal Ca(2+) transporters that was tightly associated with decreases in circulating levels of 1,25-(OH)2D3, bone length, and total bone ash weight but not with serum parathyroid hormone (PTH). Dietary fructose increased the expression of 24-hydroxylase (CYP24A1) and decreased that of 1α-hydroxylase (CYP27B1), suggesting that fructose might enhance the renal catabolism and impair the synthesis, respectively, of 1,25-(OH)2D3. Serum FGF23, which is secreted by osteocytes and inhibits CYP27B1 expression, was upregulated, suggesting a potential role of bone in mediating the fructose effects on 1,25-(OH)2D3 synthesis. Second, 1,25-(OH)2D3 treatment rescued the fructose effect and normalized intestinal and renal Ca(2+) transporter expression. The mechanism underlying the deleterious effect of excessive fructose intake on intestinal and renal Ca(2+) transporters is a reduction in serum levels of 1,25-(OH)2D3. This finding is significant because of the large amounts of fructose now consumed by Americans increasingly vulnerable to Ca(2+) and vitamin D deficiency.

  1. Excessive fructose intake causes 1,25-(OH)2D3-dependent inhibition of intestinal and renal calcium transport in growing rats

    Science.gov (United States)

    Douard, Veronique; Sabbagh, Yves; Lee, Jacklyn; Patel, Chirag; Kemp, Francis W.; Bogden, John D.; Lin, Sheldon

    2013-01-01

    We recently discovered that chronic high fructose intake by lactating rats prevented adaptive increases in rates of active intestinal Ca2+ transport and in levels of 1,25-(OH)2D3, the active form of vitamin D. Since sufficient Ca2+ absorption is essential for skeletal growth, our discovery may explain findings that excessive consumption of sweeteners compromises bone integrity in children. We tested the hypothesis that 1,25-(OH)2D3 mediates the inhibitory effect of excessive fructose intake on active Ca2+ transport. First, compared with those fed glucose or starch, growing rats fed fructose for 4 wk had a marked reduction in intestinal Ca2+ transport rate as well as in expression of intestinal and renal Ca2+ transporters that was tightly associated with decreases in circulating levels of 1,25-(OH)2D3, bone length, and total bone ash weight but not with serum parathyroid hormone (PTH). Dietary fructose increased the expression of 24-hydroxylase (CYP24A1) and decreased that of 1α-hydroxylase (CYP27B1), suggesting that fructose might enhance the renal catabolism and impair the synthesis, respectively, of 1,25-(OH)2D3. Serum FGF23, which is secreted by osteocytes and inhibits CYP27B1 expression, was upregulated, suggesting a potential role of bone in mediating the fructose effects on 1,25-(OH)2D3 synthesis. Second, 1,25-(OH)2D3 treatment rescued the fructose effect and normalized intestinal and renal Ca2+ transporter expression. The mechanism underlying the deleterious effect of excessive fructose intake on intestinal and renal Ca2+ transporters is a reduction in serum levels of 1,25-(OH)2D3. This finding is significant because of the large amounts of fructose now consumed by Americans increasingly vulnerable to Ca2+ and vitamin D deficiency. PMID:23571713

  2. Effect of drug efflux transporters on placental transport of antiretroviral agent abacavir.

    Science.gov (United States)

    Neumanova, Zuzana; Cerveny, Lukas; Greenwood, Susan L; Ceckova, Martina; Staud, Frantisek

    2015-11-01

    Abacavir is as a frequent part of combination antiretroviral therapy used in pregnant women. The aim of this study was to investigate, using in vitro, in situ and ex vivo experimental approaches, whether the transplacental pharmacokinetics of abacavir is affected by ATP-binding cassette (ABC) efflux transporters functionally expressed in the placenta: P-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2), multidrug resistance-associated protein 2 (ABCC2) and multidrug resistance-associated protein 5 (ABCC5). In vitro transport assays revealed that abacavir is a substrate of human ABCB1 and ABCG2 transporters but not of ABCC2 or ABCC5. In addition, in situ experiments using dually perfused rat term placenta confirmed interactions of abacavir with placental Abcb1/Abcg2. In contrast, uptake studies in human placental villous fragments did not reveal any interaction of abacavir with efflux transporters suggesting a large contribution of passive diffusion and/or influx mechanisms to net transplacental abacavir transfer.

  3. Drug transport into the mammalian brain: the nasal pathway and its specific metabolic barrier.

    Science.gov (United States)

    Minn, Alain; Leclerc, Séverine; Heydel, Jean-Marie; Minn, Anne-Laure; Denizcot, Claire; Cattarelli, Martine; Netter, Patrick; Gradinaru, Daniela

    2002-06-01

    It is generally accepted that the rate of entry into and distribution of drugs and other xenobiotics within the central nervous system (CNS) depends on the particular anatomy of the brain microvessels forming the blood-brain barrier (BBB), and of the choroid plexus forming the blood-cerebrospinal fluid barrier (CSF), which possess tight junctions preventing the passage of most polar substances. Drug entry to the CNS also depends on the physicochemical properties of the substances, which can be metabolised during this transport to pharmacologically inactive, non-penetrating polar products. Finally, the entry of drugs may be prevented by multiple complex specialized carriers, which are able to catalyse the active transport of numerous drugs and xenobiotics out of the CNS. Nasal delivery is currently considered as an efficient tool for systemic administration of drugs that are poorly absorbed via the oral route, and increasing evidence suggests that numerous drugs and potentially toxic xenobiotics can reach the CNS by this route. This short review summarizes recent knowledge on factors controlling the nasal pathway, focusing on drug metabolising enzymes in olfactory mucosa, olfactory bulb and brain, which should constitute a CNS metabolic barrier.

  4. Predicting Drug Extraction in the Human Gut Wall: Assessing Contributions from Drug Metabolizing Enzymes and Transporter Proteins using Preclinical Models.

    Science.gov (United States)

    Peters, Sheila Annie; Jones, Christopher R; Ungell, Anna-Lena; Hatley, Oliver J D

    2016-06-01

    Intestinal metabolism can limit oral bioavailability of drugs and increase the risk of drug interactions. It is therefore important to be able to predict and quantify it in drug discovery and early development. In recent years, a plethora of models-in vivo, in situ and in vitro-have been discussed in the literature. The primary objective of this review is to summarize the current knowledge in the quantitative prediction of gut-wall metabolism. As well as discussing the successes of current models for intestinal metabolism, the challenges in the establishment of good preclinical models are highlighted, including species differences in the isoforms; regional abundances and activities of drug metabolizing enzymes; the interplay of enzyme-transporter proteins; and lack of knowledge on enzyme abundances and availability of empirical scaling factors. Due to its broad specificity and high abundance in the intestine, CYP3A is the enzyme that is frequently implicated in human gut metabolism and is therefore the major focus of this review. A strategy to assess the impact of gut wall metabolism on oral bioavailability during drug discovery and early development phases is presented. Current gaps in the mechanistic understanding and the prediction of gut metabolism are highlighted, with suggestions on how they can be overcome in the future.

  5. 75 FR 8526 - Procedures for Transportation Workplace Drug and Alcohol Testing Programs

    Science.gov (United States)

    2010-02-25

    ... Office of the Secretary 49 CFR Part 40 RIN 2105-AD64 Procedures for Transportation Workplace Drug and... required method. However, in response to comments requesting additional flexibility in testing methods, the... may increase flexibility and lower costs for employers who choose to use them over more expensive...

  6. 75 FR 26183 - Procedures for Transportation Workplace Drug and Alcohol Testing Programs

    Science.gov (United States)

    2010-05-11

    ... Office of the Secretary 49 CFR Part 40 RIN OST 2105-AE01 Procedures for Transportation Workplace Drug and... economic effect on a substantial number of small entities, for purposes of the Regulatory Flexibility Act... been necessary for the Department to conduct a regulatory evaluation or Regulatory Flexibility Analysis...

  7. 75 FR 8528 - Procedures for Transportation Workplace Drug and Alcohol Testing Programs

    Science.gov (United States)

    2010-02-25

    ... Office of the Secretary 49 CFR Part 40 RIN OST 2105-AD84 Procedures for Transportation Workplace Drug and... Purpose In compliance with the Paperwork Reduction Act of 1995, Public Law 104-13, (44 U.S.C. 3501 et seq... Department published a Federal Register notice [71 FR 49383] to update the MIS form and its...

  8. Glycolysis inhibition inactivates ABC transporters to restore drug sensitivity in malignant cells.

    Directory of Open Access Journals (Sweden)

    Ayako Nakano

    Full Text Available Cancer cells eventually acquire drug resistance largely via the aberrant expression of ATP-binding cassette (ABC transporters, ATP-dependent efflux pumps. Because cancer cells produce ATP mostly through glycolysis, in the present study we explored the effects of inhibiting glycolysis on the ABC transporter function and drug sensitivity of malignant cells. Inhibition of glycolysis by 3-bromopyruvate (3BrPA suppressed ATP production in malignant cells, and restored the retention of daunorubicin or mitoxantrone in ABC transporter-expressing, RPMI8226 (ABCG2, KG-1 (ABCB1 and HepG2 cells (ABCB1 and ABCG2. Interestingly, although side population (SP cells isolated from RPMI8226 cells exhibited higher levels of glycolysis with an increased expression of genes involved in the glycolytic pathway, 3BrPA abolished Hoechst 33342 exclusion in SP cells. 3BrPA also disrupted clonogenic capacity in malignant cell lines including RPMI8226, KG-1, and HepG2. Furthermore, 3BrPA restored cytotoxic effects of daunorubicin and doxorubicin on KG-1 and RPMI8226 cells, and markedly suppressed subcutaneous tumor growth in combination with doxorubicin in RPMI8226-implanted mice. These results collectively suggest that the inhibition of glycolysis is able to overcome drug resistance in ABC transporter-expressing malignant cells through the inactivation of ABC transporters and impairment of SP cells with enhanced glycolysis as well as clonogenic cells.

  9. MFS transporters of Candida species and their role in clinical drug resistance.

    Science.gov (United States)

    K Redhu, Archana; Shah, Abdul H; Prasad, Rajendra

    2016-06-01

    ABC (ATP-binding cassette) and MFS (major facilitator superfamily) exporters, belonging to two different superfamilies, are one of the most prominent contributors of multidrug resistance (MDR) in yeast. While the role of ABC efflux pump proteins in the development of MDR is well documented, the MFS transporters which are also implicated in clinical drug resistance have not received due attention. The MFS superfamily is the largest known family of secondary active membrane carriers, and MFS exporters are capable of transporting a host of substrates ranging from small molecules, including organic and inorganic ions, to complex biomolecules, such as peptide and lipid moieties. A few of the members of the drug/H(+) antiporter family of the MFS superfamily function as multidrug transporters and employ downhill transport of protons to efflux their respective substrates. This review focuses on the recent developments in MFS of Candida and highlights their role in drug transport by using the example of the relatively well characterized promiscuous Mdr1 efflux pump of the pathogenic yeast C. albicans.

  10. [Two elderly case reports of renal excretion type drug poisoning caused by dehydration that was due to poor eating in home care].

    Science.gov (United States)

    Ibata, Takeshi; Hinokiyama, Hiromi; Nakashita, Chisako; Mito, Saori; Doi, Seiko; Shiki, Satomi; Hata, Akiko; Sato, Miyuki; Komuro, Ryutaro; Iijima, Hohei

    2010-12-01

    The elderly patients are susceptible to acute renal failure due to dehydration or infection. Therefore, the drug should be administered with caution. We report two cases of acute renal failure from dehydration that led to a subsequent drug poisoning. Case 1: An 85-year-old woman with a history of colorectal cancer surgery was admitted to our emergency department for appetite loss and weakness. Because she was given a normal amount of drugs under the condition of poor oral intake, she was hospitalized by digitalism. Case 2: A 72-year-old woman was admitted to our emergency department for disturbance of consciousness and appetite loss. The medication given by a staff in geriatric health services facility appeared to have caused a pilsicainide poisoning. As the elderly patients were given a normal amount of drugs under the poor oral intake condition, blood levels of renal excretion type drug had increased in both cases. Medication management for the elderly should be comprehensively considered the background of the individual.

  11. Collectrin and ACE2 in renal and intestinal amino acid transport.

    Science.gov (United States)

    Singer, Dustin; Camargo, Simone M R

    2011-01-01

    Neutral amino acid transporters of the SLC6 family are expressed at the apical membrane of kidney and/or small intestine, where they (re-)absorb amino acids into the body. In this review we present the results concerning the dependence of their apical expression with their association to partner proteins. We will in particular focus on the situation of B0AT1 and B0AT3, that associate with members of the renin-angiotensin system (RAS), namely Tmem27 and angiotensin-converting enzyme 2 (ACE2), in a tissue specific manner. The role of this association in relation to the formation of a functional unit related to Na+ or amino acid transport will be assessed. We will conclude with some remarks concerning the relevance of this association to Hartnup disorder, where some mutations have been shown to differentially interact with the partner proteins.

  12. Precision-cut kidney slices (PCKS) to study development of renal fibrosis and efficacy of drug targeting ex vivo

    NARCIS (Netherlands)

    Poosti, Fariba; Pham, Bao; Oosterhuis, Dorenda; Poelstra, Klaas; van Goor, Harry; Olinga, Peter; Hillebrands, Jan-Luuk

    2015-01-01

    Renal fibrosis is a serious clinical problem resulting in the greatest need for renal replacement therapy. No adequate preventive or curative therapy is available that could be clinically used to target renal fibrosis specifically. The search for new efficacious treatment strategies is therefore

  13. Atypical antipsychotic drugs directly impair insulin action in adipocytes: effects on glucose transport, lipogenesis, and antilipolysis.

    Science.gov (United States)

    Vestri, Helliner S; Maianu, Lidia; Moellering, Douglas R; Garvey, W Timothy

    2007-04-01

    Treatment with second-generation antipsychotics (SGAs) has been associated with weight gain and the development of diabetes mellitus, although the mechanisms are unknown. We tested the hypothesis that SGAs exert direct cellular effects on insulin action and substrate metabolism in adipocytes. We utilized two cultured cell models including 3T3-L1 adipocytes and primary cultured rat adipocytes, and tested for effects of SGAs risperidone (RISP), clozapine (CLZ), olanzapine (OLZ), and quetiapine (QUE), together with conventional antipsychotic drugs butyrophenone (BUTY), and trifluoperazine (TFP), over a wide concentration range from 1 to 500 microM. The effects of antipsychotic drugs on basal and insulin-stimulated rates of glucose transport were studied at 3 h, 15 h, and 3 days. Both CLZ and OLZ (but not RISP) at doses as low as 5 microM were able to significantly decrease the maximal insulin-stimulated glucose transport rate by approximately 40% in 3T3-L1 cells, whereas CLZ and RISP reduced insulin-stimulated glucose transport rates in primary cultured rat adipocytes by approximately 50-70%. Conventional drugs (BUTY and TFP) did not affect glucose transport rates. Regarding intracellular glucose metabolism, both SGAs (OLZ, QUE, RISP) and conventional drugs (BUTY and TFP) increased basal and/or insulin-stimulated glucose oxidation rates, whereas rates of lipogenesis were increased by CLZ, OLZ, QUE, and BUTY. Finally, rates of lipolysis in response to isoproterenol were reduced by the SGAs (CLZ, OLZ, QUE, RISP), but not by BUTY or TFP. These experiments demonstrate that antipsychotic drugs can differentially affect insulin action and metabolism through direct cellular effects in adipocytes. However, only SGAs were able to impair the insulin-responsive glucose transport system and to impair lipolysis in adipocytes. Thus, SGAs directly induce insulin resistance and alter lipogenesis and lipolysis in favor of progressive lipid accumulation and adipocyte enlargement. These

  14. Drug Transport Microdevice Mimicking an Idealized Nanoscale Bio-molecular Motor

    Institute of Scientific and Technical Information of China (English)

    Jae Hwan Lee; Ramana M. Pidaparti

    2011-01-01

    Molecular motors are nature's nano-devices and the essential agents of movement that are an integral part of many living organisms.The supramolecular motor,called Nuclear Pore Complex (NPC),controls the transport of all cellular material between the cytoplasm and the nucleus that occurs naturally in biological cells of many organisms.In order to understand the design characteristics of the NPC,we developed a microdevice for drug/fluidic transport mimicking the coarse-grained representation of the NPC geometry through computational fluid dynamic analysis and optimization.Specifically,the role of the central plug in active fluidic/particle transport and passive transport (without central plug) was investigated.Results of flow rate,pressure and velocity profiles obtained from the models indicate that the central plug plays a major role in transport through this biomolecular machine.The results of this investigation show that fluidic transport and flow passages are important factors in designing NPC based nano- and micro-devices for drug delivery.

  15. Transport of carbamazepine and drug interactions at blood-brain barrier

    Institute of Scientific and Technical Information of China (English)

    Jing-jing SUN; Lin XIE; Xiao-dong LIU

    2006-01-01

    Aim: To investigate the characteristics of carbamazepine (CBZ) transport and drug interactions at the blood-brain barrier. Methods: Cultured rat brain microvascular endothelial cells (rBMEC) were used as an in vitro model of the blood-brain barrier (BBB). When cells became confluent, CBZ uptake over time was recorded by incubation of the cells in a medium containing 10 mg/L CBZ at 37 ℃. The steady-state uptake of CBZ by rBMEC was tested for different CBZ concentrations at 37 ℃. The effects of various agents on the steady-state uptake of CBZ and efflux of CBZ from rBMEC were also studied. Results: The uptake of CBZ by rBMEC was time- and concentration-dependent. The steady-state uptake occurred at 30 min for incubation. The steady-state uptake was significantly increased (P<0.01) by treatment with dinitrophenol. The co-administration of cyclosporine A significantly increased the steady-state uptake of CBZ by the rBMEC, whereas co-administration of olanzapine significantly decreased the uptake in a concentration- and temperature-dependent manner. The efflux of CBZ from rBMEC was inhibited by CsA. Conclusion: The transport of CBZ at the BBB is mediated by many transporters. Some specific ABC (ATP-binding cassette,ABC ) efflux transporters may be involved in the transport of CBZ. Drugs influence the transport of CBZ at the BBB in different ways.

  16. Exploring multiple drug and herbicide resistance in plants--spotlight on transporter proteins.

    Science.gov (United States)

    Conte, Sarah S; Lloyd, Alan M

    2011-02-01

    Multiple drug resistance (MDR) has been extensively studied in bacteria, yeast, and mammalian cells due to the great clinical significance of this problem. MDR is not well studied in plant systems, although plant genomes contain large numbers of genes encoding putative MDR transporters (MDRTs). Biochemical pathways in the chloroplast are the targets of many herbicides and antibiotics, yet very little data is available regarding mechanisms of drug transport across the chloroplast membrane. MDRTs typically have broad substrate specificities, and may transport essential compounds and metabolites in addition to toxins. Indeed, plant transporters belonging to MDR families have also been implicated in the transport of a wide variety of compounds including auxins, flavonoids, glutathione conjugates, metal chelators, herbicides and antibiotics, although definitive evidence that a single transporter is capable of moving both toxins and metabolites has not yet been provided. Current understanding of plant MDR can be expanded via the characterization of candidate genes, especially MDRTs predicted to localize to the chloroplast, and also via traditional forward genetic approaches. Novel plant MDRTs have the potential to become endogenous selectable markers, aid in phytoremediation strategies, and help us to understand how plants have evolved to cope with toxins in their environment.

  17. Species variations among primates in responses to drugs which alter the renal excretion of uric acid.

    Science.gov (United States)

    Fannelli, G M; Weiner, I M

    1975-05-01

    The effects of salicylate, probenecid (Benemid) and pyrazinoate on uric acid excretion were determined in clearance experiments in the chimpanzee and Cebus monkey (C. albifrons and C. apella). The results were correlated with data from these species in the literature and where possible to analogous data in man. With salicylate, the rank order of responsiveness in terms of uricosuric action was chimpanzee greater than man greater than C. albifrons = C. apella. This was true when comparisons were made on the bases of drug concentration in plasma or the rate of drug excretion per milliliter of glomerular filtrate. A similar rank order was obtained with probenecid except that C. albifrons was slightly more responsive than C. apella. The latter comparisons were on the basis of plasma concentration of drug. The chimpanzee is more susceptible to the uricosuric action of pyrazinoate than is C. apella. With salicylate and pyrazinoate, there was urate retention at levels lower than those required for a uricosuric effect. The results suggest that in comparison with man, the chimpanzee is a hyperresponder to uricosuric drugs and Cebus monkeys are hyporesponders. Therefore, these findings limit extensions of quantitative results from one species to another.

  18. New Approaches to Overcome Transport Related Drug Resistance in Trypanosomatid Parasites

    Science.gov (United States)

    Garcia-Salcedo, Jose A.; Unciti-Broceta, Juan D.; Valverde-Pozo, Javier; Soriano, Miguel

    2016-01-01

    Leishmania and Trypanosoma are members of the Trypanosomatidae family that cause severe human infections such as leishmaniasis, Chagas disease, and sleeping sickness affecting millions of people worldwide. Despite efforts to eradicate them, migrations are expanding these infections to developing countries. There are no vaccines available and current treatments depend only on chemotherapy. Drug resistance is a major obstacle for the treatment of these diseases given that existing drugs are old and limited, with some having severe side effects. Most resistance mechanisms developed by these parasites are related with a decreased uptake or increased efflux of the drug due to mutations or altered expression of membrane transporters. Different new approaches have been elaborated that can overcome these mechanisms of resistance including the use of inhibitors of efflux pumps and drug carriers for both active and passive targeting. Here we review new formulations that have been successfully applied to circumvent resistance related to drug transporters, opening alternative ways to solve drug resistance in protozoan parasitic diseases. PMID:27733833

  19. New approaches to overcome transport related drug resistance in trypanosomatid parasites

    Directory of Open Access Journals (Sweden)

    Jose A Garcia-Salcedo

    2016-09-01

    Full Text Available Leishmania and Trypanosoma are members of the Trypanosomatidae family that cause severe human infections such as leishmaniasis, Chagas disease, and sleeping sickness affecting millions of people worldwide. Despite efforts to eradicate them, migrations are expanding these infections to developing countries. There are no vaccines available and current treatments depend only on chemotherapy. Drug resistance is a major obstacle for the treatment of these diseases given that existing drugs are old and limited, with some having severe side effects. Most resistance mechanisms developed by these parasites are related with a decreased uptake or increased efflux of the drug due to mutations or altered expression of membrane transporters. Different new approaches have been elaborated that can overcome these mechanisms of resistance including the use of inhibitors of efflux pumps and drug carriers for both active and passive targeting. Here we review new formulations that have been successfully applied to circumvent resistance related to drug transporters, opening alternative ways to solve drug resistance in protozoan parasitic diseases.

  20. Influence of Drug Formulation on OATP1B-Mediated Transport of Paclitaxel

    Science.gov (United States)

    Nieuweboer, Annemieke J.M.; Hu, Shuiying; Hagenbuch, Bruno; Moghaddam-Helmantel, Inge Ghobadi; Gibson, Alice A.; de Bruijn, Peter; Mathijssen, Ron H. J.; Sparreboom, Alex

    2014-01-01

    Purpose Taxane antineoplastic agents are extensively taken up into hepatocytes by OATP1B-type transporters prior to metabolism and excretion. Because the biodistributional properties imposed upon these agents by different solubilizers drive clinically-important pharmacodynamic endpoints, we tested the hypothesis that the in vitro and in vivo interaction of taxanes with OATP1B transporters is affected by the choice of drug delivery system. Experimental Design Transport of paclitaxel, docetaxel, and cabazitaxel was studied in vitro using various cell lines transfected with OATP1B1, OATP1B3, or the rodent equivalent Oatp1b2. Pharmacokinetic studies were done in wildtype and Oatp1b2-knockout mice in the presence or absence of polysorbate 80 (PS80) or Kolliphor EL (formerly Cremophor EL; CrEL). Results Paclitaxel and docetaxel, but not cabazitaxel, were transported substrates of OATP1B1, OATP1B3, and Oatp1b2, and these transport processes were strongly reduced in the presence of clinically-relevant concentrations of PS80 and CrEL. In the absence of solubilizers, deficiency of Oatp1b2 in mice was associated with a significantly decreased taxane clearance due to a liver distribution defect (P0.05). Conclusions Our findings confirm the importance of OATP1B-type transporters in the hepatic elimination of taxanes, and that this process can be inhibited by PS80 and CrEL. These results suggest that the likelihood of drug-drug interactions mediated by these transporters is strongly dependent on the selected taxane solubilizer. PMID:24755470

  1. Role of the dopamine transporter in the action of psychostimulants, nicotine, and other drugs of abuse.

    Science.gov (United States)

    Zhu, J; Reith, M E A

    2008-11-01

    A number of studies over the last two decades have demonstrated the critical importance of dopamine (DA) in the behavioral pharmacology and addictive properties of abused drugs. The DA transporter (DAT) is a major target for drugs of abuse in the category of psychostimulants, and for methylphenidate (MPH), a drug used for treating attention deficit hyperactivity disorder (ADHD), which can also be a psychostimulant drug of abuse. Other drugs of abuse such as nicotine, ethanol, heroin and morphine interact with the DAT in more indirect ways. Despite the different ways in which drugs of abuse can affect DAT function, one evolving theme in all cases is regulation of the DAT at the level of surface expression. DAT function is dynamically regulated by multiple intracellular and extracellular signaling pathways and several protein-protein interactions. In addition, DAT expression is regulated through the removal (internalization) and recycling of the protein from the cell surface. Furthermore, recent studies have demonstrated that individual differences in response to novel environments and psychostimulants can be predicted based on individual basal functional DAT expression. Although current knowledge of multiple factors regulating DAT activity has greatly expanded, many aspects of this regulation remain to be elucidated; these data will enable efforts to identify drugs that might be used therapeutically for drug dependence therapeutics.

  2. Coupled gel spreading and diffusive transport models describing microbicidal drug delivery

    Science.gov (United States)

    Funke, Claire; MacMillan, Kelsey; Ham, Anthony S.; Szeri, Andrew J.; Katz, David F.

    2016-11-01

    Gels are a drug delivery platform being evaluated for application of active pharmaceutical ingredients, termed microbicides, that act topically against infection by sexually transmitted HIV. Despite success in one Phase IIb trial of a vaginal gel delivering tenofovir, problems of user adherence to designed gel application regimen compromised results in two other trials. The microbicide field is responding to this issue by simultaneously analyzing behavioral determinants of adherence and pharmacological determinants of drug delivery. Central to both user adherence and mucosal drug delivery are gel properties (e.g. rheology) and applied volume. The specific problem to be solved here is to develop a model for how gel rheology and volume, interacting with loaded drug concentration, govern the transport of the microbicide drug tenofovir into the vaginal mucosa to its stromal layer. The analysis here builds upon our current understanding of vaginal gel deployment and drug delivery, incorporating key features of the gel's environment, fluid production and subsequent gel dilution, and vaginal wall elasticity. We consider the microbicide drug tenofovir as it is the most completely studied drug, in both in vitroand in vivostudies, for use in vaginal gel application. Our goal is to contribute to improved pharmacological understanding of gel functionality, providing a computational tool that can be used in future vaginal microbicide gel design.

  3. MRP3, an organic anion transporter able to transport anti-cancer drugs

    OpenAIRE

    Kool, Marcel; Marcel VAN DER LINDEN; Haas, Marcel; Scheffer, George L.; de Vree, J. Marleen L.; Smith, Alexander J.; Jansen, Gerrit; Peters, Godefridus J.; Ponne, Nico; Scheper, Rik J.; Elferink, Ronald P. J. Oude; Baas, Frank; Borst, Piet

    1999-01-01

    The human multidrug-resistance protein (MRP) gene family contains at least six members: MRP1, encoding the multidrug-resistance protein; MRP2 or cMOAT, encoding the canalicular multispecific organic anion transporter; and four homologs, called MRP3, MRP4, MRP5, and MRP6. In this report, we characterize MRP3, the closest homolog of MRP1. Cell lines were retrovirally transduced with MRP3 cDNA, and new monoclonal antibodies specific for MRP3 were generated. We show that MRP3 is an organic anion ...

  4. Expression of renal Oat5 and NaDC1 transporters in rats with acute biliary obstruction.

    Science.gov (United States)

    Brandoni, Anabel; Torres, Adriana Mónica

    2015-08-07

    To examine renal expression of organic anion transporter 5 (Oat5) and sodium-dicarboxylate cotransporter 1 (NaDC1), and excretion of citrate in rats with acute extrahepatic cholestasis. Obstructive jaundice was induced in rats by double ligation and division of the common bile duct (BDL group). Controls underwent sham operation that consisted of exposure, but not ligation, of the common bile duct (Sham group). Studies were performed 21 h after surgery. During this period, animals were maintained in metabolic cages in order to collect urine. The urinary volume was determined by gravimetry. The day of the experiment, blood samples were withdrawn and used to measure total and direct bilirubin as indicative parameters of hepatic function. Serum and urine samples were used for biochemical determinations. Immunoblotting for Oat5 and NaDC1 were performed in renal homogenates and brush border membranes from Sham and BDL rats. Immunohistochemistry studies were performed in kidneys from both experimental groups. Total RNA was extracted from rat renal tissue in order to perform reverse transcription polymerase chain reaction. Another set of experimental animals were used to evaluate medullar renal blood flow (mRBF) using fluorescent microspheres. Total and direct bilirubin levels were significantly higher in BDL animals, attesting to the adequacy of biliary obstruction. An important increase in mRBF was determined in BDL group (Sham: 0.53 ± 0.12 mL/min per 100 g body weight vs BDL: 1.58 ± 0.24 mL/min per 100 g body weight, P < 0.05). An increase in the urinary volume was observed in BDL animals. An important decrease in urinary levels of citrate was seen in BDL group. Besides, a decrease in urinary citrate excretion (Sham: 0.53 ± 0.11 g/g creatinine vs BDL: 0.07 ± 0.02 g/g creatinine, P < 0.05) and an increase in urinary excretion of H(+) (Sham: 0.082 ± 0.03 μmol/g creatinine vs BDL: 0.21 ± 0.04 μmol/g creatinine, P < 0.05) were observed in BDL animals. We found

  5. Intestinal transporters for endogenic and pharmaceutical organic anions: The challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug-drug interactions

    DEFF Research Database (Denmark)

    Grandvuinet, Anne Sophie; Vestergaard, Henrik Tang; Rapin, Nicolas

    2012-01-01

    Objectives This review provides an overview of intestinal human transporters for organic anions and stresses the need for standardization of the various in-vitro methods presently employed in drug-drug interaction (DDI) investigations. Key findings Current knowledge on the intestinal expression o...... the involvement of other transporters than P-glycoprotein. Moreover, the interplay between various processes that a drug is subject to in-vivo such as translocation by several transporters and dissolution should be considered. © 2012 Royal Pharmaceutical Society....

  6. Competitive inhibition of the luminal efflux by multidrug and toxin extrusions, but not basolateral uptake by organic cation transporter 2, is the likely mechanism underlying the pharmacokinetic drug-drug interactions caused by cimetidine in the kidney.

    Science.gov (United States)

    Ito, Sumito; Kusuhara, Hiroyuki; Yokochi, Miyu; Toyoshima, Junko; Inoue, Katsuhisa; Yuasa, Hiroaki; Sugiyama, Yuichi

    2012-02-01

    Cimetidine, an H₂ receptor antagonist, has been used to investigate the tubular secretion of organic cations in human kidney. We report a systematic comprehensive analysis of the inhibition potency of cimetidine for the influx and efflux transporters of organic cations [human organic cation transporter 1 (hOCT1) and hOCT2 and human multidrug and toxin extrusion 1 (hMATE1) and hMATE2-K, respectively]. Inhibition constants (K(i)) of cimetidine were determined by using five substrates [tetraethylammonium (TEA), metformin, 1-methyl-4-phenylpyridinium, 4-(4-(dimethylamino)styryl)-N-methylpyridinium, and m-iodobenzylguanidine]. They were 95 to 146 μM for hOCT2, providing at most 10% inhibition based on its clinically reported plasma unbound concentrations (3.6-7.8 μM). In contrast, cimetidine is a potent inhibitor of MATE1 and MATE2-K with K(i) values (μM) of 1.1 to 3.8 and 2.1 to 6.9, respectively. The same tendency was observed for mouse Oct1 (mOct1), mOct2, and mouse Mate1. Cimetidine showed a negligible effect on the uptake of metformin by mouse kidney slices at 20 μM. Cimetidine was administered to mice by a constant infusion to achieve a plasma unbound concentration of 21.6 μM to examine its effect on the renal disposition of Mate1 probes (metformin, TEA, and cephalexin) in vivo. The kidney- and liver-to-plasma ratios of metformin both were increased 2.4-fold by cimetidine, whereas the renal clearance was not changed. Cimetidine also increased the kidney-to-plasma ratio of TEA and cephalexin 8.0- and 3.3-fold compared with a control and decreased the renal clearance from 49 to 23 and 11 to 6.6 ml/min/kg, respectively. These results suggest that the inhibition of MATEs, but not OCT2, is a likely mechanism underlying the drug-drug interactions with cimetidine in renal elimination.

  7. Cardiac Arrhythmias in Patients with Chronic Kidney Disease: Implications of Renal Failure for Antiarrhythmic Drug Therapy.

    Science.gov (United States)

    Potpara, Tatjana S; Jokic, Vera; Dagres, Nikolaos; Marin, Francisco; Prostran, Milica S; Blomstrom-Lundqvist, Carina; Lip, Gregory Y H

    2016-01-01

    The kidney has numerous complex interactions with the heart, including shared risk factors (e.g., hypertension, dyslipidemia, etc.) and mutual amplification of morbidity and mortality. Both cardiovascular diseases and chronic kidney disease (CKD) may cause various alterations in cardiovascular system, metabolic homeostasis and autonomic nervous system that may facilitate the occurrence of cardiac arrhythmias. Also, pre-existent or incident cardiac arrhythmias such as atrial fibrillation (AF) may accelerate the progression of CKD. Patients with CKD may experience various cardiac rhythm disturbances including sudden cardiac death. Contemporary management of cardiac arrhythmias includes the use of antiarrhythmic drugs (AADs), catheter ablation and cardiac implantable electronic devices (CIEDs). Importantly, AADs are not used only as the principal treatment strategy, but also as an adjunct therapy in combination with CIEDs, to facilitate their effects or to minimize inappropriate device activation in selected patients. Along with their principal antiarrhythmic effect, AADs may also induce cardiac arrhythmias and the risk for such proarrhythmic effect(s) is particularly increased in patients with reduced left ventricular systolic function or in the setting of electrolyte imbalance. Moreover, CKD itself can induce profound alterations in the pharmacokinetics and pharmacodynamics of many drugs including AADs, thus facilitating the drug accumulation and increased exposure. Hence, the use of AADs in patients with CKD may be challenging. In this review article, we provide an overview of the characteristics of arrhythmogenesis in patients with CKD with special emphasis on the complexity of pharmacokinetics and risk for proarrhythmias when using AADs in patients with cardiac arrhythmias and CKD.

  8. Directed transport of bacteria-based drug delivery vehicles: bacterial chemotaxis dominates particle shape.

    Science.gov (United States)

    Sahari, Ali; Traore, Mahama A; Scharf, Birgit E; Behkam, Bahareh

    2014-10-01

    Several attenuated and non-pathogenic bacterial species have been demonstrated to actively target diseased sites and successfully deliver plasmid DNA, proteins and other therapeutic agents into mammalian cells. These disease-targeting bacteria can be employed for targeted delivery of therapeutic and imaging cargos in the form of a bio-hybrid system. The bio-hybrid drug delivery system constructed here is comprised of motile Escherichia coli MG1655 bacteria and elliptical disk-shaped polymeric microparticles. The transport direction for these vehicles can be controlled through biased random walk of the attached bacteria in presence of chemoattractant gradients in a process known as chemotaxis. In this work, we utilize a diffusion-based microfluidic platform to establish steady linear concentration gradients of a chemoattractant and investigate the roles of chemotaxis and geometry in transport of bio-hybrid drug delivery vehicles. Our experimental results demonstrate for the first time that bacterial chemotactic response dominates the effect of body shape in extravascular transport; thus, the non-spherical system could be more favorable for drug delivery applications owing to the known benefits of using non-spherical particles for vascular transport (e.g. relatively long circulation time).

  9. Specificity of drug transport mediated by CaMDR1: a major facilitator of Candida albicans

    Indian Academy of Sciences (India)

    Avmeet Kohli; Vinita Gupta; Shankarling Krishnamurthy; Seyed E Hasnain; Rajendra Prasad

    2001-09-01

    CaMDR1 encodes a major facilitator superfamily (MFS) protein in Candida albicans whose expression has been linked to azole resistance and which is frequently encountered in this human pathogenic yeast. In this report we have overexpressed CaMdr1p in Sf9 insect cells and demonstrated for the first time that it can mediate methotrexate (MTX) and fluconazole (FLC) transport. MTX appeared to be a better substrate for CaMdr1p among these two tested drugs. Due to severe toxicity of these drugs to insect cells, further characterization of CaMdr1p as a drug transporter could not be done with this system. Therefore, as an alternative, CaMdr1p and Cdr1p, which is an ABC protein (ATP binding cassette) also involved in azole resistance in C. albicans, were independently expressed in a common hypersensitive host JG436 of Saccharomyces cerevisiae. This allowed a better comparison between the functionality of the two export pumps. We observed that while both FLC and MTX are effluxed by CaMdr1p, MTX appeared to be a poor substrate for Cdr1p. JG436 cells expressing Cdr1p thus conferred resistance to other antifungal drugs but remained hypersensitive to MTX. Since MTX is preferentially transported by CaMdr1p, it can be used for studying the function of this MFS protein.

  10. The importance of drug-transporting P-glycoproteins in toxicology.

    Science.gov (United States)

    van Tellingen, O

    2001-03-31

    The importance of specific transport in toxicology is becoming increasingly clear and the work on P-glycoprotein has certainly been a major contribution to these growing insights. P-Glycoproteins were discovered by their ability to confer multidrug resistance in mammalian tumour cells. They are localised in the cell membrane where they actively extrude a wide range of compounds including many anti-cancer drugs from the cell. Besides in tumour cells, drug-transporting P-glycoproteins are also expressed in a polarised fashion in normal tissues that perform an excretory or barrier function, such as the liver, kidneys, intestines, brain endothelial cells. Based on this expression profile, it has been proposed that P-glycoproteins are important in protecting the host by reducing exposure to xenobiotics. Further studies with P-glycoprotein knockout mice have clearly established this protective function. In general, the clearance of substrate drugs is lower in knockout mice due to a diminished hepatobiliary excretion, direct intestinal excretion and/or increased enterohepatic cycling. Moreover, their uptake in sanctuary sites, such as the brain or the foetus, was profoundly higher in P-glycoprotein knockout mice, as was the uptake of drugs from the gastro-intestinal tract into the systemic circulation following oral ingestion. These results clearly highlight the impact that transport proteins can play in toxicology.

  11. A minor role of WNK3 in regulating phosphorylation of renal NKCC2 and NCC co-transporters in vivo.

    Science.gov (United States)

    Oi, Katsuyuki; Sohara, Eisei; Rai, Tatemitsu; Misawa, Moko; Chiga, Motoko; Alessi, Dario R; Sasaki, Sei; Uchida, Shinichi

    2012-02-15

    Mutations in WNK1 and WNK4 kinase genes have been shown to cause a human hereditary hypertensive disease, pseudohypoaldosteronism type II (PHAII). We previously discovered that WNK kinases phosphorylate and activate OSR1/SPAK kinases that regulate renal SLC12A family transporters such as NKCC2 and NCC, and clarified that the constitutive activation of this cascade causes PHAII. WNK3, another member of the WNK kinase family, was reported to be a strong activator of NCC/NKCC2 when assayed in Xenopus oocytes, suggesting that WNK3 also plays a major role in regulating blood pressure and sodium reabsorption in the kidney. However, it remains to be determined whether WNK3 is in fact involved in the regulation of these transporters in vivo. To clarify this issue, we generated and analyzed WNK3 knockout mice. Surprisingly, phosphorylation and expression of OSR1, SPAK, NKCC2 and NCC did not decrease in knockout mouse kidney under normal and low-salt diets. Similarly, expression of epithelial Na channel and Na/H exchanger 3 were not affected in knockout mice. Na(+) and K(+) excretion in urine in WNK3 knockout mice was not affected under different salt diets. Blood pressure in WNK3 knockout mice was not lower under normal diet. However, lower blood pressure was observed in WNK3 knockout mice fed low-salt diet. WNK4 and WNK1 expression was slightly elevated in the knockout mice under low-salt diet, suggesting compensation for WNK3 knockout by these WNKs. Thus, WNK3 may have some role in the WNK-OSR1/SPAK-NCC/NKCC2 signal cascade in the kidney, but its contribution to total WNK kinase activity may be minimal.

  12. A minor role of WNK3 in regulating phosphorylation of renal NKCC2 and NCC co-transporters in vivo

    Directory of Open Access Journals (Sweden)

    Katsuyuki Oi

    2012-02-01

    Mutations in WNK1 and WNK4 kinase genes have been shown to cause a human hereditary hypertensive disease, pseudohypoaldosteronism type II (PHAII. We previously discovered that WNK kinases phosphorylate and activate OSR1/SPAK kinases that regulate renal SLC12A family transporters such as NKCC2 and NCC, and clarified that the constitutive activation of this cascade causes PHAII. WNK3, another member of the WNK kinase family, was reported to be a strong activator of NCC/NKCC2 when assayed in Xenopus oocytes, suggesting that WNK3 also plays a major role in regulating blood pressure and sodium reabsorption in the kidney. However, it remains to be determined whether WNK3 is in fact involved in the regulation of these transporters in vivo. To clarify this issue, we generated and analyzed WNK3 knockout mice. Surprisingly, phosphorylation and expression of OSR1, SPAK, NKCC2 and NCC did not decrease in knockout mouse kidney under normal and low-salt diets. Similarly, expression of epithelial Na channel and Na/H exchanger 3 were not affected in knockout mice. Na+ and K+ excretion in urine in WNK3 knockout mice was not affected under different salt diets. Blood pressure in WNK3 knockout mice was not lower under normal diet. However, lower blood pressure was observed in WNK3 knockout mice fed low-salt diet. WNK4 and WNK1 expression was slightly elevated in the knockout mice under low-salt diet, suggesting compensation for WNK3 knockout by these WNKs. Thus, WNK3 may have some role in the WNK-OSR1/SPAK-NCC/NKCC2 signal cascade in the kidney, but its contribution to total WNK kinase activity may be minimal.

  13. Potential role of gene-environment interactions in ion transport mechanisms in the etiology of renal cell cancer

    Science.gov (United States)

    Deckers, Ivette A. G.; van den Brandt, Piet A.; van Engeland, Manon; van Schooten, Frederik J.; Godschalk, Roger W. L.; Keszei, András P.; Hogervorst, Janneke G. F.; Schouten, Leo J.

    2016-01-01

    We investigated the ion transport mechanism (ITM) in renal cell cancer (RCC) etiology using gene-environment interactions between candidate single nucleotide polymorphisms (SNPs) and associated environmental factors, including dietary intakes of sodium, potassium and fluid, hypertension and diuretic medication. A literature-based selection of 13 SNPs in ten ITM genes were successfully genotyped in toenail DNA of 3,048 subcohort members and 419 RCC cases from the Netherlands Cohort Study. Diet and lifestyle were measured with baseline questionnaires. Cox regression analyses were conducted for main effects and gene-environment interactions. ADD1_rs4961 was significantly associated with RCC risk, showing a Hazard Ratio (HR) of 1.24 (95% confidence intervals (CI): 1.01–1.53) for the GT + TT (versus GG) genotype. Four of 65 tested gene-environment interactions were statistically significant. Three of these interactions clustered in SLC9A3_rs4957061, including the ones with fluid and potassium intake, and diuretic medication. For fluid intake, the RCC risk was significantly lower for high versus low intake in participants with the CC genotype (HR(95% CI): 0.47(0.26–0.86)), but not for the CT + TT genotype (P-interaction = 0.002). None of the main genetic effects and gene-environment interactions remained significant after adjustment for multiple testing. Data do not support the general hypothesis that the ITM is a disease mechanism in RCC etiology. PMID:27686058

  14. High density lipoprotein (HDL) particles from end-stage renal disease patients are defective in promoting reverse cholesterol transport.

    Science.gov (United States)

    Anderson, Josephine L C; Gautier, Thomas; Nijstad, Niels; Tölle, Markus; Schuchardt, Mirjam; van der Giet, Markus; Tietge, Uwe J F

    2017-02-02

    Atherosclerotic cardiovascular disease (CVD) represents the largest cause of mortality in end-stage renal disease (ESRD). CVD in ESRD is not explained by classical CVD risk factors such as HDL cholesterol mass levels making functional alterations of lipoproteins conceivable. HDL functions in atheroprotection by promoting reverse cholesterol transport (RCT), comprising cholesterol efflux from macrophage foam cells, uptake into hepatocytes and final excretion into the feces. ESRD-HDL (n = 15) were compared to healthy control HDL (n = 15) for their capacity to promote in vitro (i) cholesterol efflux from THP-1 macrophage foam cells and (ii) SR-BI-mediated selective uptake into ldla[SR-BI] cells as well as (iii) in vivo RCT. Compared with HDL from controls, ESRD-HDL displayed a significant reduction in mediating cholesterol efflux (p HDL to promote RCT when infused into wild-type mice was significantly impaired (p HDL from healthy controls with hypochloric acid was able to fully mimic the impaired biological activities of ESRD-HDL. In conclusion, we demonstrate that HDL from ESRD patients is dysfunctional in key steps as well as overall RCT, likely due to oxidative modification.

  15. The Impact of Blood Rheology on Drug Transport in Stented Arteries: Steady Simulations

    Science.gov (United States)

    Vijayaratnam, Pujith R. S.; O’Brien, Caroline C.; Reizes, John A.; Barber, Tracie J.; Edelman, Elazer R.

    2015-01-01

    Background and Methods It is important to ensure that blood flow is modelled accurately in numerical studies of arteries featuring drug-eluting stents due to the significant proportion of drug transport from the stent into the arterial wall which is flow-mediated. Modelling blood is complicated, however, by variations in blood rheological behaviour between individuals, blood’s complex near-wall behaviour, and the large number of rheological models which have been proposed. In this study, a series of steady-state computational fluid dynamics analyses were performed in which the traditional Newtonian model was compared against a range of non-Newtonian models. The impact of these rheological models was elucidated through comparisons of haemodynamic flow details and drug transport behaviour at various blood flow rates. Results Recirculation lengths were found to reduce by as much as 24% with the inclusion of a non-Newtonian rheological model. Another model possessing the viscosity and density of blood plasma was also implemented to account for near-wall red blood cell losses and yielded recirculation length increases of up to 59%. However, the deviation from the average drug concentration in the tissue obtained with the Newtonian model was observed to be less than 5% in all cases except one. Despite the small sensitivity to the effects of viscosity variations, the spatial distribution of drug matter in the tissue was found to be significantly affected by rheological model selection. Conclusions/Significance These results may be used to guide blood rheological model selection in future numerical studies. The clinical significance of these results is that they convey that the magnitude of drug uptake in stent-based drug delivery is relatively insensitive to individual variations in blood rheology. Furthermore, the finding that flow separation regions formed downstream of the stent struts diminish drug uptake may be of interest to device designers. PMID:26066041

  16. Characterization of rhodamine-123 as a tracer dye for use in in vitro drug transport assays.

    Directory of Open Access Journals (Sweden)

    Samantha Forster

    Full Text Available Fluorescent tracer dyes represent an important class of sub-cellular probes and allow the examination of cellular processes in real-time with minimal impact upon these processes. Such tracer dyes are becoming increasingly used for the examination of membrane transport processes, as they are easy-to-use, cost effective probe substrates for a number of membrane protein transporters. Rhodamine 123, a member of the rhodamine family of flurone dyes, has been used to examine membrane transport by the ABCB1 gene product, MDR1. MDR1 is viewed as the archetypal drug transport protein, and is able to efflux a large number of clinically relevant drugs. In addition, ectopic activity of MDR1 has been associated with the development of multiple drug resistance phenotype, which results in a poor patient response to therapeutic intervention. It is thus important to be able to examine the potential for novel compounds to be MDR1 substrates. Given the increasing use rhodamine 123 as a tracer dye for MDR1, a full characterisation of its spectral properties in a range of in vitro assay-relevant media is warranted. Herein, we determine λmax for excitation and emission or rhodamine 123 and its metabolite rhodamine 110 in commonly used solvents and extraction buffers, demonstrating that fluorescence is highly dependent on the chemical environment: Optimal parameters are 1% (v/v methanol in HBSS, with λex = 505 nm, λem = 525 nm. We characterise the uptake of rhodamine 123 into cells, via both passive and active processes, and demonstrate that this occurs primarily through OATP1A2-mediated facilitated transport at concentrations below 2 µM, and via micelle-mediated passive diffusion above this. Finally, we quantify the intracellular sequestration and metabolism of rhodamine 123, demonstrating that these are both cell line-dependent factors that may influence the interpretation of transport assays.

  17. Anti-cancer drug disposition: In vitro and in vivo functions of ABC efflux and OATP uptake transporters

    NARCIS (Netherlands)

    Durmus, S.

    2014-01-01

    ATP-binding cassette (ABC) efflux and Organic Anion-Transporting Polypeptide (OATP) uptake transporters are two major membrane transporter superfamilies that have major roles in the absorption, disposition and toxicity of drugs. They are widely expressed in several pharmacokinetically relevant organ

  18. Is nose-to-brain transport of drugs in man a reality?

    Science.gov (United States)

    Illum, Lisbeth

    2004-01-01

    The blood-brain barrier that segregates the brain interstitial fluid from the circulating blood provides an efficient barrier for the diffusion of most, especially polar, drugs from the blood to receptors in the central nervous system (CNS). Hence limitations are evident in the treatment of CNS diseases, such as Parkinson's and Alzheimer's diseases, especially exploiting neuropeptides and similar polar and large molecular weight drugs. In recent years interest has been expressed in the use of the nasal route for delivery of drugs to the brain, exploiting the olfactory pathway. A wealth of studies has reported proof of nose-to-brain delivery of a range of different drugs in animal models, such as the rat. Studies in man have mostly compared the pharmacological effects (e.g. brain functions) of nasally applied drugs with parenterally applied drugs and have shown a distinct indication of direct nose-to-brain transport. Recent studies in volunteers involving cerebrospinal fluid sampling, blood sampling and pharmacokinetic analysis after nasal, and in some instances parenteral administration of different drugs, have in my opinion confirmed the likely existence of a direct pathway from nose to brain.

  19. Intestinal drug transport via the proton-coupled amino acid transporter PAT1 (SLC36A1) is inhibited by Gly-X(aa) dipeptides

    DEFF Research Database (Denmark)

    Frølund, Sidsel; Langthaler, Louise; Kall, Morten A

    2012-01-01

    The oral absorption of some drug substances is mediated by nutrient transporters. As a consequence, nutrients and drugs may compete for available transporters, and interactions at the level of intestinal absorption are possible. Recently, we have identified δ-aminolevulinic acid, Gly-Gly, and Gly......-Sar as substrates of the amino acid transporter PAT1. The aim of the present study is to investigate if other Gly-containing dipeptides interact with PAT1, and whether they can inhibit PAT1 mediated drug absorption, in vitro and in vivo. The in vitro methods included two-electrode voltage clamp measurements on h......PAT1 expressing Xenopus laevis oocytes, which were used to investigate the PAT1-mediated transport of 17 different Gly-containing dipeptides (Gly-X(aa) or X(aa)-Gly). Also, the transepithelial transport of the PAT1 substrate gaboxadol was investigated across Caco-2 cell monolayers in the presence...

  20. Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug-drug interactions.

    Science.gov (United States)

    Grandvuinet, Anne Sophie; Vestergaard, Henrik Tang; Rapin, Nicolas; Steffansen, Bente

    2012-11-01

    This review provides an overview of intestinal human transporters for organic anions and stresses the need for standardization of the various in-vitro methods presently employed in drug-drug interaction (DDI) investigations. Current knowledge on the intestinal expression of the apical sodium-dependent bile acid transporter (ASBT), the breast cancer resistance protein (BCRP), the monocarboxylate transporters (MCT) 1, MCT3-5, the multidrug resistance associated proteins (MRP) 1-6, the organic anion transporting polypetides (OATP) 2B1, 1A2, 3A1 and 4A1, and the organic solute transporter α/β (OSTα/β) has been covered along with an overview of their substrates and inhibitors. Furthermore, the many challenges in predicting clinically relevant DDIs from in-vitro studies have been discussed with focus on intestinal transporters and the various methods for deducting in-vitro parameters for transporters (K(m) /K(i) /IC50, efflux ratio). The applicability of using a cut-off value (estimated based on the intestinal drug concentration divided by the K(i) or IC50) has also been considered. A re-evaluation of the current approaches for the prediction of DDIs is necessary when considering the involvement of other transporters than P-glycoprotein. Moreover, the interplay between various processes that a drug is subject to in-vivo such as translocation by several transporters and dissolution should be considered. © 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society.

  1. Editor's Highlight: Comparative Renal Safety Assessment of the Hepatitis B Drugs, Adefovir, Tenofovir, Telbivudine and Entecavir in Rats.

    Science.gov (United States)

    Uteng, Marianne; Mahl, Andreas; Beckmann, Nicolau; Piaia, Alessandro; Ledieu, David; Dubost, Valerie; Tritto, Elaine; Wolf, Armin; Moulin, Pierre; Li, Li; Chibout, Salah-Dine; Pognan, Francois

    2017-01-01

    The aim of this study was to determine the relative safety of 4 antiviral drugs (telbivudine, tenofovir, adefovir, and entecavir) against hepatitis B virus with respect to kidney function and toxicity in male Sprague Dawley rats. The antiviral drugs were administered once daily for 4 weeks by oral gavage at ∼10 and 25-40 times the human equivalent dose. Main assessments included markers of renal toxicity in urine, magnetic resonance imaging (MRI) of kidney function, histopathology, and electron microscopic examination. Administration of adefovir at 11 and 28 mg/kg for 4 weeks caused functional and morphological kidney alterations in a time- and dose-dependent manner, affecting mainly the proximal tubules and suggesting a mechanism of toxicity related to mitochondrial degeneration/depletion. Of note, the observed adefovir-induced reduction of kidney function was not detected by the standard method of glomerular filtration rate (GFR) measurements (clearance rate of the endogenous marker, creatinine), thereby emphasizing the superiority of MRI in terms of sensitive detection of GFR in rats. For the low dose of 300 mg/kg of tenofovir, minor kidney effects such as nuclear enlargement in the tubular epithelium, and hyaline droplets accumulation were detected, which was also observed for the low dose (11 mg/kg) of adefovir. No assessments could be done at the higher dose of 600/1000 mg/kg tenofovir due to gastrointestinal tract toxicity which prevented treatment of the animals for longer than 1 week. Entecavir at 1 and 3 mg/kg and telbivudine at 600 and 1600 mg/kg caused no toxicologically relevant effects on the kidney. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  2. Are elderly end-stage renal disease patients more susceptible for drug resistant organisms in their sputum?

    Directory of Open Access Journals (Sweden)

    Subash Shantha Ghanshyam

    2010-01-01

    Full Text Available End stage renal disease (ESRD patients are at risk for pneumonia in view of their impaired immune status. Similar empiric antibiotic regimens are used in elderly as well as young ESRD patients with respiratory tract infections. We conducted an observational, cross sectional study between June 2007 and June 2008 in 100 ESRD patients half being > 65 yrs. All patients had positive sputum culture and chest X-ray findings of pneumonia Streptococcus pneumoniae was the commonest in younger while Klebsiella pneumoniae in > 65yrs old patients. Elderly patients had significant resistance to common antibiotics. Ceftrioxone was the most suitable antibiotic in the younger patients while a combination of piperacillin with gentamycin was the best choice in the geriatric age group. In conclusion, organisms cultured from sputum in ESRD patients with pneumo-nia were different in the ESRD patients of more than and less than 65 years of age as well as the drug susceptibility. We should probably redefine the management of pneumonia according to the sensitivities in our local populations to better treat these patients.

  3. [An orientational examination of the effects of extracts from mixtures of herbal drugs on selected renal functions].

    Science.gov (United States)

    Masteiková, R; Klimas, R; Samura, B B; Savickas, A; Samura, B A; Belaij, S I; Samura, I B; Rabisková, M; Chalupová, Z; Bernatoniene, J

    2007-04-01

    The paper aimed to determine the effects of mixtures of selected medicinal plants on some physiological renal functions, i.e. excretion of urine and electrolytes and changes in the quantity of prostaglandins E2 (PGE2) and kallikrein-kinins in rat blood plasma after water and salt load. The following medicinal plants were selected for the examination: downy birch (Betula pubescens EHRH.), everlasting flower (Helichrysum arenarium L. MOENCH.), hawthorn (Crataegus oxyacantha L.), woodland strawberry (Fragaria vesca L.), sweet corn (Zea mays L.), German chamomile (Matricaria recutita L.), and field horsetail (Equisetum arvense L.). Herbal drugs were used to compose 6 mixtures. Extracts from these mixtures were administered to Wistar strain males and their effects were compared with the effects of an administered suspension of hydrochlorothiazide, an extract from field horsetail herb alone, and a control group of animals which was not administered any preparation. The greatest diuretic effect was found in a mixture composed of birch leaves (Betulae folium), hawthorn berries (Crataegi fructus), strawberry leaves (Fragariae folium), corn silk (Maydis stigmata), chamomile flowers (Matricariae flos), and horsetail herb (Equiseti herba). Its effect was greater by 47% and 34% than the effect of a horsetail herb extract and a hydrochlorothiazide suspension (p < 0.05), respectively. The extract from this mixture also increased the quantity of prostaglandins E2 and kallikrein-kinins in rat blood plasma in water and salt load.

  4. Transport of citrate across renal brush border membrane: effects of dietary acid and alkali loading

    Energy Technology Data Exchange (ETDEWEB)

    Jenkins, A.D.; Dousa, T.P.; Smith, L.H.

    1985-10-01

    Dietary acid or alkali loading was given to rats by providing 150 mM NH4Cl or 150 mM NaHCO3 in place of drinking water for 6 days; control animals received 150 mM NaCl. After 6 days, the citrate clearance was 0.04 +/- 0.01 ml/min (mean +/- SE) in the acid-loaded group, 0.9 +/- 0.1 ml/min in the control group, and 2.5 +/- 0.2 ml/min in the alkali-loaded group. At the end of the experiment, the rats were killed, and the Na gradient-dependent citrate uptake was measured in brush border membrane (BBM) vesicles prepared from each group. At 0.3 min, the ( UC)citrate uptake was 198 +/- 8 pmol/mg protein (mean +/- SE) in the acid-loaded group, 94 +/- 16 pmol/mg protein in the control group, and 94 +/- 13 pmol/mg protein in the alkali-loaded group. The rate of Na -independent (NaCl in medium replaced by KCl) ( UC)-citrate uptake by BBM vesicles was the same for acid-loaded, control, and alkali-loaded animals. Thus, the increased capacity of the proximal tubular BBM to transport citrate from the tubular lumen into the cell interior may be an important factor that contributes to decreased urinary citrate in the presence of metabolic acidosis induced by chronic dietary acid loading.

  5. Active lithium transport by rat renal proximal tubule: a micropuncture study

    DEFF Research Database (Denmark)

    Leyssac, P P; Frederiksen, O; Holstein-Rathlou, N H

    1994-01-01

    We tested the hypothesis that proximal tubular Li+ reabsorption is due to passive transport. Clearances of [14C]inulin (CIn) and Li+ (CLi), proximal transepithelial electrical potential difference (PD), and tubular fluid-to-plasma Li+ concentration ratios [(TF/P)Li] were measured in anesthetized...... rats before and after induction of osmotic mannitol diuresis. Late proximal (TF/P)Li was measured after acute intravenous LiCl administration and after addition of LiCl to the diet for 2 days. Glomerular filtration rate (CIn) decreased, whereas CNa and CLi increased during osmotic diuresis. Control...... early proximal PD was -0.6 mV (lumen negative); late proximal PD (PDLP) was 1.1 mV (lumen positive). PDLP decreased by 1.5 mV to -0.4 mV (lumen negative) after mannitol infusion. Late proximal (TF/P)Li was 1.01 after oral Li+, 1.16 after intravenous Li+ (P osmotic diuresis...

  6. Electrically enhanced microextraction for highly selective transport of three β-blocker drugs.

    Science.gov (United States)

    Seidi, Shahram; Yamini, Yadollah; Rezazadeh, Maryam

    2011-12-15

    Facilitated transport of three β-blocker drugs including atenolol (ATE), betaxolol (BET) and propranolol (PRO) was investigated under electrical field across a supported liquid membrane (SLM) using phosphoric acid derivatives as selective ion carriers, dissolved in 2-nitro phenyl octyl ether (NPOE). In the presence of di-(2-ethylhexyl) phosphate (DEHP) and tris-(2-ethylhexyl) phosphate (TEHP) in the membrane phase, the three β-blockers showed completely different transport behaviors which enabled highly selective separation of the drugs. Each β-blocker migrated from 3 mL of sample solutions, through a thin layer of specific organic solvent immobilized in the pores of a porous hollow fiber, and into a 15 μL acidic aqueous acceptor solution present inside the lumen of the fiber. The influences of fundamental parameters affecting the transport of target drugs including type of ion carrier for selective separation of each drug and its concentration in the membrane phase, extraction voltage, time of transport, pH of donor and acceptor phases, stirring speed of donor phase and salt effect were studied and optimized. After microextraction process, the extracts were analyzed by high-performance liquid chromatography with ultraviolet detection. Under optimal conditions, ATE was selectively extracted from different saliva samples with recovery of 37%, which corresponded to preconcentration factor of 74. A good linearity was achieved for calibration curve with a coefficient of determination higher than 0.997. Limits of detection and intra-day precision (n=3) were less than 2 μg L(-1) and 8.8%, respectively.

  7. Sulfate transport by chick renal tubule brush-border and basolateral membranes

    Energy Technology Data Exchange (ETDEWEB)

    Renfro, J.L.; Clark, N.B.; Metts, R.E.; Lynch, M.A.

    1987-01-01

    Brush-border and basolateral membrane vesicles (BBMV and BLMV, respectively) were prepared from chick kidney by a calcium precipitation method and by centrifugation on an 8% Percoll self-generating gradient, respectively. In BBMV a 100-mM Na gluconate gradient, out>in, caused concentrative (/sup 35/S) sulfate uptake approximately fivefold greater at 1 min than at 60 min (equilibrium) whether or not the membranes were short-circuited with 100 mM K gluconate, in=out, plus 20 ..mu..g valinomycin/mg protein. A 48-mM HCO/sub 3//sup -/ gradient, in>out, stimulated a 2.5-fold higher uptake at 1 min than at 60 min, and short circuiting as above had no effect on the magnitude of this response. Imposition of a H/sup +/ gradient caused concentrative uptake fourfold higher at 1 min than at equilibrium. Short circuiting as above or addition of 0.1 mM carbonyl cyanide m-chlorophenylhydrazone (CCCP) significantly inhibited the pH gradient effect. Creation of an inside positive electrical potential with 100 mM K gluconate, out>in, plus valinomycin, also caused concentrative sulfate uptake. Based on inhibitor/competitor effects, these are distinct sulfate transport processes. In chick BLMV, imposition of an HCO/sub 3//sup -/ gradient, in>out, produced concentrative sulfate uptake. 4-Acetamido-4'-isothiocyanostilbene 2,2'-disulfonic acid disodium at 0.1 mM was an effective inhibitor of BLMV bicarbonate-sulfate exchange.

  8. Coupled gel spreading and diffusive transport models describing microbicidal drug delivery.

    Science.gov (United States)

    Funke, Claire; MacMillan, Kelsey; Ham, Anthony; Szeri, Andrew J; Katz, David F

    2016-10-02

    Gels are a drug delivery platform that is being evaluated for application of active pharmaceutical ingredients, termed microbicides, that act topically against vaginal and rectal mucosal infection by sexually transmitted HIV. Despite success in one Phase IIb trial of a vaginal gel delivering tenofovir, problems of user adherence to designed gel application scheduling have compromised results in two other trials. The microbicides field is responding to this dilemma by expanding behavioral analysis of the determinants of adherence while simultaneously improving the pharmacological, biochemical, and biophysical analyses of the determinants of microbicide drug delivery. The intent is to combine results of these two complementary perspectives on microbicide performance and epidemiological success to create an improved product design paradigm. Central to both user sensory perceptions and preferences, key factors that underlie adherence, and to vaginal gel mucosal drug delivery, that underlies anti-HIV efficacy, are gel properties (e.g. rheology) and volume. The specific engineering problem to be solved here is to develop a model for how gel rheology and volume, interacting with loaded drug concentration, govern the transport of the microbicide drug tenofovir into the vaginal mucosa to its stromal layer. These are factors that can be controlled in microbicide gel design. The analysis here builds upon our current understanding of vaginal gel deployment and drug delivery, incorporating key features of the gel's environment, the vaginal canal, fluid production and subsequent gel dilution, and vaginal wall elasticity. These have not previously been included in the modeling of drug delivery. We consider the microbicide drug tenofovir, which is the drug most completely studied for gels: in vitro, in animal studies in vivo, and in human clinical trials with both vaginal or rectal gel application. Our goal is to contribute to improved biophysical and pharmacological understanding

  9. Fruit juice inhibition of uptake transport: a new type of food–drug interaction

    Science.gov (United States)

    Bailey, David G

    2010-01-01

    A new type of interaction in which fruit juices diminish oral drug bioavailability through inhibition of uptake transport is the focus of this review. The discovery was based on an opposite to anticipated finding when assessing the possibility of grapefruit juice increasing oral fexofenadine bioavailability in humans through inhibition of intestinal MDR1-mediated efflux transport. In follow-up investigations, grapefruit or orange juice at low concentrations potentially and selectively inhibited in vitro OATP1A2-mediated uptake compared with MDR1-caused efflux substrate transport. These juices at high volume dramatically depressed oral fexofenadine bioavailability. Grapefruit was the representative juice to characterize the interaction subsequently. A volume–effect relationship study using a normal juice amount halved average fexofenadine absorption. Individual variability and reproducibility data indicated the clinical interaction involved direct inhibition of intestinal OATP1A2. Naringin was a major causal component suggesting that other flavonoids in fruits and vegetables might also produce the effect. Duration of juice clinical inhibition of fexofenadine absorption lasted more than 2 h but less than 4 h indicating the interaction was avoidable with appropriate interval of time between juice and drug consumption. Grapefruit juice lowered the oral bioavailability of several medications transported by OATP1A2 (acebutolol, celiprolol, fexofenadine, talinolol, L-thyroxine) while orange juice did the same for others (atenolol, celiprolol, ciprofloxacin, fexofenadine). Juice clinical inhibition of OATP2B1 was unresolved while that of OATP1B1 seemed unlikely. The interaction between grapefruit juice and etoposide also seemed relevant. Knowledge of both affected uptake transporter and drug hydrophilicity assisted prediction of the clinical interaction with grapefruit or orange juice. PMID:21039758

  10. Modeling structure-function relationships for diffusive drug transport in inert porous geopolymer matrices.

    Science.gov (United States)

    Jämstorp, Erik; Strømme, Maria; Frenning, Göran

    2011-10-01

    A unique structure-function relationship investigation of mechanically strong geopolymer drug delivery vehicles for sustained release of potent substances is presented. The effect of in-synthesis water content on geopolymer pore structure and diffusive drug transport is investigated. Scanning electron microscopy, N2 gas adsorption, mercury intrusion porosimetry, compression strength test, drug permeation, and release experiments are performed. Effective diffusion coefficients are measured and compared with corresponding theoretical values as derived from pore size distribution and connectivity via pore-network modeling. By solely varying the in-synthesis water content, mesoporous and mechanically strong geopolymers with porosities of 8%-45% are obtained. Effective diffusion coefficients of the model drugs Saccharin and Zolpidem are observed to span two orders of magnitude (∼1.6-120 × 10(-8) cm(2) /s), comparing very well to theoretical estimations. The ability to predict drug permeation and release from geopolymers, and materials alike, allows future formulations to be tailored on a structural and chemical level for specific applications such as controlled drug delivery of highly potent substances.

  11. Transporter protein and drug-conjugated gold nanoparticles capable of bypassing the blood-brain barrier

    Science.gov (United States)

    Zhang, Yanhua; Walker, Janelle Buttry; Minic, Zeljka; Liu, Fangchao; Goshgarian, Harry; Mao, Guangzhao

    2016-05-01

    Drug delivery to the central nervous system (CNS) is challenging due to the inability of many drugs to cross the blood-brain barrier (BBB). Here, we show that wheat germ agglutinin horse radish peroxidase (WGA-HRP) chemically conjugated to gold nanoparticles (AuNPs) can be transported to the spinal cord and brainstem following intramuscular injection into the diaphragm of rats. We synthesized and determined the size and chemical composition of a three-part nanoconjugate consisting of WGA-HRP, AuNPs, and drugs for the treatment of diaphragm paralysis associated with high cervical spinal cord injury (SCI). Upon injection into the diaphragm muscle of rats, we show that the nanoconjugate is capable of delivering the drug at a much lower dose than the unconjugated drug injected systemically to effectively induce respiratory recovery in rats following SCI. This study not only demonstrates a promising strategy to deliver drugs to the CNS bypassing the BBB but also contributes a potential nanotherapy for the treatment of respiratory muscle paralysis resulted from cervical SCI.

  12. 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.

  13. Blood pressure reductions following catheter-based renal denervation are not related to improvements in adherence to antihypertensive drugs measured by urine/plasma toxicological analysis.

    Science.gov (United States)

    Ewen, Sebastian; Meyer, Markus R; Cremers, Bodo; Laufs, Ulrich; Helfer, Andreas G; Linz, Dominik; Kindermann, Ingrid; Ukena, Christian; Burnier, Michel; Wagenpfeil, Stefan; Maurer, Hans H; Böhm, Michael; Mahfoud, Felix

    2015-12-01

    Renal denervation can reduce blood pressure in patients with uncontrolled hypertension. The adherence to prescribed antihypertensive medication following renal denervation is unknown. This study investigated adherence to prescribed antihypertensive treatment by liquid chromatography-high resolution tandem mass spectrometry in plasma and urine at baseline and 6 months after renal denervation in 100 patients with resistant hypertension, defined as baseline office systolic blood pressure ≥140 mmHg despite treatment with ≥3 antihypertensive agents. At baseline, complete adherence to all prescribed antihypertensive agents was observed in 52 patients, 46 patients were partially adherent, and two patients were completely non-adherent. Baseline office blood pressure was 167/88 ± 19/16 mmHg with a corresponding 24-h blood pressure of 154/86 ± 15/13 mmHg. Renal denervation significantly reduced office and ambulatory blood pressure at 6-month follow-up by 15/5 mmHg (p treatment was significantly reduced from 85.0 % at baseline to 80.7 %, 6 months after renal denervation (p = 0.005). The blood pressure decrease was not explained by improvements in adherence following the procedure. Patients not responding to treatment significantly reduced their drug intake following the procedure. Adherence was highest for angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and beta blockers (>90 %) and lowest for vasodilators (21 %). In conclusion, renal denervation can reduce office and ambulatory blood pressure in patients with resistant hypertension despite a significant reduction in adherence to antihypertensive treatment after 6 months.

  14. Pharmacokinetics, Efficacy, and Safety of Hepatitis C Virus Drugs in Patients with Liver and/or Renal Impairment

    NARCIS (Netherlands)

    Smolders, Elise J; de Kanter, Clara T M M; van Hoek, Bart; Arends, Joop E; Drenth, Joost P H; Burger, David M

    2016-01-01

    Hepatitis C virus (HCV)-infected patients often suffer from liver cirrhosis, which can be complicated by renal impairment. Therefore, in this review we describe the treatment possibilities in HCV patients with hepatic and renal impairment. Cirrhosis alters the structure of the liver, which affects d

  15. Genetically encoded photocrosslinkers locate the high-affinity binding site of antidepressant drugs in the human serotonin transporter

    DEFF Research Database (Denmark)

    Rannversson, Hafsteinn; Andersen, Jacob; Hall, Lena Sørensen;

    2016-01-01

    Despite the well-established role of the human serotonin transporter (hSERT) in the treatment of depression, the molecular details of antidepressant drug binding are still not fully understood. Here we utilize amber codon suppression in a membrane-bound transporter protein to encode photocrosslin......Despite the well-established role of the human serotonin transporter (hSERT) in the treatment of depression, the molecular details of antidepressant drug binding are still not fully understood. Here we utilize amber codon suppression in a membrane-bound transporter protein to encode...

  16. Studies of renal injury. II. Activation of the glucose transporter 1 (GLUT1) gene and glycolysis in LLC-PK1 cells under Ca2+ stress.

    Science.gov (United States)

    Dominguez, J H; Song, B; Liu-Chen, S; Qulali, M; Howard, R; Lee, C H; McAteer, J

    1996-01-01

    Injury to the renal proximal tubule is common and may be followed by either recovery or cell death. The survival of injured cells is supported by a transient change in cellular metabolism that maintains life even when oxygen tension is reduced. This adaptive process involves the activation of the gene encoding the glucose transporter GLUT1, which is essential to maintain the high rates of glucose influx demanded by glycolysis. We hypothesized that after cell injury increases of cell Ca2+ (Ca2+i) initiate the flow of information that culminates with the upregulation of the stress response gene GLUT1. We found that elevations of Ca2+i caused by the calcium ionophore A23187 activated the expression of the GLUT1 gene in LLC-PK1 cells. The stimulatory effect of Ca2+i on GLUT1 gene expression was, at least in part, transcriptional and resulted in higher levels of GLUT1 mRNA, cognate protein, cellular hexose transport activity, glucose consumption, and lactate production. This response was vital to the renal cells, as its interruption severely increased Ca2+-induced cytotoxicity and cell mortality. We propose that increases of Ca2+i initiate stress responses, represented in part by activation of the GLUT1 gene, and that disruption to the flow of information originating from Ca2+-induced stress, or to the coordinated expression of the stress response, prevents cell recovery after injury and may be an important cause of permanent renal cell injury and cell death. PMID:8755650

  17. Transport proteins determine drug sensitivity and resistance in a protozoan parasite, Trypanosoma brucei

    Science.gov (United States)

    Munday, Jane C.; Settimo, Luca; de Koning, Harry P.

    2015-01-01

    Drug resistance in pathogenic protozoa is very often caused by changes to the ‘transportome’ of the parasites. In Trypanosoma brucei, several transporters have been implicated in uptake of the main classes of drugs, diamidines and melaminophenyl arsenicals. The resistance mechanism had been thought to be due to loss of a transporter known to carry both types of agents: the aminopurine transporter P2, encoded by the gene TbAT1. However, although loss of P2 activity is well-documented as the cause of resistance to the veterinary diamidine diminazene aceturate (DA; Berenil®), cross-resistance between the human-use arsenical melarsoprol and the diamidine pentamidine (melarsoprol/pentamidine cross resistance, MPXR) is the result of loss of a separate high affinity pentamidine transporter (HAPT1). A genome-wide RNAi library screen for resistance to pentamidine, published in 2012, gave the key to the genetic identity of HAPT1 by linking the phenomenon to a locus that contains the closely related T. brucei aquaglyceroporin genes TbAQP2 and TbAQP3. Further analysis determined that knockdown of only one pore, TbAQP2, produced the MPXR phenotype. TbAQP2 is an unconventional aquaglyceroporin with unique residues in the “selectivity region” of the pore, and it was found that in several MPXR lab strains the WT gene was either absent or replaced by a chimeric protein, recombined with parts of TbAQP3. Importantly, wild-type AQP2 was also absent in field isolates of T. b. gambiense, correlating with the outcome of melarsoprol treatment. Expression of a wild-type copy of TbAQP2 in even the most resistant strain completely reversed MPXR and re-introduced HAPT1 function and transport kinetics. Expression of TbAQP2 in Leishmania mexicana introduced a pentamidine transport activity indistinguishable from HAPT1. Although TbAQP2 has been shown to function as a classical aquaglyceroporin it is now clear that it is also a high affinity drug transporter, HAPT1. We discuss here a

  18. Transport proteins determine drug sensitivity and resistance in a protozoan parasite, Trypanosoma brucei

    Directory of Open Access Journals (Sweden)

    Jane Claire Munday

    2015-03-01

    Full Text Available Drug resistance in pathogenic protozoa is very often caused by changes to the ‘transportome’ of the parasites. In Trypanosoma brucei, several transporters have been implicated in uptake of the main classes of drugs, diamidines and melaminophenyl arsenicals. The resistance mechanism had been thought to be due to loss of a transporter known to carry both types of agents: the aminopurine transporter P2, encoded by the gene TbAT1. However, although loss of P2 activity is well-documented as the cause of resistance to the veterinary diamidine diminazene aceturate (Berenil®, cross-resistance between the human-use arsenical melarsoprol and the diamidine pentamidine (MPXR is the result of loss of a separate High Affinity Pentamidine Transporter (HAPT1. A genome-wide RNAi library screen for resistance to pentamidine, published in 2012, gave the key to the genetic identity of HAPT1 by linking the phenomenon to a locus that contains the closely related T. brucei aquaglyceroporin genes TbAQP2 and TbAQP3. Further analysis determined that knockdown of only one pore, TbAQP2, produced the MPXR phenotype. TbAQP2 is an unconventional aquaglyceroporin with unique residues in the selectivity region of the pore, and it was found that in several MPXR lab strains the WT gene was either absent or replaced by a chimeric protein, recombined with parts of TbAQP3. Importantly, wild-type AQP2 was also absent in field isolates of T. b. gambiense, correlating with the outcome of melarsoprol treatment. Expression of a wild-type copy of TbAQP2 in even the most resistant strain completely reversed MPXR and re-introduced HAPT1 function and transport kinetics. Expression of TbAQP2 in Leishmania mexicana introduced a pentamidine transport activity indistinguishable from HAPT1. Although TbAQP2 has been shown to function as a classical aquaglyceroporin it is now clear that it is also a high affinity drug transporter, HAPT1. We discuss here a possible structural rationale for this

  19. Effect of hepatic or renal impairment on the pharmacokinetics of canagliflozin, a sodium glucose co-transporter 2 inhibitor.

    Science.gov (United States)

    Devineni, Damayanthi; Curtin, Christopher R; Marbury, Thomas C; Smith, William; Vaccaro, Nicole; Wexler, David; Vandebosch, An; Rusch, Sarah; Stieltjes, Hans; Wajs, Ewa

    2015-03-01

    Canagliflozin is a sodium-glucose cotransporter 2 inhibitor approved for the treatment of type 2 diabetes mellitus (T2DM). Because T2DM is often associated with renal or hepatic impairment, understanding the effects of these comorbid conditions on the pharmacokinetics of canagliflozin, and further assessing its safety, in these special populations is essential. Two open-label studies evaluated the pharmacokinetics, pharmacodynamics (renal study only), and safety of canagliflozin in participants with hepatic or renal impairment. Participants in the hepatic study (8 in each group) were categorized based on their Child-Pugh score (normal hepatic function, mild impairment [Child-Pugh score of 5 or 6], and moderate impairment [Child-Pugh score of 7-9]) and received a single oral dose of canagliflozin 300 mg. Participants in the renal study (8 in each group) were categorized based on their creatinine clearance (CLCR) (normal renal function [CLCR ≥80 mL/min]; mild [CLCR 50 to canagliflozin 200 mg; the exception was those with ESRD, who received 1 dose postdialysis and 1 dose predialysis (10 days later). Canagliflozin's pharmacokinetics and pharmacodynamics (urinary glucose excretion [UGE] and renal threshold for glucose excretion [RTG]) were assessed at predetermined time points. Mean maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to infinite (AUC)0-∞ values differed by Canagliflozin's pharmacokinetics were not affected by mild or moderate hepatic impairment. Systemic exposure to canagliflozin increased in the renal impairment groups relative to participants with normal renal function. Pharmacodynamic response to canagliflozin, measured by using UGE and RTG, declined with increasing severity of renal impairment. A single oral dose of canagliflozin was well tolerated by participants in both studies. ClinicalTrials.gov identifiers: NCT01186588 and NCT01759576. Copyright © 2015 Elsevier HS Journals, Inc. All rights

  20. The Mesenteric Lymph Duct Cannulated Rat Model: Application to the Assessment of Intestinal Lymphatic Drug Transport

    Science.gov (United States)

    Trevaskis, Natalie L.; Hu, Luojuan; Caliph, Suzanne M.; Han, Sifei; Porter, Christopher J.H.

    2015-01-01

    The intestinal lymphatic system plays key roles in fluid transport, lipid absorption and immune function. Lymph flows directly from the small intestine via a series of lymphatic vessels and nodes that converge at the superior mesenteric lymph duct. Cannulation of the mesenteric lymph duct thus enables the collection of mesenteric lymph flowing from the intestine. Mesenteric lymph consists of a cellular fraction of immune cells (99% lymphocytes), aqueous fraction (fluid, peptides and proteins such as cytokines and gut hormones) and lipoprotein fraction (lipids, lipophilic molecules and apo-proteins). The mesenteric lymph duct cannulation model can therefore be used to measure the concentration and rate of transport of a range of factors from the intestine via the lymphatic system. Changes to these factors in response to different challenges (e.g., diets, antigens, drugs) and in disease (e.g., inflammatory bowel disease, HIV, diabetes) can also be determined. An area of expanding interest is the role of lymphatic transport in the absorption of orally administered lipophilic drugs and prodrugs that associate with intestinal lipid absorption pathways. Here we describe, in detail, a mesenteric lymph duct cannulated rat model which enables evaluation of the rate and extent of lipid and drug transport via the lymphatic system for several hours following intestinal delivery. The method is easily adaptable to the measurement of other parameters in lymph. We provide detailed descriptions of the difficulties that may be encountered when establishing this complex surgical method, as well as representative data from failed and successful experiments to provide instruction on how to confirm experimental success and interpret the data obtained. PMID:25866901

  1. Regulation of Expression of Renal Organic Anion Transporters OAT1 and OAT3 in a Model of Ischemia/Reperfusion Injury

    Directory of Open Access Journals (Sweden)

    Christina Preising

    2015-08-01

    Full Text Available Background: Recently, we gained evidence that impairment of rOat1 and rOat3 expression induced by ischemic acute kidney injury (AKI is mediated by COX metabolites and this suppression might be critically involved in renal damage. Methods: (i Basolateral organic anion uptake into proximal tubular cells after model ischemia and reperfusion (I/R was investigated by fluorescein uptake. The putative promoter sequences from hOAT1 (SLC22A6 and hOAT3 (SCL22A8 were cloned into a reporter plasmid, transfected into HEK cells and (ii transcriptional activity was determined after model ischemia and reperfusion as a SEAP reporter gen assay. Inhibitors or antagonists were applied with the beginning of reperfusion. Results: By using inhibitors of PKA (H89 and PLC (U73122, antagonists of E prostanoid receptor type 2 (AH6809 and type 4 (L161,982, we gained evidence that I/R induced down regulation of organic anion transport is mediated by COX1 metabolites via E prostanoid receptor type 4. The latter signaling was confirmed by application of butaprost (EP2 agonist or TCS2510 (EP4 agonist to control cells. In brief, the latter signaling was verified for the transcriptional activity in the reporter gen assay established. Therein, selective inhibitors for COX1 (SC58125 and COX2 (SC560 were also applied. Conclusion: Our data show (a that COX1 metabolites are involved in the regulation of renal organic anion transport(ers after I/R via the EP4 receptor and (b that this is due to transcriptional regulation of the respective transporters. As the promoter sequences cloned were of human origin and expressed in a human renal epithelial cell line we (c hypothesize that the regulatory mechanisms described after I/R is meaningful for humans as well.

  2. Cyclosporine-inhibitable Blood-Brain Barrier Drug Transport Influences Clinical Morphine Pharmacodynamics

    Science.gov (United States)

    Meissner, Konrad; Avram, Michael J.; Yermolenka, Viktar; Francis, Amber M.; Blood, Jane; Kharasch, Evan D.

    2013-01-01

    Background The blood-brain barrier is richly populated by active influx and efflux transporters influencing brain drug concentrations. Morphine, a drug with delayed clinical onset, is a substrate for the efflux transporter P-glycoprotein in vitro and in animals. This investigation tested whether morphine is a transporter substrate in humans. Methods Fourteen healthy volunteers received morphine (0.1 mg/kg, 1 h intravenous infusion) in a crossover study after nothing (control) or the validated P-glycoprotein inhibitor cyclosporine (5 mg/kg, 2 h infusion). Plasma and urine morphine and morphine glucuronide metabolite concentrations were measured by mass spectrometry. Morphine effects were measured by miosis and analgesia. Results Cyclosporine minimally altered morphine disposition, increasing the area under the plasma morphine concentration versus time curve to 100 ± 21 versus 85 ± 24 ng/ml•hr (p Cyclosporine enhanced (3.2 ± 0.9 vs. 2.5 ± 1.0 mm peak) and prolonged miosis, and increased the area under the miosis-time curve (18 ± 9 vs. 11 ± 5 mm-hr), plasma-effect site transfer rate constant (ke0, median 0.27 vs. 0.17 hr−1), and maximum calculated effect site morphine concentration (11.5 ± 3.7 vs. 7.6 ± 2.9 ng/ml) (all p cyclosporine-related pain. Conclusions Morphine is a transporter substrate at the human blood-brain barrier. Results suggest a role for P-glycoprotein or other efflux transporters in brain morphine access, although the magnitude of the effect is small, and unlikely to be a major determinant of morphine clinical effects. Efflux may explain some variability in clinical morphine effects. PMID:23851346

  3. Targeting the Plasmodium vivax equilibrative nucleoside transporter 1 (PvENT1 for antimalarial drug development

    Directory of Open Access Journals (Sweden)

    Roman Deniskin

    2016-04-01

    Full Text Available Infection with Plasmodium falciparum and vivax cause most cases of malaria. Emerging resistance to current antimalarial medications makes new drug development imperative. Ideally a new antimalarial drug should treat both falciparum and vivax malaria. Because malaria parasites are purine auxotrophic, they rely on purines imported from the host erythrocyte via Equilibrative Nucleoside Transporters (ENTs. Thus, the purine import transporters represent a potential target for antimalarial drug development. For falciparum parasites the primary purine transporter is the P. falciparum Equilibrative Nucleoside Transporter Type 1 (PfENT1. Recently we identified potent PfENT1 inhibitors with nanomolar IC50 values using a robust, yeast-based high throughput screening assay. In the current work we characterized the Plasmodium vivax ENT1 (PvENT1 homologue and its sensitivity to the PfENT1 inhibitors. We expressed a yeast codon-optimized PvENT1 gene in Saccharomyces cerevisiae. PvENT1-expressing yeast imported both purines ([3H]adenosine and pyrimidines ([3H]uridine, whereas wild type (fui1Δ yeast did not. Based on radiolabel substrate uptake inhibition experiments, inosine had the lowest IC50 (3.8 μM, compared to guanosine (14.9 μM and adenosine (142 μM. For pyrimidines, thymidine had an IC50 of 183 μM (vs. cytidine and uridine; mM range. IC50 values were higher for nucleobases compared to the corresponding nucleosides; hypoxanthine had a 25-fold higher IC50 than inosine. The archetypal human ENT1 inhibitor 4-nitrobenzylthioinosine (NBMPR had no effect on PvENT1, whereas dipyridamole inhibited PvENT1, albeit with a 40 μM IC50, a 1000-fold less sensitive than human ENT1 (hENT1. The PfENT1 inhibitors blocked transport activity of PvENT1 and the five known naturally occurring non-synonymous single nucleotide polymorphisms (SNPs with similar IC50 values. Thus, the PfENT1 inhibitors also target PvENT1. This implies that development of novel

  4. Targeting the Plasmodium vivax equilibrative nucleoside transporter 1 (PvENT1) for antimalarial drug development.

    Science.gov (United States)

    Deniskin, Roman; Frame, I J; Sosa, Yvett; Akabas, Myles H

    2016-04-01

    Infection with Plasmodium falciparum and vivax cause most cases of malaria. Emerging resistance to current antimalarial medications makes new drug development imperative. Ideally a new antimalarial drug should treat both falciparum and vivax malaria. Because malaria parasites are purine auxotrophic, they rely on purines imported from the host erythrocyte via Equilibrative Nucleoside Transporters (ENTs). Thus, the purine import transporters represent a potential target for antimalarial drug development. For falciparum parasites the primary purine transporter is the P. falciparum Equilibrative Nucleoside Transporter Type 1 (PfENT1). Recently we identified potent PfENT1 inhibitors with nanomolar IC50 values using a robust, yeast-based high throughput screening assay. In the current work we characterized the Plasmodium vivax ENT1 (PvENT1) homologue and its sensitivity to the PfENT1 inhibitors. We expressed a yeast codon-optimized PvENT1 gene in Saccharomyces cerevisiae. PvENT1-expressing yeast imported both purines ([(3)H]adenosine) and pyrimidines ([(3)H]uridine), whereas wild type (fui1Δ) yeast did not. Based on radiolabel substrate uptake inhibition experiments, inosine had the lowest IC50 (3.8 μM), compared to guanosine (14.9 μM) and adenosine (142 μM). For pyrimidines, thymidine had an IC50 of 183 μM (vs. cytidine and uridine; mM range). IC50 values were higher for nucleobases compared to the corresponding nucleosides; hypoxanthine had a 25-fold higher IC50 than inosine. The archetypal human ENT1 inhibitor 4-nitrobenzylthioinosine (NBMPR) had no effect on PvENT1, whereas dipyridamole inhibited PvENT1, albeit with a 40 μM IC50, a 1000-fold less sensitive than human ENT1 (hENT1). The PfENT1 inhibitors blocked transport activity of PvENT1 and the five known naturally occurring non-synonymous single nucleotide polymorphisms (SNPs) with similar IC50 values. Thus, the PfENT1 inhibitors also target PvENT1. This implies that development of novel antimalarial drugs

  5. Physiologically based pharmacokinetic-pharmacodynamic modeling to predict concentrations and actions of sodium-dependent glucose transporter 2 inhibitor canagliflozin in human intestines and renal tubules.

    Science.gov (United States)

    Mori, Kazumi; Saito, Ryuta; Nakamaru, Yoshinobu; Shimizu, Makiko; Yamazaki, Hiroshi

    2016-11-01

    Canagliflozin is a recently developed sodium-glucose cotransporter (SGLT) 2 inhibitor that promotes renal glucose excretion and is considered to inhibit renal SGLT2 from the luminal side of proximal tubules. Canagliflozin reportedly inhibits SGLT1 weakly and suppresses postprandial plasma glucose, suggesting that it also inhibits intestinal SGLT1. However, it is difficult to measure the drug concentrations of these assumed sites of action directly. The pharmacokinetic-pharmacodynamic (PK/PD) relationships of canagliflozin remain poorly characterized. Therefore, a physiologically based pharmacokinetic (PBPK) model of canagliflozin was developed based on clinical data from healthy volunteers and it was used to simulate luminal concentrations in intestines and renal tubules. In small intestine simulations, the inhibition ratios for SGLT1 were predicted to be 40%-60% after the oral administration of clinical doses (100-300 mg/day). In contrast, inhibition ratios of canagliflozin for renal SGLT2 and SGLT1 were predicted to be approximately 100% and 0.2%-0.4%, respectively. These analyses suggest that canagliflozin only inhibits SGLT2 in the kidney. Using the simulated proximal tubule luminal concentrations of canagliflozin, the urinary glucose excretion rates in canagliflozin-treated diabetic patients were accurately predicted using the renal glucose reabsorption model as a PD model. Because the simulation of canagliflozin pharmacokinetics was successful, this PBPK methodology was further validated by successfully simulating the pharmacokinetics of dapagliflozin, another SGLT2 inhibitor. The present results suggest the utility of this PBPK/PD model for predicting canagliflozin concentrations at target sites and help to elucidate the pharmacological effects of SGLT1/2 inhibition in humans. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  6. Functional characterization of liver enhancers that regulate drug-associated transporters.

    Science.gov (United States)

    Kim, M J; Skewes-Cox, P; Fukushima, H; Hesselson, S; Yee, S W; Ramsey, L B; Nguyen, L; Eshragh, J L; Castro, R A; Wen, C C; Stryke, D; Johns, S J; Ferrin, T E; Kwok, P-Y; Relling, M V; Giacomini, K M; Kroetz, D L; Ahituv, N

    2011-04-01

    Little is known about how genetic variations in enhancers influence drug response. In this study, we investigated whether nucleotide variations in enhancers that regulate drug transporters can alter their expression levels. Using comparative genomics and liver-specific transcription factor binding site (TFBS) analyses, we identified evolutionary conserved regions (ECRs) surrounding nine liver membrane transporters that interact with commonly used pharmaceuticals. The top 50 ECRs were screened for enhancer activity in vivo, of which five--located around ABCB11, SLC10A1, SLCO1B1, SLCO1A2, and SLC47A1--exhibited significant enhancer activity. Common variants identified in a large ethnically diverse cohort (n = 272) were assayed for differential enhancer activity, and three variants were found to have significant effects on reporter activity as compared with the reference allele. In addition, one variant was associated with reduced SLCO1A2 mRNA expression levels in human liver tissues, and another was associated with increased methotrexate (MTX) clearance in patients. This work provides a general model for the rapid characterization of liver enhancers and identifies associations between enhancer variants and drug response.

  7. Drug transport mechanism of P-glycoprotein monitored by single molecule fluorescence resonance energy transfer

    Science.gov (United States)

    Ernst, S.; Verhalen, B.; Zarrabi, N.; Wilkens, S.; Börsch, M.

    2011-03-01

    In this work we monitor the catalytic mechanism of P-glycoprotein (Pgp) using single-molecule fluorescence resonance energy transfer (FRET). Pgp, a member of the ATP binding cassette family of transport proteins, is found in the plasma membrane of animal cells where it is involved in the ATP hydrolysis driven export of hydrophobic molecules. When expressed in the plasma membrane of cancer cells, the transport activity of Pgp can lead to the failure of chemotherapy by excluding the mostly hydrophobic drugs from the interior of the cell. Despite ongoing effort, the catalytic mechanism by which Pgp couples MgATP binding and hydrolysis to translocation of drug molecules across the lipid bilayer is poorly understood. Using site directed mutagenesis, we have introduced cysteine residues for fluorescence labeling into different regions of the nucleotide binding domains (NBDs) of Pgp. Double-labeled single Pgp molecules showed fluctuating FRET efficiencies during drug stimulated ATP hydrolysis suggesting that the NBDs undergo significant movements during catalysis. Duty cycle-optimized alternating laser excitation (DCO-ALEX) is applied to minimize FRET artifacts and to select the appropriate molecules. The data show that Pgp is a highly dynamic enzyme that appears to fluctuate between at least two major conformations during steady state turnover.

  8. A water gradient can be used to regulate drug transport across skin.

    Science.gov (United States)

    Björklund, Sebastian; Engblom, Johan; Thuresson, Krister; Sparr, Emma

    2010-04-19

    At normal conditions there is a substantial water gradient over the skin as it separates the water-rich inside of the body from the dry outside. This leads to a variation in the degree of hydration from the inside to the outside of skin and changes in this gradient may affect its structure and function. In this study we raise the question: How do changes in the water gradient across skin affect its permeability? We approach this problem in novel diffusion experiments that permit strict control of the gradient in the chemical potential of water and hence well-defined boundary conditions. The results demonstrate that a water gradient can be used to regulate transport of drugs with different lipophilic characteristics across the skin barrier. It is shown that the transport of metronidazole (log P(o/w)=0.0) and methyl salicylate (log P(o/w)=2.5) across skin increases abruptly at low water gradients, corresponding to high degrees of skin hydration, and that this effect is reversible. This phenomenon is highly relevant to drug delivery applications due to its potential of temporarily open the skin barrier for transdermal drug delivery and subsequently close the barrier after treatment. Further, the results contribute to the understanding of the occlusion effect and indicate the boundary conditions of the water gradient needed to make use of this effect. Copyright 2010 Elsevier B.V. All rights reserved.

  9. Repositioning of Tyrosine Kinase Inhibitors as Antagonists of ATP-Binding Cassette Transporters in Anticancer Drug Resistance

    Directory of Open Access Journals (Sweden)

    Yi-Jun Wang

    2014-09-01

    Full Text Available The phenomenon of multidrug resistance (MDR has attenuated the efficacy of anticancer drugs and the possibility of successful cancer chemotherapy. ATP-binding cassette (ABC transporters play an essential role in mediating MDR in cancer cells by increasing efflux of drugs from cancer cells, hence reducing the intracellular accumulation of chemotherapeutic drugs. Interestingly, small-molecule tyrosine kinase inhibitors (TKIs, such as AST1306, lapatinib, linsitinib, masitinib, motesanib, nilotinib, telatinib and WHI-P154, have been found to have the capability to overcome anticancer drug resistance by inhibiting ABC transporters in recent years. This review will focus on some of the latest and clinical developments with ABC transporters, TKIs and anticancer drug resistance.

  10. Differential expression of several drug transporter genes in HepG2 and Huh-7 cell lines.

    Science.gov (United States)

    Louisa, Melva; Suyatna, Frans D; Wanandi, Septelia Inawati; Asih, Puji Budi Setia; Syafruddin, Din

    2016-01-01

    Cell culture techniques have many advantages for investigation of drug transport to target organ like liver. HepG2 and Huh-7 are two cell lines available from hepatoma that can be used as a model for hepatic drug transport. The present study is aimed to analyze the expression level of several drug transporter genes in two hepatoma cell lines, HepG2 and Huh-7 and their response to inhibitors. This is an in vitro study using HepG2 and Huh-7 cells. The expression level of the following drug transporter genes was quantified: P-glycoprotein/multidrug resistance protein 1, Organic Anionic Transporter Protein 1B1 (OATP1B1) and Organic Cationic Transporter-1 (OCT1). Ribonucleic acid was extracted from the cells using Tripure isolation reagent, then gene expression level of the transporters is quantified using Applied Biosystems quantitative reverse transcriptase polymerase chain reaction. Verapamil (P-glycoprotein inhibitor), nelfinavir (OATP1B1 inhibitor), quinidine (OCT1 inhibitor) were used to differentiate the inhibitory properties of these agents to the transporter expressions in HepG2 and Huh-7 cells. Huh-7 shows a higher level of P-glycoprotein, OATP1B1 and OCT1 expressions compared with those of HepG2. Verapamil reduces the expressions of P-glycoprotein in HepG2 and Huh-7; nelfinavir reduces the expression of OATP1B1 in HepG2 and Huh-7; while quinidine reduces the OCT1 gene expressions in HepG2, but not in Huh-7 cells. This study indicates that HepG2 might be a more suitable in vitro model than Huh-7 to study drug transport in hepatocytes involving drug transporters.

  11. Meclofenamate elicits a nephropreventing effect in a rat model of ischemic acute kidney injury by suppressing indoxyl sulfate production and restoring renal organic anion transporters

    Directory of Open Access Journals (Sweden)

    Saigo C

    2014-08-01

    Full Text Available Chika Saigo,1 Yui Nomura,1 Yuko Yamamoto,1 Masataka Sagata,1 Rika Matsunaga,1 Hirofumi Jono,1,2 Kazuhiko Nishi,3 Hideyuki Saito1,2 1Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 2Department of Pharmacy, Kumamoto University Hospital, 3Department of Hemo-Dialysis, Kumamoto University Hospital, Kumamoto, Japan Abstract: Indoxyl sulfate (IS, a putative low-molecular weight uremic toxin, is excreted in the urine under normal kidney function, but is retained in the circulation and tissues during renal dysfunction in acute kidney injury and chronic kidney disease. IS, which is one of the most potent inducers of oxidative stress in the kidney and cardiovascular system, is enzymatically produced in the liver from indole by cytochrome P450-mediated hydroxylation to indoxyl, followed by sulfotransferase-mediated sulfate conjugation. We used rat liver S9 fraction to identify inhibitors of IS production. After testing several compounds, including phytochemical polyphenols, we identified meclofenamate as a potent inhibitor of IS production with an apparent IC50 value of 1.34 µM. Ischemia/reperfusion (I/R of rat kidney caused a marked elevation in the serum IS concentration 48 hours after surgery. However, intravenous administration of meclofenamate (10 mg/kg significantly suppressed this increase in the serum level of IS. Moreover, IS concentrations in both kidney and liver were dramatically elevated by renal I/R treatment, but this increase was blocked by meclofenamate. Serum creatinine and blood urea nitrogen were markedly elevated in rats after renal I/R treatment, but these increases were significantly restored by administration of meclofenamate. Renal expression of both basolateral membrane-localized organic anion transporters rOAT1 and rOAT3 was downregulated by I/R treatment. However, expression of rOAT1 and rOAT3 recovered after administration of meclofenamate, which is associated

  12. Contribution of multidrug resistance protein 2 (MRP2/ABCC2) to the renal excretion of p-aminohippurate (PAH) and identification of MRP4 (ABCC4) as a novel PAH transporter.

    NARCIS (Netherlands)

    Smeets, P.H.E.; Aubel, R.A.M.H. van; Wouterse, A.C.; Heuvel, J.J.T.M.; Russel, F.G.M.

    2004-01-01

    p-Aminohippurate (PAH) is the classical substrate used in the characterization of organic anion transport in renal proximal tubular cells. Although basolateral transporters for PAH uptake from blood into the cell have been well characterized, there is still little knowledge on the apical urinary eff

  13. Assay development of inducible human renal phosphate transporter Npt2A (SLC34A1) in Flp-In-Trex-HEK293 cells.

    Science.gov (United States)

    Wu, Hongzhong; Mao, Chonghong; Duenstl, Georg; Su, Wan; Qian, Su

    2013-12-01

    Hyperphosphatemia is associated with severe decline of renal function in chronic kidney disease and elevates cardiovascular mortality. Type II sodium dependent phosphate transporter 2A (Npt2A) plays a major role in renal phosphate reabsorption and could be explored as a target for anti-hyperphosphatemia therapy. Human Npt2A transporter activity was examined upon transfection into CHO, MDCK, HEK293, Flp-In-CHO and Flp-In-HEK293 cells. Only kidney-derived cells expressed functional Npt2A. HEK293 and Flp-In-HEK293 cell lines stably transfected with hNpt2A could be selected, but these cells were inactive in phosphate transport. This suggests that high-level, constitutive Npt2A expression has deleterious effects on the cell. By using the conditional promoter in the Flp-In-Trex vector, functional expression of Npt2A was achieved by doxycycline induction in HEK293 cells. The EGFP tagged and non-tagged, inducible stable hNpt2A-HEK293 cell lines afforded development of a robust phosphate uptake assay mediated by hNpt2A, which can be used to screen hNpt2A inhibitors and inducers of hNpt2A expression. Using this assay, the small molecule LC-1 was identified as a potent inhibitor of hNpt2A, suggesting that it is feasible to develop potent specific hNpt2A inhibitors to control phosphate overloading for hyperphosphatemia therapy.

  14. Strategies of Drug Transporter Quantitation by LC-MS: Importance of Peptide Selection and Digestion Efficiency.

    Science.gov (United States)

    Chen, Buyun; Liu, Liling; Ho, Hoangdung; Chen, Yuan; Yang, Ze; Liang, Xiaorong; Payandeh, Jian; Dean, Brian; Hop, Cornelis E C A; Deng, Yuzhong

    2017-06-06

    Huge variation of drug transporter abundance was seen in the literature, making PBPK prediction difficult when transporters play a major role. Among multiple factors such as membrane fraction, digestion, and peptide selection that contributed to such variation, peptide selection is the least discussed. Herein, a strategy was established by using a small amount of purified protein standard to select a peptide with near 100% digestion efficiency for quantitation of a transporter protein MDR1. The impact of native membrane protein's tertiary structure on the digestion efficiency of surrogate peptides of MDR1 was investigated. Peptides in more solvent accessible regions are found to be digested much more efficiently than those in large stretches of helical structures. The concentration of peptide EALDESIPPVSFWR(EAL) in the most solvent accessible linker region of MDR1 was found closest to the true protein concentration. When using EAL for MDR1 quantitation, the abundance is over 10 times higher than previously reported, indicating the importance of peptide selection for transporter quantitation. In addition, this study also proposes a screening strategy to select peptides appropriate for relative quantitation for in vitro-in vivo extrapolation in the absence of any protein standard.

  15. Application of magnetic liposomes for magnetically guided transport of muscle relaxants and anti-cancer photodynamic drugs

    Energy Technology Data Exchange (ETDEWEB)

    Kuznetsov, Anatoly A.; Filippov, Victor I.; Alyautdin, Renat N.; Torshina, N.L.; Kuznetsov, O.A. E-mail: oleg@louisiana.edu

    2001-07-01

    Magnetic liposomes containing submicron-sized ferromagnetic particles were prepared encapsulating the muscle relaxant drugs, diadony or diperony, for local anesthesia. Alternatively, metal phthalocyanines (Photosense or Teraphthal), sensitizers for photodynamic or catalytic cancer therapy were loaded into the magnetic liposomes. Animal trials demonstrated successful magnetically guided transport of the drug-loaded liposomes.

  16. The cooperative roles of the dopamine receptors, D1R and D5R, on the regulation of renal sodium transport.

    Science.gov (United States)

    Gildea, John J; Shah, Ishan T; Van Sciver, Robert E; Israel, Jonathan A; Enzensperger, Christoph; McGrath, Helen E; Jose, Pedro A; Felder, Robin A

    2014-07-01

    Determining the individual roles of the two dopamine D1-like receptors (D1R and D5R) on sodium transport in the human renal proximal tubule has been complicated by their structural and functional similarity. Here we used a novel D5R-selective antagonist (LE-PM436) and D1R- or D5R-specific gene silencing to determine second messenger coupling pathways and heterologous receptor interaction between the two receptors. D1R and D5R colocalize in renal proximal tubule cells and physically interact, as determined by co-immunoprecipitation and fluorescent resonance energy transfer microscopy. Stimulation of renal proximal tubule cells with fenoldopam (D1R/D5R agonist) led to both adenylyl cyclase and phospholipase C (PLC) activation using real-time fluorescent resonance energy transfer biosensors ICUE3 and CYPHR, respectively. Fenoldopam increased cAMP accumulation and PLC activity and inhibited both NHE3 and NaKATPase activities. LE-PM436 and D5R siRNA blocked the fenoldopam-stimulated PLC pathway but not cAMP accumulation, whereas D1R siRNA blocked both fenoldopam-stimulated cAMP accumulation and PLC signaling. Either D1R or D5R siRNA, or LE-PM436 blocked the fenoldopam-dependent inhibition of sodium transport. Further studies using the cAMP-selective D1R/D5R agonist SKF83822 and PLC-selective D1R/D5R agonist SKF83959 confirmed the cooperative influence of the two pathways on sodium transport. Thus, D1R and D5R interact in the inhibition of NHE3 and NaKATPase activity, the D1R primarily by cAMP, whereas the D1R/D5R heteromer modulates the D1R effect through a PLC pathway.

  17. Incretins and selective renal sodium-glucose co-transporter 2 inhibitors in hypertension and coronary heart disease

    Institute of Scientific and Technical Information of China (English)

    Ramiro; A; Sanchez; Hugo; Sanabria; Cecilia; de; los; Santos; Agustin; J; Ramirez

    2015-01-01

    Hyperglycemia is associated with an increased risk of cardiovascular disease,and the consequences ofintensive therapy may depend on the mechanism of the anti-diabetic agent(s)used to achieve a tight control.In animal models,stable analogues of glucagon-like peptide-1(GLP-1)were able to reduce body weight and blood pressure and also had favorable effects on ischemia following coronary reperfusion.In a similar way,dipeptidyl peptidase IV(DPPIV)showed to have favorable effects in animal models of ischemia/reperfusion.This could be due to the fact that DPPIV inhibitors were able to prevent the breakdown of GLP-1 and glucose-dependent insulinotropic polypeptide,but they also decreased the degradation of several vasoactive peptides.Preclinical data for GLP-1,its derivatives and inhibitors of the DPPIV enzyme degradation suggests that these agents may be able to,besides controlling glycaemia,induce cardio-protective and vasodilator effects.Notwithstanding the many favorable cardiovascular effects of GLP-1/incretins reported in different studies,many questions remain unanswered due the limited number of studies in human beings that aim to examine the effects of GLP-1 on cardiovascular endpoints.For this reason,long-term trials searching for positive cardiovascular effects are now in process,such as the CAROLINA and CARMELINA trials,which are supported by small pilot studies performed in humans(and many more animal studies)with incretin-based therapies.On the other hand,selective renal sodium-glucose co-transporter 2 inhibitors were also evaluated in the prevention of cardiovascular outcomes in type 2 diabetes.However,it is quite early to draw conclusions,since data on cardiovascular outcomes and cardiovascular death are limited and long-term studies are still ongoing.In this review,we will analyze the mechanisms underlying the cardiovascular effects of incretins and,at the same time,we will present a critical position about the real value of these compounds in the

  18. Active transmembrane drug transport in microgravity: a validation study using an ABC transporter model [v1; ref status: indexed, http://f1000r.es/41n

    Directory of Open Access Journals (Sweden)

    Sergi Vaquer

    2014-08-01

    Full Text Available Abstract Microgravity has been shown to influence the expression of ABC (ATP-Binding Cassette transporters in bacteria, fungi and mammals, but also to modify the activity of certain cellular components with structural and functional similarities to ABC transporters. Changes in activity of ABC transporters could lead to important metabolic disorders and undesired pharmacological effects during spaceflights. However, no current means exist to study the functionality of these transporters in microgravity. To this end, a Vesicular Transport Assay® (Solvo Biotechnology, Hungary was adapted to evaluate multi-drug resistance-associated protein 2 (MRP2 trans-membrane estradiol-17-β-glucuronide (E17βG transport activity, when activated by adenosine-tri-phosphate (ATP during parabolic flights. Simple diffusion, ATP-independent transport and benzbromarone inhibition were also evaluated. A high accuracy engineering system was designed to perform, monitor and synchronize all procedures. Samples were analysed using a validated high sensitivity drug detection protocol. Experiments were performed in microgravity during parabolic flights, and compared to 1g on ground results using identical equipment and procedures in all cases. Our results revealed that sufficient equipment accuracy and analytical sensitivity were reached to detect transport activity in both gravitational conditions. Additionally, transport activity levels of on ground samples were within commercial transport standards, proving the validity of the methods and equipment used. MRP2 net transport activity was significantly reduced in microgravity, so was signal detected in simple diffusion samples. Ultra-structural changes induced by gravitational stress upon vesicle membranes or transporters could explain the current results, although alternative explanations are possible. Further research is needed to provide a conclusive answer in this regard. Nevertheless, the present validated technology

  19. Iontoforese no transporte ocular de drogas Iontophoresis for ocular drug delivery

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    Sílvia Ligório Fialho

    2004-10-01

    Full Text Available O método mais comum de administração de drogas no olho é por meio de colírios. Entretanto, por este método, não é possível atingir a concentração terapêutica nos fluidos e tecidos posteriores do olho. A administração sistêmica apresenta reduzido acesso ao segmento posterior do olho devido à presença das barreiras oculares. Injeções subconjuntivais e retrobulbares não são capazes de proporcionar níveis adequados da droga, e a injeção intravítrea é método invasivo, inconveniente e que apre-senta riscos de perfuração do bulbo ocular ou descolamento da retina. A iontoforese, no entanto, apresenta-se como alternativa para o transporte de doses terapêuticas de drogas para o segmento posterior do olho. A iontoforese é uma técnica que consiste na administração de drogas para o organismo através dos tecidos, utilizando um campo elétrico. O eletrodo ativo, que se encontra em contato com a droga, é colocado no local a ser tratado, e um segundo eletrodo, com a finalidade de fechar o circuito elétrico, é colocado em outro local do organismo. O campo elétrico facilita o transporte da droga, que deve se encontrar, preferencialmente, na forma ionizada. A iontoforese pode ser considerada como um método seguro e não invasivo de transporte de drogas para locais específicos do olho. Aplicada experimentalmente para o tratamento de doenças oculares, esta técnica tem evoluído muito nos últimos anos e, atualmente, testes clínicos de fase III encontram-se em andamento.The most traditional method of ocular drug delivery is through the use of eyedrops. However, by this method, the therapeutic concentration in deep ocular fluids and tissues can not be efficiently reached. Systemic administration presents poor access to the posterior segment of the eye due to ocular barriers. Subconjuntival and retrobulbar injections are not able to produce adequate levels of the drug, and intravitreal injection is an invasive and problematic

  20. Nonsteroidal Anti-Inflammatory Drugs and the Kidney

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    Walter H. Hörl

    2010-07-01

    Full Text Available Non-steroidal anti-inflammatory drugs (NSAIDs inhibit the isoenzymes COX-1 and COX-2 of cyclooxygenase (COX. Renal side effects (e.g., kidney function, fluid and urinary electrolyte excretion vary with the extent of COX-2-COX-1 selectivity and the administered dose of these compounds. While young healthy subjects will rarely experience adverse renal effects with the use of NSAIDs, elderly patients and those with co-morbibity (e.g., congestive heart failure, liver cirrhosis or chronic kidney disease and drug combinations (e.g., renin-angiotensin blockers, diuretics plus NSAIDs may develop acute renal failure. This review summarizes our present knowledge how traditional NSAIDs and selective COX-2 inhibitors may affect the kidney under various experimental and clinical conditions, and how these drugs may influence renal inflammation, water transport, sodium and potassium balance and how renal dysfunction or hypertension may result.

  1. Perinatal Na+ overload programs raised renal proximal Na+ transport and enalapril-sensitive alterations of Ang II signaling pathways during adulthood.

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    Edjair V Cabral

    Full Text Available BACKGROUND: High Na(+ intake is a reality in nowadays and is frequently accompanied by renal and cardiovascular alterations. In this study, renal mechanisms underlying perinatal Na(+ overload-programmed alterations in Na(+ transporters and the renin/angiotensin system (RAS were investigated, together with effects of short-term treatment with enalapril in terms of reprogramming molecular alterations in kidney. METHODOLOGY/PRINCIPAL FINDINGS: Male adult Wistar rats were obtained from dams maintained throughout pregnancy and lactation on a standard diet and drinking water (control or 0.17 M NaCl (saline group. Enalapril (100 mg/l, an angiotensin converting enzyme inhibitor, was administered for three weeks after weaning. Ninety day old offspring from dams that drank saline presented with proximal tubules exhibiting increased (Na(++K(+ATPase expression and activity. Ouabain-insensitive Na(+-ATPase activity remained unchanged but its response to angiotensin II (Ang II was lost. PKC, PKA, renal thiobarbituric acid reactive substances (TBARS, macrophage infiltration and collagen deposition markedly increased, and AT(2 receptor expression decreased while AT(1 expression was unaltered. Early treatment with enalapril reduced expression and activity of (Na(++K(+ATPase, partially recovered the response of Na(+-ATPase to Ang II, and reduced PKC and PKA activities independently of whether offspring were exposed to high perinatal Na(+ or not. In addition, treatment with enalapril per se reduced AT(2 receptor expression, and increased TBARS, macrophage infiltration and collagen deposition. The perinatally Na(+-overloaded offspring presented high numbers of Ang II-positive cortical cells, and significantly lower circulating Ang I, indicating that programming/reprogramming impacted systemic and local RAS. CONCLUSIONS/SIGNIFICANCE: Maternal Na(+ overload programmed alterations in renal Na(+ transporters and in its regulation, as well as severe structural lesions

  2. Uptake of NO-releasing drugs by the P2 nucleoside transporter in trypanosomes

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    L. Soulère

    1999-11-01

    Full Text Available Nitric oxide (NO· has been identified as a principal regulatory molecule of the immune system and the major cytotoxic mediator of activated immune cells. NO· can also react rapidly with a variety of biological species, particularly with the superoxide radical anion O2·- at almost diffusion-limited rates to form peroxynitrite anion (ONOO-. ONOO- and its proton-catalyzed decomposition products are capable of oxidizing a great diversity of biomolecules and can act as a source of toxic hydroxyl radicals. As a consequence, a strategy for the development of molecules with potential trypanocidal activities could be developed to increase the concentration of nitric oxide in the parasites through NO·-releasing compounds. In this way, the rate of formation of peroxynitrite from NO· and O2·- would be faster than the rate of dismutation of superoxide radicals by superoxide dismutases which constitute the primary antioxidant enzymatic defense system in trypanosomes. The adenosine transport systems of parasitic protozoa, which are also in certain cases implicated in the selective uptake of active drugs such as melarsoprol or pentamidine, could be exploited to specifically target these NO·-releasing compounds inside the parasites. In this work, we present the synthesis, characterization and biological evaluation of a series of molecules that contain both a group which would specifically target these drugs inside the parasites via the purine transporter, and an NO·-donor group that would exert a specific pharmacological effect by increasing NO level, and thus the peroxynitrite concentration inside the parasite.

  3. Fruit juice, organic anion transporting polypeptides, and drug interactions in psychiatry.

    Science.gov (United States)

    Andrade, Chittaranjan

    2014-11-01

    Organic anion transporting polypeptides (OATPs) are a group of membrane transport proteins that facilitate the influx of endogenous and exogenous substances across biological membranes. OATPs are found in enterocytes and hepatocytes and in brain, kidney, and other tissues. In enterocytes, OATPs facilitate the gastrointestinal absorption of certain orally administered drugs. Fruit juices such as grapefruit juice, orange juice, and apple juice contain substances that are OATP inhibitors. These fruit juices diminish the gastrointestinal absorption of certain antiallergen, antibiotic, antihypertensive, and β-blocker drugs. While there is no evidence, so far, that OATP inhibition affects the absorption of psychotropic medications, there is no room for complacency because the field is still nascent and because the necessary studies have not been conducted. Patients should therefore err on the side of caution, taking their medications at least 4 hours distant from fruit juice intake. Doing so is especially desirable with grapefruit juice, orange juice, and apple juice; with commercial fruit juices in which OATP-inhibiting substances are likely to be present in higher concentrations; with calcium-fortified fruit juices; and with medications such as atenolol and fexofenadine, the absorption of which is substantially diminished by concurrent fruit juice intake.

  4. ATP-binding cassette transporter controls leaf surface secretion of anticancer drug components in Catharanthus roseus.

    Science.gov (United States)

    Yu, Fang; De Luca, Vincenzo

    2013-09-24

    The Madagascar periwinkle (Catharanthus roseus) is highly specialized for the biosynthesis of many different monoterpenoid indole alkaloids (MIAs), many of which have powerful biological activities. Such MIAs include the commercially important chemotherapy drugs vinblastine, vincristine, and other synthetic derivatives that are derived from the coupling of catharanthine and vindoline. However, previous studies have shown that biosynthesis of these MIAs involves extensive movement of metabolites between specialized internal leaf cells and the leaf epidermis that require the involvement of unknown secretory processes for mobilizing catharanthine to the leaf surface and vindoline to internal leaf cells. Spatial separation of vindoline and catharanthine provides a clear explanation for the low levels of dimers that accumulate in intact plants. The present work describes the molecular cloning and functional identification of a unique catharanthine transporter (CrTPT2) that is expressed predominantly in the epidermis of young leaves. CrTPT2 gene expression is activated by treatment with catharanthine, and its in planta silencing redistributes catharanthine to increase the levels of catharanthine-vindoline drug dimers in the leaves. Phylogenetic analysis shows that CrTPT2 is closely related to a key transporter involved in cuticle assembly in plants and that may be unique to MIA-producing plant species, where it mediates secretion of alkaloids to the plant surface.

  5. Identification of a novel topoisomerase inhibitor effective in cells overexpressing drug efflux transporters.

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    Walid Fayad

    Full Text Available BACKGROUND: Natural product structures have high chemical diversity and are attractive as lead structures for discovery of new drugs. One of the disease areas where natural products are most frequently used as therapeutics is oncology. METHOD AND FINDINGS: A library of natural products (NCI Natural Product set was screened for compounds that induce apoptosis of HCT116 colon carcinoma cells using an assay that measures an endogenous caspase-cleavage product. One of the apoptosis-inducing compounds identified in the screen was thaspine (taspine, an alkaloid from the South American tree Croton lechleri. The cortex of this tree is used for medicinal purposes by tribes in the Amazonas basin. Thaspine was found to induce conformational activation of the pro-apoptotic proteins Bak and Bax, mitochondrial cytochrome c release and mitochondrial membrane permeabilization in HCT116 cells. Analysis of the gene expression signature of thaspine-treated cells suggested that thaspine is a topoisomerase inhibitor. Inhibition of both topoisomerase I and II was observed using in vitro assays, and thaspine was found to have a reduced cytotoxic effect on a cell line with a mutated topoisomerase II enzyme. Interestingly, in contrast to the topoisomerase II inhibitors doxorubicin, etoposide and mitoxantrone, thaspine was cytotoxic to cell lines overexpressing the PgP or MRP drug efflux transporters. We finally show that thaspine induces wide-spread apoptosis in colon carcinoma multicellular spheroids and that apoptosis is induced in two xenograft mouse models in vivo. CONCLUSIONS: The alkaloid thaspine from the cortex of Croton lechleri is a dual topoisomerase inhibitor effective in cells overexpressing drug efflux transporters and induces wide-spread apoptosis in multicellular spheroids.

  6. Measurement of multiple drug resistance transporter activity in putative cancer stem/progenitor cells.

    Science.gov (United States)

    Donnenberg, Vera S; Meyer, E Michael; Donnenberg, Albert D

    2009-01-01

    Multiple drug resistance, mediated by the expression and activity of ABC-transporters, is a major obstacle to antineoplastic therapy. Normal tissue stem cells and their malignant counterparts share MDR transporter activity as a major mechanism of self-protection. Although MDR activity is upregulated in response to substrate chemotherapeutic agents, it is also constitutively expressed on both normal tissue stem cells and a subset of tumor cells prior to the initiation of therapy, representing a built-in obstacle to therapeutic ratio. Constitutive and induced MDR activity can be detected in cellular subsets of disaggregated tissues, using the fluorescent substrates Rhodamine 123 and Hoechst 33342 for ABCB1 (also known as P-gp and MDR1) and ABCG2 (BCRP1). In this chapter, we will describe the complete procedure for the detection of MDR activity, including: (1) Preparing single-cell suspensions from tumor and normal tissue specimens; (2) An efficient method to perform cell surface marker staining on large numbers of cells; (3) Flow cytometer setup and controls; (4) Simultaneous measurement of Hoechst 33342 and Rhodamine123 transport; and (5) Data acquisition and analysis.

  7. Analysis of perfusion, microcirculation and drug transport in tumors. A computational study.

    Science.gov (United States)

    Zunino, Paolo; Cattaneo, Laura

    2013-11-01

    We address blood flow through a network of capillaries surrounded by a porous interstitium. We develop a computational model based on the Immersed Boundary method [C. S. Peskin. Acta Numer. 2002.]. The advantage of such an approach relies in its efficiency, because it does not need a full description of the real geometry allowing for a large economy of memory and CPU time and it facilitates handling fully realistic vascular networks [L. Cattaneo and P. Zunino. Technical report, MOX, Department of Mathematics, Politecnico di Milano, 2013.]. The analysis of perfusion and drug release in vascularized tumors is a relevant application of such techniques. Blood vessels in tumors are substantially leakier than in healthy tissue and they are tortuous. These vascular abnormalities lead to an impaired blood supply and abnormal tumor microenvironment characterized by hypoxia and elevated interstitial fluid pressure that reduces the distribution of drugs through advection [L.T. Baxter and R.K. Jain. Microvascular Research, 1989]. Finally, we discuss the application of the model to deliver nanoparticles. In particular, transport of nanoparticles in the vessels network, their adhesion to the vessel wall and the drug release in the surrounding tissue will be addressed.

  8. Hepatitis B Virus Infection and the Kidney: Renal Abnormalities in HBV Patients, Antiviral Drugs Handling, and Specific Follow-Up

    Directory of Open Access Journals (Sweden)

    Gilbert Deray

    2015-01-01

    Full Text Available Chronic hepatitis B virus (CHB infection is one of the most common causes of chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC worldwide. Many patients with CHB have variable degrees of functional renal impairment, and approximately 2 to 15% of patients on hemodialysis have CHB. Several therapeutic regimens have been developed in the past years, among which oral nucleoside and nucleotide analogues have been demonstrated to be efficient and well tolerated. However, they all are excreted in the urine and may thus require dosage adjustment in patients with decreased renal function. Furthermore, a number of them may in addition be toxic to the kidneys, especially in those patients presenting with renal insufficiency.

  9. Renal Drug Dosing. Effectiveness of Outpatient Pharmacist-Based vs. Prescriber-Based Clinical Decision Support Systems.

    Science.gov (United States)

    Vogel, Erin A; Billups, Sarah J; Herner, Sheryl J; Delate, Thomas

    2016-07-27

    The purpose of this study was to compare the effectiveness of an outpatient renal dose adjustment alert via a computerized provider order entry (CPOE) clinical decision support system (CDSS) versus a CDSS with alerts made to dispensing pharmacists. This was a retrospective analysis of patients with renal impairment and 30 medications that are contraindicated or require dose-adjustment in such patients. The primary outcome was the rate of renal dosing errors for study medications that were dispensed between August and December 2013, when a pharmacist-based CDSS was in place, versus August through December 2014, when a prescriber-based CDSS was in place. A dosing error was defined as a prescription for one of the study medications dispensed to a patient where the medication was contraindicated or improperly dosed based on the patient's renal function. The denominator was all prescriptions for the study medications dispensed during each respective study period. During the pharmacist- and prescriber-based CDSS study periods, 49,054 and 50,678 prescriptions, respectively, were dispensed for one of the included medications. Of these, 878 (1.8%) and 758 (1.5%) prescriptions were dispensed to patients with renal impairment in the respective study periods. Patients in each group were similar with respect to age, sex, and renal function stage. Overall, the five-month error rate was 0.38%. Error rates were similar between the two groups: 0.36% and 0.40% in the pharmacist- and prescriber-based CDSS, respectively (p=0.523). The medication with the highest error rate was dofetilide (0.51% overall) while the medications with the lowest error rate were dabigatran, fondaparinux, and spironolactone (0.00% overall). Prescriber- and pharmacist-based CDSS provided comparable, low rates of potential medication errors. Future studies should be undertaken to examine patient benefits of the prescriber-based CDSS.

  10. Drug transport and transport-metabolism interplay in the human and rat intestine : ex vivo studies with precision-cut intestinal slices

    NARCIS (Netherlands)

    Li, Ming

    2016-01-01

    The intestine plays an important role in uptake and metabolism of physiological, but also xenobiotic compounds, such as medical drugs. This function is supported by specialized transporters and metabolic enzymes. Together these proteins determine the concentration of compounds in intestinal cells an

  11. In vitro drug response and efflux transporters associated with drug resistance in pediatric high grade glioma and diffuse intrinsic pontine glioma.

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    Susanna J E Veringa

    Full Text Available Pediatric high-grade gliomas (pHGG, including diffuse intrinsic pontine gliomas (DIPG, are the leading cause of cancer-related death in children. While it is clear that surgery (if possible, and radiotherapy are beneficial for treatment, the role of chemotherapy for these tumors is still unclear. Therefore, we performed an in vitro drug screen on primary glioma cells, including three DIPG cultures, to determine drug sensitivity of these tumours, without the possible confounding effect of insufficient drug delivery. This screen revealed a high in vitro cytotoxicity for melphalan, doxorubicine, mitoxantrone, and BCNU, and for the novel, targeted agents vandetanib and bortezomib in pHGG and DIPG cells. We subsequently determined the expression of the drug efflux transporters P-gp, BCRP1, and MRP1 in glioma cultures and their corresponding tumor tissues. Results indicate the presence of P-gp, MRP1 and BCRP1 in the tumor vasculature, and expression of MRP1 in the glioma cells themselves. Our results show that pediatric glioma and DIPG tumors per se are not resistant to chemotherapy. Treatment failure observed in clinical trials, may rather be contributed to the presence of drug efflux transporters that constitute a first line of drug resistance located at the blood-brain barrier or other resistance mechanism. As such, we suggest that alternative ways of drug delivery may offer new possibilities for the treatment of pediatric high-grade glioma patients, and DIPG in particular.

  12. Fractional derivatives in the transport of drugs across biological materials and human skin

    Science.gov (United States)

    Caputo, Michele; Cametti, Cesare

    2016-11-01

    The diffusion of drugs across a composite structure such as a biological membrane is a rather complex phenomenon, because of its inhomogeneous nature, yielding a diffusion rate and a drug solubility strongly dependent on the local position across the membrane itself. These problems are particularly strengthened in composite structures of a considerable thickness like, for example, the human skin, where the high heterogeneity provokes the transport through different simultaneous pathways. In this note, we propose a generalization of the diffusion model based on Fick's 2nd equation by substituting a diffusion constant by means of the memory formalism approach (diffusion with memory). In particular, we employ two different definitions of the fractional derivative, i.e., the usual Caputo fractional derivative and a new definition recently proposed by Caputo and Fabrizio. The model predictions have been compared to experimental results concerning the permeation of two different compounds through human skin in vivo, such as piroxicam, an anti-inflammatory drug, and 4-cyanophenol, a test chemical model compound. Moreover, we have also considered water penetration across human stratum corneum and the diffusion of an antiviral agent employed as model drugs across the skin of male hairless rats. In all cases, a satisfactory good agreement based on the diffusion with memory has been found. However, the model based on the new definition of fractional derivative gives a better description of the experimental data, on the basis of the residuals analysis. The use of the new definition widens the applicability of the fractional derivative to diffusion processes in highly heterogeneous systems.

  13. Drug-induced haemolysis, renal failure, thrombocytopenia and lactic acidosis in patients with HIV and cryptococcal meningitis: a diagnostic challenge.

    Science.gov (United States)

    Camara-Lemarroy, Carlos R; Flores-Cantu, Hazael; Calderon-Hernandez, Hector J; Diaz-Torres, Marco A; Villareal-Velazquez, Hector J

    2015-12-01

    Patients with HIV are at risk of both primary and secondary haematological disorders. We report two cases of patients with HIV and cryptococcal meningitis who developed severe haemolytic anaemia, thrombocytopenia, renal failure and lactic acidosis while on treatment with amphotericin B and co-trimoxazole.

  14. Recapitulation of complex transport and action of drugs at the tumor microenvironment using tumor-microenvironment-on-chip.

    Science.gov (United States)

    Han, Bumsoo; Qu, Chunjing; Park, Kinam; Konieczny, Stephen F; Korc, Murray

    2016-09-28

    Targeted delivery aims to selectively distribute drugs to targeted tumor tissues but not to healthy tissues. This can address many clinical challenges by maximizing the efficacy but minimizing the toxicity of anti-cancer drugs. However, a complex tumor microenvironment poses various barriers hindering the transport of drugs and drug delivery systems. New tumor models that allow for the systematic study of these complex environments are highly desired to provide reliable test beds to develop drug delivery systems for targeted delivery. Recently, research efforts have yielded new in vitro tumor models, the so called tumor-microenvironment-on-chip, that recapitulate certain characteristics of the tumor microenvironment. These new models show benefits over other conventional tumor models, and have the potential to accelerate drug discovery and enable precision medicine. However, further research is warranted to overcome their limitations and to properly interpret the data obtained from these models. In this article, key features of the in vivo tumor microenvironment that are relevant to drug transport processes for targeted delivery were discussed, and the current status and challenges for developing in vitro transport model systems were reviewed.

  15. Modeling of drug and drug-encapsulated nanoparticle transport in patient-specific coronary artery walls to treat vulnerable plaques

    KAUST Repository

    Hossain, Shaolie S.

    2010-01-01

    The main objective of this work is to develop computational tools to support the design of a catheter-based local drug delivery system that uses nanoparticles as drug carriers in order to treat vulnerable plaques and diffuse atherosclerotic disease.

  16. Role of Transporters in Central Nervous System Drug Delivery and Blood-Brain Barrier Protection: Relevance to Treatment of Stroke

    Directory of Open Access Journals (Sweden)

    Hrvoje Brzica

    2017-03-01

    Full Text Available Ischemic stroke is a leading cause of morbidity and mortality in the United States. The only approved pharmacologic treatment for ischemic stroke is thrombolysis via recombinant tissue plasminogen activator (r-tPA. A short therapeutic window and serious adverse events (ie, hemorrhage, excitotoxicity greatly limit r-tPA therapy, which indicates an essential need to develop novel stroke treatment paradigms. Transporters expressed at the blood-brain barrier (BBB provide a significant opportunity to advance stroke therapy via central nervous system delivery of drugs that have neuroprotective properties. Examples of such transporters include organic anion–transporting polypeptides (Oatps and organic cation transporters (Octs. In addition, multidrug resistance proteins (Mrps are transporter targets in brain microvascular endothelial cells that can be exploited to preserve BBB integrity in the setting of stroke. Here, we review current knowledge on stroke pharmacotherapy and demonstrate how endogenous BBB transporters can be targeted for improvement of ischemic stroke treatment.

  17. Blood-brain barrier transport of drugs for the treatment of brain diseases.

    Science.gov (United States)

    Gabathuler, Reinhard

    2009-06-01

    The central nervous system is a sanctuary protected by barriers that regulate brain homeostasis and control the transport of endogenous compounds into the brain. The blood-brain barrier, formed by endothelial cells of the brain capillaries, restricts access to brain cells allowing entry only to amino acids, glucose and hormones needed for normal brain cell function and metabolism. This very tight regulation of brain cell access is essential for the survival of neurons which do not have a significant capacity to regenerate, but also prevents therapeutic compounds, small and large, from reaching the brain. As a result, various strategies are being developed to enhance access of drugs to the brain parenchyma at therapeutically meaningful concentrations to effectively manage disease.

  18. Expression of the mammalian renal peptide transporter PEPT2 in the yeast Pichia pastoris and applications of the yeast system for functional analysis.

    Science.gov (United States)

    Döring, F; Michel, T; Rösel, A; Nickolaus, M; Daniel, H

    1998-01-01

    It has recently been identified the PEPT2 cDNA encodes the high affinity proton-coupled peptide transporter in rabbit kidney cortex. PEPT2 represents a 729 amino acid protein with 12 putative transmembrane domains that mediates H+/H3O+ dependent electrogenic transmembrane transport of di- and tripeptides and of selected peptidomimetics. Here the functional expression of PEPT2 in the methylotropic yeast Pichia pastoris is described under the control of a methanol inducible promoter. Western blot analysis of Pichia cell membranes prepared from a recombinant clone identified a protein with an apparent molecular mass of about 85-87 kDa. Peptide uptake into cells expressing PEPT2 was up to 80 times higher than in control cells. Cells of recombinant clones showed a saturable peptide transport activity for the hydrolysis resistant dipeptide 3H-D-Phe-Ala with an app. K0.5 of 0.143 +/- 0.016 mM. Inhibition of 3H-D-Phe-Ala uptake by selected di- and tripeptides and beta-lactam antibiotics revealed the same substrate specificity as obtained in renal membrane vesicles or for PEPT2 when expressed in Xenopus laevis oocytes. A novel fluorescence based assay for assessing transport function based on a coumarin-labeled fluorescent peptide analogue has also been developed. Moreover, using a histidyl auxotrophe strain a PEPT2 expressing cell clone in which transport function can be monitored by a simple yeast growth test was established. In conclusion, this is one of only a few reports on successful functional expression of mammalian membrane transport proteins in yeast. The high expression level will provide a simple means for future studies either on the structure-affinity relationship for substrate interaction with PEPT2 or for selection of mutants generated by random mutagenesis.

  19. Effect of cationized gelatins on the paracellular transport of drugs through caco-2 cell monolayers.

    Science.gov (United States)

    Seki, Toshinobu; Kanbayashi, Hiroshi; Nagao, Tomonobu; Chono, Sumio; Tabata, Yasuhiko; Morimoto, Kazuhiro

    2006-06-01

    Cationized gelatins, candidate absorption enhancers, were prepared by addition of ethylenediamine or spermine to gelatin and the effects of the resulting ethylenediaminated gelatin (EG) and sperminated gelatin (SG) on the paracellular transport of 5(6)-carboxyfluorescein (CF), FITC-dextran-4 (FD4), and insulin through caco-2 cell monolayers were examined. The Renkin function was used for characterization of the paracellular pathway and changes in the pore radius (R) and pore occupancy/length ratio (epsilon/L) calculated from the apparent permeability coefficients (P(app)) of CF and FD4 are discussed. Ethylenediaminetetraacetic acid (EDTA) increased the R of the caco-2 cell monolayer and the P(app) of all compounds examined was markedly increased by the addition of EDTA. On the other hand, EG and SG did not increase R and their enhancing effects were not as strong as those of EDTA. The increase in epsilon/L could be the enhancing mechanism for the cationized gelatins. The number of pathways for water-soluble drugs, such as CF and FD4, in the caco-2 monolayers could be increased by the addition of the cationized gelatins. The ratios of the permeability coefficients of insulin (observed/calculated based on the Renkin function) suggest that insulin undergoes enzymatic degradation during transport which is not inhibited by enhancers.

  20. Flavonoid-mediated inhibition of intestinal ABC transporters may affect the oral bioavailability of drugs, food-borne toxic compounds and bioactive ingredients

    NARCIS (Netherlands)

    Brand, W.; Schutte, M.E.; Bladeren, van P.J.; Rietjens, I.M.C.M.

    2006-01-01

    The transcellular transport of ingested food ingredients across the intestinal epithelial barrier is an important factor determining bioavailability upon oral intake. This transcellular transport of many chemicals, food ingredients, drugs or toxic compounds over the intestinal epithelium can be high

  1. Flavonoid-mediated inhibition of intestinal ABC transporters may affect the oral bioavailability of drugs, food-borne toxic compounds and bioactive ingredients

    NARCIS (Netherlands)

    Brand, W.; Schutte, M.E.; Bladeren, van P.J.; Rietjens, I.M.C.M.

    2006-01-01

    The transcellular transport of ingested food ingredients across the intestinal epithelial barrier is an important factor determining bioavailability upon oral intake. This transcellular transport of many chemicals, food ingredients, drugs or toxic compounds over the intestinal epithelium can be high

  2. Dipeptidomimetic ketomethylene isosteres as pro-moieties for drug transport via the human intestinal di-/tripeptide transporter hPEPT1

    DEFF Research Database (Denmark)

    Våbenø, Jon; Nielsen, Carsten Uhd; Ingebrigtsen, Truls

    2004-01-01

    . The stability, the affinity for the di-/tripeptide transporter hPEPT1, and the transepithelial transport properties of the model prodrugs were investigated. ValPsi[COCH(2)]Asp(OBn) was the compound with highest chemical stability in buffers at pH 6.0 and 7.4, with half-lives of 190 and 43 h, respectively. All......Five dipeptidomimetic-based model prodrugs containing ketomethylene amide bond replacements were synthesized from readily available alpha,beta-unsaturated gamma-ketoesters. The model drug (BnOH) was attached to the C-terminus or to one of the side chain positions of the dipeptidomimetic...... five compounds showed high affinity for hPEPT1 (K(i) values transport component was demonstrated for the transepithelial transport of three...

  3. Sodium glucose co-transporter inhibitors – A new class of old drugs

    Science.gov (United States)

    Malhotra, Aneeta; Kudyar, Surbhi; Gupta, Anil K.; Kudyar, Rattan P.; Malhotra, Pavan

    2015-01-01

    Sodium glucose co-transporter (SGLT) inhibitors are a new class of drugs which are used in the pharmacotherapy of Type-II diabetes, which happens to be a major risk factor for developing both micro as well as macro-vascular complications. These drugs inhibit the glucose reabsorption by inhibiting SGLT, which exhibits a novel and promising mechanism of action by promoting the urinary glucose excretion hence providing a basis of therapeutic intervention. Results of SGLT-II inhibitors are very encouraging as there is a significant elevation of GLP-1 level, which forms the basis of relevance in treatment of diabetes. It targets the HbA1C and keeps a check on its levels. It also exerts other positive benefits such as weight loss, reduction in blood glucose levels, reduction in blood pressure and improvement in insulin resistance and β-cell dysfunction: All contributing to effective glycemic control. SGLT inhibition will develop as effective modality as it has the capability of inhibiting reabsorption of greater percentage of filtered glucose load. PMID:26539362

  4. A Combined Approach Using Transporter-Flux Assays and Mass Spectrometry to Examine Psychostimulant Street Drugs of Unknown Content

    OpenAIRE

    Rosenauer, Rudolf; Luf, Anton; Holy, Marion; Freissmuth, Michael; SCHMID, RAINER; Sitte, Harald H

    2012-01-01

    The illicit consumption of psychoactive compounds may cause short and long-term health problems and addiction. This is also true for amphetamines and cocaine, which target monoamine transporters. In the recent past, an increasing number of new compounds with amphetamine-like structure such as mephedrone or 3,4-methylenedioxypyrovalerone (MDPV) entered the market of illicit drugs. Subtle structural changes circumvent legal restrictions placed on the parent compound. These novel drugs are effec...

  5. Antibacterial drug treatment increases intestinal bile acid absorption via elevated levels of ileal apical sodium-dependent bile acid transporter but not organic solute transporter α protein.

    Science.gov (United States)

    Miyata, Masaaki; Hayashi, Kenjiro; Yamakawa, Hiroki; Yamazoe, Yasushi; Yoshinari, Kouichi

    2015-01-01

    Antibacterial drug treatment increases the bile acid pool size and hepatic bile acid concentration through the elevation of hepatic bile acid synthesis. However, the involvement of intestinal bile acid absorption in the increased bile acid pool size remains unclear. To determine whether intestinal bile acid absorption contributes to the increased bile acid pool in mice treated with antibacterial drugs, we evaluated the levels of bile acid transporter proteins and the capacity of intestinal bile acid absorption. Ileal apical sodium-dependent bile acid transporter (ASBT) mRNA and protein levels were significantly increased in ampicillin (ABPC)-treated mice, whereas organic solute transporter α (OSTα) mRNA levels, but not protein levels, significantly decreased in mice. Similar alterations in the expression levels of bile acid transporters were observed in mice treated with bacitracin/neomycin/streptomycin. The capacity for intestinal bile acid absorption was evaluated by an in situ loop method. Increased ileal absorption of taurochenodeoxycholic acid was observed in mice treated with ABPC. These results suggest that intestinal bile acid absorption is elevated in an ASBT-dependent manner in mice treated with antibacterial drugs.

  6. Non-steroidal anti-inflammatory drugs affect the methotrexate transport in IEC-6 cells.

    Science.gov (United States)

    Sosogi, Aiko; Gao, Feng; Tomimatsu, Takashi; Hirata, Koji; Horie, Toshiharu

    2003-06-13

    Methotrexate (MTX) is used not only for the cancer chemotherapy but also for the treatment of rheumatic disease, often together with non-steroidal anti-inflammatory drugs (NSAIDs). MTX is actively cotransported with H(+) in the small intestine, mediated by a reduced folate carrier (RFC). The coadministration of some NSAIDs with MTX to rats caused a decrease of MTX absorption through the small intestine. This may be due to the uncoupling effect of oxidative phosphorylation of the NSAIDs. The present study investigated whether flufenamic acid, diclofenac and indomethacin, NSAIDs, decreased ATP content of rat-derived intestinal epithelial cell line IEC-6 cells and affected the MTX transport in IEC-6 cells. The MTX uptake in IEC-6 cells was dependent on medium pH and maximum around pH 4.5-5.5. The MTX uptake was composed of a transport inhibited by 4, 4'-diisothiocyanostilbene-2, 2'-disulfonic acid (DIDS) and a non-saturable one. The DIDS-sensitive component in the MTX uptake showed a saturation kinetics (Michaelis-Menten constant (Km): 3.91 +/- 0.52 microM, Maximum velocity (Vmax): 94.66 +/- 6.56 pmol/mg protein/5 min). The cellular ATP content in IEC-6 cells decreased significantly at 30 min after the cells were started to incubate with the NSAIDs (250 microM flufenamic acid, 500 microM diclofenac and 500 microM indomethacin). The MTX uptake in IEC-6 cells in the presence of the NSAIDs decreased with the reduction of cellular ATP content and showed a good correlation with the ATP content (correlation coefficient: 0.982). Thus it seems likely that the ATP content in IEC-6 cells with the NSAIDs decreased due to the uncoupling effect of oxidative phosphorylation of the NSAIDs, resulting in the inhibition of the secondary active transport of MTX in IEC-6 cells. The present results also suggest that IEC-6 cells are useful to evaluate the drug interaction relating to this carrier system.

  7. Trauma renal Renal trauma

    Directory of Open Access Journals (Sweden)

    Gerson Alves Pereira Júnior

    1999-02-01

    Full Text Available Apresentamos uma revisão sobre trauma renal, com ênfase na avaliação radiológica, particularmente com o uso da tomografia computadorizada, que tem se tornado o exame de eleição, ao invés da urografia excretora e arteriografia. O sucesso no tratamento conservador dos pacientes com trauma renal depende de um acurado estadiamento da extensão da lesão, classificado de acordo com a Organ Injury Scaling do Colégio Americano de Cirurgiões. O tratamento conservador não-operatório é seguro e consiste de observação contínua, repouso no leito, hidratação endovenosa adequada e antibioti- coterapia profilática, evitando-se uma exploração cirúrgica desnecessária e possível perda renal. As indicações para exploração cirúrgica imediata são abdome agudo, rápida queda do hematócrito ou lesões associadas determinadas na avaliação radiológica. Quando indicada, a exploração renal após controle vascular prévio é segura, permitindo cuidadosa inspeção do rim e sua reconstrução com sucesso, reduzindo a probabilidade de nefrectomia.We present a revision of the renal trauma with emphasis in the radiographic evaluation, particularly CT scan that it has largely replaced the excretory urogram and arteriogram in the diagnostic worh-up and management of the patient with renal trauma. The successful management of renal injuries depends upon the accurate assessment of their extent in agreement with Organ Injury Scaling classification. The conservative therapy managed by careful continuous observation, bed rest, appropriate fluid ressuscitation and prophylactic antibiotic coverage after radiographic staging for severely injured kidneys can yield favorable results and save patients from unnecessary exploration and possible renal loss. The indications for immediate exploratory laparotomy were acute abdomen, rapidly dropping hematocrit or associated injuries as determinated from radiologic evaluation. When indicated, renal exploration

  8. Are elderly end-stage renal disease patients more susceptible for drug resistant organisms in their sputum?

    OpenAIRE

    2010-01-01

    End stage renal disease (ESRD) patients are at risk for pneumonia in view of their impaired immune status. Similar empiric antibiotic regimens are used in elderly as well as young ESRD patients with respiratory tract infections. We conducted an observational, cross sectional study between June 2007 and June 2008 in 100 ESRD patients half being > 65 yrs. All patients had positive sputum culture and chest X-ray findings of pneumonia Streptococcus pneumoniae was the commonest in younger while...

  9. The Signature Sequence Region of the Human Drug Transporter Organic Anion Transporting Polypeptide 1B1 Is Important for Protein Surface Expression

    Directory of Open Access Journals (Sweden)

    Jennina Taylor-Wells

    2014-01-01

    Full Text Available The organic anion transporting polypeptides (OATPs encompass a family of membrane transport proteins responsible for the uptake of xenobiotic compounds. Human organic anion transporting polypeptide 1B1 (OATP1B1 mediates the uptake of clinically relevant compounds such as statins and chemotherapeutic agents into hepatocytes, playing an important role in drug delivery and detoxification. The OATPs have a putative 12-transmembrane domain topology and a highly conserved signature sequence (human OATP1B1: DSRWVGAWWLNFL, spanning the extracellular loop 3/TM6 boundary. The presence of three conserved tryptophan residues at the TM interface suggests a structural role for the sequence. This was investigated by site-directed mutagenesis of selected amino acids within the sequence D251E, W254F, W258/259F, and N261A. Transport was measured using the substrate estrone-3-sulfate and surface expression detected by luminometry and confocal microscopy, facilitated by an extracellular FLAG epitope. Uptake of estrone-3-sulfate and the surface expression of D251E, W254F, and W258/259F were both significantly reduced from the wild type OATP1B1-FLAG in transfected HEK293T cells. Confocal microscopy revealed that protein was produced but was retained intracellularly. The uptake and expression of N261A were not significantly different. The reduction in surface expression and intracellular protein retention indicates a structural and/or membrane localization role for these signature sequence residues in the human drug transporter OATP1B1.

  10. The Signature Sequence Region of the Human Drug Transporter Organic Anion Transporting Polypeptide 1B1 Is Important for Protein Surface Expression.

    Science.gov (United States)

    Taylor-Wells, Jennina; Meredith, David

    2014-01-01

    The organic anion transporting polypeptides (OATPs) encompass a family of membrane transport proteins responsible for the uptake of xenobiotic compounds. Human organic anion transporting polypeptide 1B1 (OATP1B1) mediates the uptake of clinically relevant compounds such as statins and chemotherapeutic agents into hepatocytes, playing an important role in drug delivery and detoxification. The OATPs have a putative 12-transmembrane domain topology and a highly conserved signature sequence (human OATP1B1: DSRWVGAWWLNFL), spanning the extracellular loop 3/TM6 boundary. The presence of three conserved tryptophan residues at the TM interface suggests a structural role for the sequence. This was investigated by site-directed mutagenesis of selected amino acids within the sequence D251E, W254F, W258/259F, and N261A. Transport was measured using the substrate estrone-3-sulfate and surface expression detected by luminometry and confocal microscopy, facilitated by an extracellular FLAG epitope. Uptake of estrone-3-sulfate and the surface expression of D251E, W254F, and W258/259F were both significantly reduced from the wild type OATP1B1-FLAG in transfected HEK293T cells. Confocal microscopy revealed that protein was produced but was retained intracellularly. The uptake and expression of N261A were not significantly different. The reduction in surface expression and intracellular protein retention indicates a structural and/or membrane localization role for these signature sequence residues in the human drug transporter OATP1B1.

  11. Raltegravir permeability across blood-tissue barriers and the potential role of drug efflux transporters.

    Science.gov (United States)

    Hoque, M Tozammel; Kis, Olena; De Rosa, María F; Bendayan, Reina

    2015-05-01

    The objectives of this study were to investigate raltegravir transport across several blood-tissue barrier models and the potential interactions with drug efflux transporters. Raltegravir uptake, accumulation, and permeability were evaluated in vitro in (i) P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), multidrug resistance-associated protein 1 (MRP1), or MRP4-overexpressing MDA-MDR1 (P-gp), HEK-ABCG2, HeLa-MRP1, or HEK-MRP4 cells, respectively; (ii) cell culture systems of the human blood-brain (hCMEC/D3), mouse blood-testicular (TM4), and human blood-intestinal (Caco-2) barriers; and (iii) rat jejunum and ileum segments using an in situ single-pass intestinal perfusion model. [(3)H]Raltegravir accumulation by MDA-MDR1 (P-gp) and HEK-ABCG2-overexpressing cells was significantly enhanced in the presence of PSC833 {6-[(2S,4R,6E)-4-methyl-2-(methylamino)-3-oxo-6-octenoic acid]-7-L-valine-cyclosporine}, a P-gp inhibitor, or Ko143 [(3S,6S,12aS)-1,2,3,4,6,7,12,12a-octahydro-9-methoxy-6-(2-methylpropyl)-1,4-dioxopyrazino[1',2':1,6]pyrido[3,4-b]indole-3-propanoic acid 1,1-dimethylethyl ester], a BCRP inhibitor, suggesting the inhibition of a P-gp- or BCRP-mediated efflux process, respectively. Furthermore, [(3)H]raltegravir accumulation by human cerebral microvessel endothelial hCMEC/D3 and mouse Sertoli TM4 cells was significantly increased by PSC833 and Ko143. In human intestinal Caco-2 cells grown on Transwell filters, PSC833, but not Ko143, significantly decreased the [(3)H]raltegravir efflux ratios. In rat intestinal segments, [(3)H]raltegravir in situ permeability was significantly enhanced by the concurrent administration of PSC833 and Ko143. In contrast, in the transporter inhibition assays, raltegravir (10 to 500 μM) did not increase the accumulation of substrate for P-gp (rhodamine-6G), BCRP ([(3)H]mitoxantrone), or MRP1 [2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF)] by MDA-MDR1 (P-gp)-, HEK-ABCG2-, or HeLa-MRP1-overexpressing

  12. Renal arteriography

    Science.gov (United States)

    ... Read More Acute arterial occlusion - kidney Acute kidney failure Aneurysm Atheroembolic renal disease Blood clots Renal cell carcinoma Renal venogram X-ray Review Date 1/5/2016 Updated by: Jason Levy, ...

  13. H+, Water and Urea Transport in the Inner Medullary Collecting Duct and Their Role in the Prevention and Pathogenesis of Renal Stone Disease

    Science.gov (United States)

    Wall, Susan M.; Klein, Janet D.

    2008-09-01

    The inner medullary collecting duct (IMCD) is the final site within the kidney for the reabsorption of urea, water and electrolytes and for the secretion of H+ before the luminal fluid becomes the final urine. Transporters expressed in the IMCD contribute to the generation of the large ion gradients that exist between the interstitium and the collecting duct lumen. Thus, the luminal fluid within the human IMCD can reach an osmolality of 1200 mOsm/kg H2O and a pH of 4. This ability of the human nephron to concentrate and acidify the urine might predispose to stone formation. However, under treatment conditions that predispose to stone formation, such as during hypercalciuria, the kidney mitigates stone formation by reducing solute concentration by reducing H2O reabsorption. Moreover, the kidney attenuates stone formation by tightly controlling acid-base balance, which prevents the bone loss, hypocitraturia and hypercalciuria observed during metabolic acidosis by augmenting net H+ excretion by tightly regulating H+ transporter function and through luminal buffering, particularly with NH3. This article will review the ion transporters present in the mammalian IMCD and their role in the prevention and in the pathogenesis of renal stone formation.

  14. Highlights From the American Association of Pharmaceutical Scientists/ International Transporter Consortium Joint Workshop on Drug Transporters in Absorption, Distribution, Metabolism, and Excretion: From the Bench to the Bedside - Clinical Pharmacology Considerations.

    Science.gov (United States)

    Ronaldson, P T; Bauer, B; El-Kattan, A F; Shen, H; Salphati, L; Louie, S W

    2016-11-01

    The American Association of Pharmaceutical Scientists/International Transporter Consortium Joint Workshop on Drug Transporters in absorption, distribution, metabolism, and excretion was held with the objective of discussing innovative advances in transporter pharmacology. Specific topics included (i) transporters at the blood-brain barrier (BBB); (ii) emerging transport proteins; (iii) recent advances in achieving hepatoselectivity and optimizing clearance for organic anion-transporting polypeptide (OATP) substrates; (iv) utility of animal models for transporter studies; and (v) clinical correlation of transporter polymorphisms. Here, we present state-of-the-art highlights from this workshop in these key areas of focus.

  15. Ion channels and transporters in the development of drug resistance in cancer cells

    DEFF Research Database (Denmark)

    Hoffmann, Else Kay; Lambert, Ian Henry

    2014-01-01

    Multi-drug resistance (MDR) to chemotherapy is the major challenge in the treatment of cancer. MDR can develop by numerous mechanisms including decreased drug uptake, increased drug efflux and the failure to undergo drug-induced apoptosis. Evasion of drug-induced apoptosis through modulation of ion...

  16. Quantitative evaluation of the combination between cytotoxic drug and efflux transporter inhibitors based on a tumour growth inhibition model.

    Science.gov (United States)

    Sostelly, Alexandre; Payen, Léa; Guitton, Jérôme; Di Pietro, Attilio; Falson, Pierre; Honorat, Mylène; Boumendjel, Ahcène; Gèze, Annabelle; Freyer, Gilles; Tod, Michel

    2014-04-01

    ATP-Binding Cassette transporters such as ABCG2 confer resistance to various anticancer drugs including irinotecan and its active metabolite, SN38. Early quantitative evaluation of efflux transporter inhibitors-cytotoxic combination requires quantitative drug-disease models. A proof-of-concept study has been carried out for studying the effect of a new ABCG2 transporter inhibitor, MBLI87 combined to irinotecan in mice xenografted with cells overexpressing ABCG2. Mice were treated with irinotecan alone or combined to MBLI87, and tumour size was periodically measured. To model those data, a tumour growth inhibition model was developed. Unperturbed tumour growth was modelled using Simeoni's model. Drug effect kinetics was accounted for by a Kinetic-Pharmacodynamic approach. Effect of inhibitor was described with a pharmacodynamic interaction model where inhibitor enhances activity of cytotoxic. This model correctly predicted tumour growth dynamics from our study. MBLI87 increased irinotecan potency by 20% per μmol of MBLI87. This model retains enough complexity to simultaneously describe tumour growth and effect of this type of drug combination. It can thus be used as a template to early evaluate efflux transporter inhibitors in-vivo.

  17. Inhibition of bile salt transport by drugs associated with liver injury in primary hepatocytes from human, monkey, dog, rat, and mouse.

    Science.gov (United States)

    Zhang, Jie; He, Kan; Cai, Lining; Chen, Yu-Chuan; Yang, Yifan; Shi, Qin; Woolf, Thomas F; Ge, Weigong; Guo, Lei; Borlak, Jürgen; Tong, Weida

    2016-08-05

    Interference of bile salt transport is one of the underlying mechanisms for drug-induced liver injury (DILI). We developed a novel bile salt transport activity assay involving in situ biosynthesis of bile salts from their precursors in primary human, monkey, dog, rat, and mouse hepatocytes in suspension as well as LC-MS/MS determination of extracellular bile salts transported out of hepatocytes. Glycine- and taurine-conjugated bile acids were rapidly formed in hepatocytes and effectively transported into the extracellular medium. The bile salt formation and transport activities were time‒ and bile-acid-concentration‒dependent in primary human hepatocytes. The transport activity was inhibited by the bile salt export pump (BSEP) inhibitors ketoconazole, saquinavir, cyclosporine, and troglitazone. The assay was used to test 86 drugs for their potential to inhibit bile salt transport activity in human hepatocytes, which included 35 drugs associated with severe DILI (sDILI) and 51 with non-severe DILI (non-sDILI). Approximately 60% of the sDILI drugs showed potent inhibition (with IC50 values drugs showed this strength of inhibition in primary human hepatocytes and these drugs are associated only with cholestatic and mixed hepatocellular cholestatic (mixed) injuries. The sDILI drugs, which did not show substantial inhibition of bile salt transport activity, are likely to be associated with immune-mediated liver injury. Twenty-four drugs were also tested in monkey, dog, rat and mouse hepatocytes. Species differences in potency were observed with mouse being less sensitive than other species to inhibition of bile salt transport. In summary, a novel assay has been developed using hepatocytes in suspension from human and animal species that can be used to assess the potential for drugs and/or drug-derived metabolites to inhibit bile salt transport and/or formation activity. Drugs causing sDILI, except those by immune-mediated mechanism, are highly associated with potent

  18. Dietary Intake as a Link between Obesity, Systemic Inflammation, and the Assumption of Multiple Cardiovascular and Antidiabetic Drugs in Renal Transplant Recipients

    Directory of Open Access Journals (Sweden)

    Bruna Guida

    2013-01-01

    Full Text Available We evaluated dietary intake and nutritional-inflammation status in ninety-six renal transplant recipients, years after transplantation. Patients were classified as normoweight (NW, overweight (OW, and obese (OB, if their body mass index was between 18.5 and 24.9, 25.0 and 29.9, and ≥30 kg/m2, respectively. Food composition tables were used to estimate nutrient intakes. The values obtained were compared with those recommended in current nutritional guidelines. 52% of the patients were NW, 29% were OW, and 19% were OB. Total energy, fat, and dietary n-6 PUFAs intake was higher in OB than in NW. IL-6 and hs-CRP were higher in OB than in NW. The prevalence of multidrug regimen was higher in OB. In all patients, total energy, protein, saturated fatty acids, and sodium intake were higher than guideline recommendations. On the contrary, the intake of unsaturated and n-6 and n-3 polyunsaturated fatty acids and fiber was lower than recommended. In conclusion, the prevalence of obesity was high in our patients, and it was associated with inflammation and the assumption of multiple cardiovascular and antidiabetic drugs. Dietary intake did not meet nutritional recommendations in all patients, especially in obese ones, highlighting the need of a long-term nutritional support in renal transplant recipients.

  19. A Drosophila model to identify polyamine-drug conjugates that target the polyamine transporter in an intact epithelium.

    Science.gov (United States)

    Tsen, Chung; Iltis, Mark; Kaur, Navneet; Bayer, Cynthia; Delcros, Jean-Guy; von Kalm, Laurence; Phanstiel, Otto

    2008-01-24

    Polyamine transport is elevated in many tumor types, suggesting that toxic polyamine-drug conjugates could be targeted to cancer cells via the polyamine transporter (PAT). We have previously reported the use of Chinese hamster ovary (CHO) cells and its PAT-deficient mutant cell line, CHO-MG, to screen anthracene-polyamine conjugates for their PAT-selective targeting ability. We report here a novel Drosophila-based model for screening anthracene-polyamine conjugates in a developing and intact epithelium ( Drosophila imaginal discs), wherein cell-cell adhesion properties are maintained. Data from the Drosophila assay are consistent with previous results in CHO cells, indicating that the Drosophila epithelium has a PAT with vertebrate-like characteristics. This assay will be of use to medicinal chemists interested in screening drugs that use PAT for cellular entry, and it offers the possibility of genetic dissection of the polyamine transport process, including identification of a Drosophila PAT.

  20. Drug interactions with HMG-CoA reductase inhibitors (statins): the importance of CYP enzymes, transporters and pharmacogenetics.

    Science.gov (United States)

    Neuvonen, Pertti J

    2010-03-01

    HMG-CoA reductase inhibitors (statins) can cause skeletal muscle toxicity; the risk of toxicity is elevated by drug interactions and pharmacogenetic factors that increase the concentration of statins in the plasma. Statins are substrates for several membrane transporters that may mediate drug interactions. Inhibitors of the organic anion transporting polypeptide 1B1 can decrease the hepatic uptake of many statins, as well as the therapeutic index of these agents. Potent inhibitors of cytochrome P450 (CYP)3A4 can significantly increase the plasma concentrations of the active forms of simvastatin, lovastatin and atorvastatin. Fluvastatin, which is metabolized by CYP2C9, is less prone to pharmacokinetic interactions, while pravastatin, rosuvastatin and pitavastatin are not susceptible to any CYP inhibition. An understanding of the mechanisms of statin interactions will help to minimize drug interactions and to develop statins that are less prone to adverse interactions.

  1. Interaction of nonsteroidal anti-inflammatory drugs with multidrug resistance protein (MRP) 2/ABCC2- and MRP4/ABCC4-mediated methotrexate transport

    NARCIS (Netherlands)

    El-Sheikh, A.A.K.; Heuvel, J.J.M.W. van den; Koenderink, J.B.; Russel, F.G.M.

    2007-01-01

    Methotrexate (MTX) has been used in combination with nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of inflammatory diseases as well as malignancies. Especially at high MTX dosages, severe adverse effects with this combination may occur, usually resulting from an impaired renal elimi

  2. High-quality genotyping data from formalin-fixed, paraffin-embedded tissue on the drug metabolizing enzymes and transporters plus array

    NARCIS (Netherlands)

    Vos, H.I.; Straaten, T. van der; Coenen, M.J.H.; Flucke, U.E.; Loo, D.M.W.M. te; Guchelaar, H.J.

    2015-01-01

    The Affymetrix Drug Metabolizing Enzymes and Transporters (DMET) Plus array covers 1936 markers in 231 genes involved in drug metabolism and transport. Blood- and saliva-derived DNA works well on the DMET array, but the utility of DNA from FFPE tissue has not been reported for this array. As the abi

  3. Renal responses to long-term carotid baroreflex activation therapy in patients with drug-resistant hypertension.

    Science.gov (United States)

    Alnima, Teba; de Leeuw, Peter W; Tan, Frans E S; Kroon, Abraham A

    2013-06-01

    Carotid baroreflex activation has been demonstrated to provide enduring reductions in arterial blood pressure. The aim of this study was to investigate the effect of long-term therapy on renal function. A total of 322 patients were enrolled in the Rheos Pivotal Trial. Group 1 consisted of 236 patients who started baroreflex activation therapy 1 month after device implantation, whereas in the 86 patients from group 2 the device was activated 6 months later. Serum creatinine and urine albumin/creatinine ratio were collected at screening (before device activation), and at months 6 and 12. Multilevel statistical analyses were adjusted for various covariables. Serum creatinine increased from 78 to 84 μmol/L, and glomerular filtration rate decreased from 92 to 87 mL/min per 1.73 m(2) in group 1 at month 6 (Pblood pressure reduction seemed to be significantly related to the change in glomerular filtration rate in both groups. Albumin/creatinine ratio did not change in both groups during follow-up. In conclusion, baroreflex activation therapy in hypertensive patients is associated with an initial mild decrease in glomerular filtration rate, which may be considered as a normal hemodynamic response to the drop in blood pressure. Long-term treatment does not result in further decrease in renal function, indicating baroreflex activation as a safe and effective therapy.

  4. A short update on the structure of drug binding sites on neurotransmitter transporters

    Directory of Open Access Journals (Sweden)

    Gabrielsen Mari

    2011-12-01

    Full Text Available Abstract Background The dopamine (DAT, noradrenalin (NET and serotonin (SERT transporters are molecular targets for different classes of psychotropic drugs. Cocaine and the SSRI (S-citalopram block neurotransmitter reuptake competitively, but while cocaine is a non-selective reuptake inhibitor, (S-citalopram is a selective SERT inhibitor. Findings Here we present comparisons of the binding sites and the electrostatic potential surfaces (EPS of DAT, NET and SERT homology models based on two different LeuTAa templates; with a substrate (leucine in an occluded conformation (PDB id 2a65, and with an inhibitor (tryptophan in an open-to-out conformation (PDB id 3f3a. In the occluded homology models, two conserved aromatic amino acids (tyrosine and phenylalanine formed a gate between the putative binding pockets, and this contact was interrupted in the open to out conformation. The EPS of DAT and NET were generally negative in the vestibular area, whereas the EPS of the vestibular area of SERT was more neutral. Conclusions The findings presented here contribute as an update on the structure of the binding sites of DAT, NET and SERT. The updated models, which have larger ligand binding site areas than models based on other templates, may serve as improved tools for virtual ligand screening.

  5. Should we still focus that much on cardiovascular mortality in end stage renal disease patients? The CONvective TRAnsport STudy.

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    Claire H den Hoedt

    Full Text Available BACKGROUND: We studied the distribution of causes of death in the CONTRAST cohort and compared the proportion of cardiovascular deaths with other populations to answer the question whether cardiovascular mortality is still the principal cause of death in end stage renal disease. In addition, we compared patients who died from the three most common death causes. Finally, we aimed to study factors related to dialysis withdrawal. METHODS: We used data from CONTRAST, a randomized controlled trial in 714 chronic hemodialysis patients comparing the effects of online hemodiafiltration versus low-flux hemodialysis. Causes of death were adjudicated. The distribution of causes of death was compared to that of the Dutch dialysis registry and of the Dutch general population. RESULTS: In CONTRAST, 231 patients died on treatment. 32% died from cardiovascular disease, 22% due to infection and 23% because of dialysis withdrawal. These proportions were similar to those in the Dutch dialysis registry and the proportional cardiovascular mortality was similar to that of the Dutch general population. cardiovascular death was more common in patients <60 years. Patients who withdrew were older, had more co-morbidity and a lower mental quality of life at baseline. Patients who withdrew had much co-morbidity. 46% died within 5 days after the last dialysis session. CONCLUSIONS: Although the absolute risk of death is much higher, the proportion of cardiovascular deaths in a prevalent end stage renal disease population is similar to that of the general population. In older hemodialysis patients cardiovascular and non-cardiovascular death risk are equally important. Particularly the registration of dialysis withdrawal deserves attention. These findings may be partly limited to the Dutch population.

  6. Therapeutic drug monitoring of continuous-infusion acylovir for disseminated herpes simplex virus infection in a neonate receiving concurrent extracorporeal life support and continuous renal replacement therapy.

    Science.gov (United States)

    Cies, Jeffrey J; Moore, Wayne S; Miller, Kyle; Small, Christine; Carella, Dominick; Conley, Susan; Parker, Jason; Shea, Paul; Chopra, Arun

    2015-02-01

    Disseminated herpes simplex virus (HSV) infection in neonates represents a devastating entity that yields high mortality. Acyclovir is the primary antiviral agent used to treat life-threatening HSV infections in neonates; however, even though the agent has reduced morbidity overall from these infections, mortality with disseminated disease remains high. Currently, to our knowledge, no data exist regarding therapeutic drug monitoring of acyclovir in the setting of extracorporeal life support (ECLS) or continuous renal replacement therapy (CRRT) coupled with ECLS. We describe the case of a 14-day-old female with disseminated HSV-1 infection that progressed to fulminant hepatic and renal failure, necessitating the use of ECLS for hemodynamic support and CRRT as a treatment modality for hepatic and renal failure. The standard dosage of acyclovir 20 mg/kg/dose intravenously every 8 hours had been initiated, but after conversion to ECLS and CRRT, the patient's dosage was increased to 30 mg/kg/dose every 8 hours. After a repeat viral load remained unchanged from the initial viral load at 1 × 10(8)  copies/ml, the patient was transitioned from intermittent dosing to a continuous infusion of acyclovir added to the dialysate solution for CRRT at a concentration of 5.5 mg/L. To provide an optimal outcome, dosing was designed to maintain acyclovir plasma concentrations of at least 3 mg/L in order to maintain an acyclovir concentration of at least 1 mg/L in the cerebrospinal fluid. The patient's acyclovir serum concentrations measured at 24 and 72 hours after starting continuous-infusion acyclovir via the dialysate were 8.8 and 5.3 mg/L, respectively, allowing for a continuous serum concentration above 3 mg/L. Unfortunately, before a repeat viral load could be obtained to assess the efficacy of the continuous infusion acyclovir, the patient experienced an intracerebral hemorrhage as a complication related to ECLS after which technological support was withdrawn

  7. A bioartificial renal tubule device embedding human renal stem/progenitor cells.

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    Anna Giovanna Sciancalepore

    Full Text Available We present a bio-inspired renal microdevice that resembles the in vivo structure of a kidney proximal tubule. For the first time, a population of tubular adult renal stem/progenitor cells (ARPCs was embedded into a microsystem to create a bioengineered renal tubule. These cells have both multipotent differentiation abilities and an extraordinary capacity for injured renal cell regeneration. Therefore, ARPCs may be considered a promising tool for promoting regenerative processes in the kidney to treat acute and chronic renal injury. Here ARPCs were grown to confluence and exposed to a laminar fluid shear stress into the chip, in order to induce a functional cell polarization. Exposing ARPCs to fluid shear stress in the chip led the aquaporin-2 transporter to localize at their apical region and the Na(+K(+ATPase pump at their basolateral portion, in contrast to statically cultured ARPCs. A recovery of urea and creatinine of (20±5% and (13±5%, respectively, was obtained by the device. The microengineered biochip here-proposed might be an innovative "lab-on-a-chip" platform to investigate in vitro ARPCs behaviour or to test drugs for therapeutic and toxicological responses.

  8. Mechanisms of renal cell repair and regeneration after acute renal failure.

    Science.gov (United States)

    Nony, Paul A; Schnellmann, Rick G

    2003-03-01

    In many cases, acute renal failure (ARF) is the result of proximal tubular cell injury and death and can arise in a variety of clinical situations, especially following renal ischemia and drug or toxicant exposure. Although much research has focused on the cellular events leading to ARF, less emphasis has been placed on the mechanisms of renal cell repair and regeneration, although ARF is reversed in over half of those who acquire it. Studies using in vivo and in vitro models have demonstrated the importance of proliferation, migration, and repair of physiological functions of injured renal proximal tubular cells (RPTC) in the reversal of ARF. Growth factors have been shown to produce migration and proliferation of injured RPTC, although the specific mechanisms through which growth factors promote renal regeneration in vivo are unclear. Recently, interactions between integrins and extracellular matrix proteins such as collagen IV were shown to promote the repair of physiological functions in injured RPTC. Specifically, collagen IV synthesis and deposition following cellular injury restored integrin polarity and promoted repair of mitochondrial function and active Na(+) transport. Furthermore, exogenous collagen IV, but not collagen I, fibronectin, or laminin, promoted the repair of physiological functions without stimulating proliferation. These findings suggest the importance of establishing and/or maintaining collagen IV-integrin interactions in the stimulation of repair of physiological functions following sublethal cellular injury. Furthermore, the pathway that stimulates repair is distinct from that of proliferation and migration and may be a viable target for pharmacological intervention.

  9. Renal tuberculosis

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    Džamić Zoran

    2016-01-01

    Full Text Available Tuberculosis is still a significant health problem in the world, mostly in developing countries. The special significance lies in immunocompromised patients, particularly those suffering from the HIV. Urogenital tuberculosis is one of the most common forms of extrapulmonary tuberculosis, while the most commonly involved organ is the kidney. Renal tuberculosis occurs by hematogenous dissemination of mycobacterium tuberculosis from a primary tuberculosis foci in the body. Tuberculosis is characterized by the formation of pathognomonic lesions in the tissues - granulomata. These granulomata may heal spontaneously or remain stable for years. In certain circumstances in the body associated with immunosuppression, the disease may be activated. Central caseous necrosis occurs within tuberculoma, leading to formation of cavities that destroy renal parenchyma. The process may gain access to the collecting system, forming the caverns. In this way, infection can be spread distally to renal pelvis, ureter and bladder. Scaring of tissue by tuberculosis process may lead to development of strictures of the urinary tract. The clinical manifestations are presented by nonspecific symptoms and signs, so tuberculosis can often be overlooked. Sterile pyuria is characteristic for urinary tuberculosis. Dysuric complaints, flank pain or hematuria may be presented in patients. Constitutional symptoms of fever, weight loss and night sweats are presented in some severe cases. Diagnosis is made by isolation of mycobacterium tuberculosis in urine samples, by cultures carried out on standard solid media optimized for mycobacterial growth. Different imaging studies are used in diagnostics - IVU, CT and NMR are the most important. Medical therapy is the main modality of tuberculosis treatment. The first line anti-tuberculosis drugs include isoniazid, rifampicin, pyrazinamide and ethambutol. Surgical treatment is required in some cases, to remove severely damaged kidney, if

  10. Identification of a mechanism by which the methylmercury antidotes N-acetylcysteine and dimercaptopropanesulfonate enhance urinary metal excretion: transport by the renal organic anion transporter-1.

    Science.gov (United States)

    Koh, Albert S; Simmons-Willis, Tracey A; Pritchard, John B; Grassl, Steven M; Ballatori, Nazzareno

    2002-10-01

    N-Acetylcysteine (NAC) and dimercaptopropanesulfonate (DMPS) are sulfhydryl-containing compounds that produce a dramatic acceleration of urinary methylmercury (MeHg) excretion in poisoned animals, but the molecular mechanism for this effect is unknown. NAC and DMPS are themselves excreted in urine in high concentrations. The present study tested the hypothesis that the complexes formed between MeHg and these anionic chelating agents are transported from blood into proximal tubule cells by the basolateral membrane organic anion transporters (Oat) 1 and Oat3. Xenopus laevis oocytes expressing rat Oat1 showed increased uptake of [(14)C]MeHg when complexed with either NAC or DMPS but not when complexed with L-cysteine, glutathione, dimercaptosuccinate, penicillamine, or gamma-glutamylcysteine. In contrast, none of these MeHg complexes were transported by Oat3-expressing oocytes. The apparent K(m) values for Oat1-mediated transport were 31 +/- 2 microM for MeHg-NAC and 9 +/- 2 microM for MeHg-DMPS, indicating that these are relatively high-affinity substrates. Oat1-mediated uptake of [(14)C]MeHg-NAC and [(14)C]MeHg-DMPS was inhibited by prototypical substrates for Oat1, including p-aminohippurate (PAH), and was trans-stimulated when oocytes were preloaded with 2 mM glutarate but not glutamate. Conversely, efflux of [(3)H]PAH from Oat1-expressing oocytes was trans-stimulated by glutarate, PAH, NAC, DMPS, MeHg-NAC, MeHg-DMPS, and a mercapturic acid, indicating that these are transported solutes. [(3)H]PAH uptake was competitively inhibited by NAC (K(i) of 2.0 +/- 0.3 mM) and DMPS (K(i) of 0.10 +/- 0.02 mM), providing further evidence that these chelating agents are substrates for Oat1. These results indicate that the MeHg antidotes NAC and DMPS and their mercaptide complexes are transported by Oat1 but are comparatively poor substrates for Oat3. This is the first molecular identification of a transport mechanism by which these antidotes may enhance urinary excretion of

  11. The Pharmacokinetics of Fentanyl Family Drugs in Patients with Renal Inadequacy%肾功能不全患者芬太尼族药物的药动学

    Institute of Scientific and Technical Information of China (English)

    邵伟栋

    2013-01-01

    芬太尼族药物包括芬太尼、瑞芬太尼、舒芬太尼和阿芬太尼等,已广泛用于临床麻醉及术后镇痛.肾功能不全患者常伴有贫血、低血容量和低蛋白血症,许多药物不良反应发生率明显高于肾功能正常者.肾功能不全时芬太尼族药物的吸收、分布、生物转化和排泄等都可能发生改变.总结分析对肾功能不全患者芬太尼族药物药动学研究的进展,有助于指导临床用药,减少药物不良反应.%Fentanyl,remifentanil,sufentanil,and alfentanil are the fentanyl family of drugs. They have been widely used in clinical anesthesia and postoperative analgesia. Patients with renal inadequacy often have anemia,hypovolemia and hypoproteinemia, the incidence of adverse drug reactions in patients with renal inadequacy is significantly higher than in patients with the normal renal function. The absorption, distribution, biotransformation and excretion of fentanyl family of drugs may change in patients with renal failure. Here is to make a review of pharmacokinetics of the fentanyl family of drugs in patients with renal failure and provide guidance for clinical medication,reducing adverse drug reactions.

  12. Modeling Organic Anion-Transporting Polypeptide 1B1 Inhibition to Elucidate Interaction Risks in Early Drug Design.

    Science.gov (United States)

    Zamora, Ismael; Winiwarter, Susanne

    2016-10-01

    The importance of transporter proteins for the disposition of drugs has become increasingly apparent during the past decade. A noted drug-drug interaction risk is the inhibition of organic anion-transporting polypeptides (OATPs), key transporters for the liver uptake of the widely used statins. We show here the development of a ligand-based in silico model for interaction with OATP1B1, an important representative of the OATP family. The model is based on a structural overlay of 6 known OATP1B1 inhibitors. A data set of about 150 compounds with published OATP1B1 inhibition data was compared to the resulting "transportophor," and a similarity threshold was defined to distinguish between active and inactive molecules. In addition, using a statistical model based on physicochemical properties of the compounds as prefilter was found to enhance the overall predictivity of the model (final accuracy 0.73, specificity 074, and sensitivity 0.71, based on 126 compounds). The combined model was validated using an in-house data set (accuracy, specificity, and sensitivity were 0.63, 0.59, and 0.78, respectively; 62 compounds). The model gives also a structural overlay to the most similar template enabling visualization of where a change in a given structure might reduce the interaction with the transporter.

  13. Combining PET biodistribution and equilibrium dialysis assays to assess the free brain concentration and BBB transport of CNS drugs

    Science.gov (United States)

    Gunn, Roger N; Summerfield, Scott G; Salinas, Cristian A; Read, Kevin D; Guo, Qi; Searle, Graham E; Parker, Christine A; Jeffrey, Phil; Laruelle, Marc

    2012-01-01

    The passage of drugs in and out of the brain is controlled by the blood–brain barrier (BBB), typically, using either passive diffusion across a concentration gradient or active transport via a protein carrier. In-vitro and preclinical measurements of BBB penetration do not always accurately predict the in-vivo situation in humans. Thus, the ability to assay the concentration of novel drug candidates in the human brain in vivo provides valuable information for derisking of candidate molecules early in drug development. Here, positron emission tomography (PET) measurements are combined with in-vitro equilibrium dialysis assays to enable assessment of transport and estimation of the free brain concentration in vivo. The PET and equilibrium dialysis data were obtained for 36 compounds in the pig. Predicted P-glycoprotein (P-gp) status of the compounds was consistent with the PET/equilibrium dialysis results. In particular, Loperamide, a well-known P-gp substrate, exhibited a significant concentration gradient consistent with active efflux and after inhibition of the P-gp process the gradient was removed. The ability to measure the free brain concentration and assess transport of novel compounds in the human brain with combined PET and equilibrium dialysis assays can be a useful tool in central nervous system (CNS) drug development. PMID:22274741

  14. Investigating how the attributes of self-associated drug complexes influence the passive transport of molecules through biological membranes.

    Science.gov (United States)

    Inacio, R; Barlow, D; Kong, X; Keeble, J; Jones, S A

    2016-05-01

    Relatively little is known about how drug self-association influences absorption into the human body. This study presented two hydrophobic membranes with a series of solutions containing different types of tetracaine aggregates with the aim of understanding how the attributes of supramolecular aggregate formation influenced passive membrane transport. The data showed that aqueous solutions of the unprotonated form of tetracaine displayed a significantly higher (ptransport compared to solutions with mixtures of the unprotonated and protonated drug microspecies (e.g. transport through the skin was 0.96±0.31μgcm(-2)min(-1) and 1.59±0.26μgcm(-2)min(-1) respectively). However, despite an enhanced rate of drug transport and a better membrane partitioning the unionised molecules showed a significantly longer (ptransport studies showed that larger tetracaine aggregates with smaller surface charge gave rise to the longer lag times. These large aggregates demonstrated more extensive intermolecular bonding and therefore, it was suggest that it was the enhanced propensity of the unionised species to form tightly bound drug aggregates that caused the delay in the membrane penetration.

  15. Effect of graded Nrf2 activation on phase-I and -II drug metabolizing enzymes and transporters in mouse liver.

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    Kai Connie Wu

    Full Text Available Nuclear factor erythroid 2-related factor 2 (Nrf2 is a transcription factor that induces a battery of cytoprotective genes in response to oxidative/electrophilic stress. Kelch-like ECH associating protein 1 (Keap1 sequesters Nrf2 in the cytosol. The purpose of this study was to investigate the role of Nrf2 in regulating the mRNA of genes encoding drug metabolizing enzymes and xenobiotic transporters. Microarray analysis was performed in livers of Nrf2-null, wild-type, Keap1-knockdown mice with increased Nrf2 activation, and Keap1-hepatocyte knockout mice with maximum Nrf2 activation. In general, Nrf2 did not have a marked effect on uptake transporters, but the mRNAs of organic anion transporting polypeptide 1a1, sodium taurocholate cotransporting polypeptide, and organic anion transporter 2 were decreased with Nrf2 activation. The effect of Nrf2 on cytochrome P450 (Cyp genes was minimal, with only Cyp2a5, Cyp2c50, Cyp2c54, and Cyp2g1 increased, and Cyp2u1 decreased with enhanced Nrf2 activation. However, Nrf2 increased mRNA of many other phase-I enzymes, such as aldo-keto reductases, carbonyl reductases, and aldehyde dehydrogenase 1. Many genes involved in phase-II drug metabolism were induced by Nrf2, including glutathione S-transferases, UDP- glucuronosyltransferases, and UDP-glucuronic acid synthesis enzymes. Efflux transporters, such as multidrug resistance-associated proteins, breast cancer resistant protein, as well as ATP-binding cassette g5 and g8 were induced by Nrf2. In conclusion, Nrf2 markedly alters hepatic mRNA of a large number of drug metabolizing enzymes and xenobiotic transporters, and thus Nrf2 plays a central role in xenobiotic metabolism and detoxification.

  16. In situ mass spectrometry imaging and ex vivo characterization of renal crystalline deposits induced in multiple preclinical drug toxicology studies.

    Directory of Open Access Journals (Sweden)

    Anna Nilsson

    Full Text Available Drug toxicity observed in animal studies during drug development accounts for the discontinuation of many drug candidates, with the kidney being a major site of tissue damage. Extensive investigations are often required to reveal the mechanisms underlying such toxicological events and in the case of crystalline deposits the chemical composition can be problematic to determine. In the present study, we have used mass spectrometry imaging combined with a set of advanced analytical techniques to characterize such crystalline deposits in situ. Two potential microsomal prostaglandin E synthase 1 inhibitors, with similar chemical structure, were administered to rats over a seven day period. This resulted in kidney damage with marked tubular degeneration/regeneration and crystal deposits within the tissue that was detected by histopathology. Results from direct tissue section analysis by matrix-assisted laser desorption ionization mass spectrometry imaging were combined with data obtained following manual crystal dissection analyzed by liquid chromatography mass spectrometry and nuclear magnetic resonance spectroscopy. The chemical composition of the crystal deposits was successfully identified as a common metabolite, bisulphonamide, of the two drug candidates. In addition, an un-targeted analysis revealed molecular changes in the kidney that were specifically associated with the area of the tissue defined as pathologically damaged. In the presented study, we show the usefulness of combining mass spectrometry imaging with an array of powerful analytical tools to solve complex toxicological problems occurring during drug development.

  17. Delineating the Role of Various Factors in Renal Disposition of Digoxin through Application of Physiologically Based Kidney Model to Renal Impairment Populations

    Science.gov (United States)

    Scotcher, Daniel; Jones, Christopher R.; Galetin, Aleksandra

    2017-01-01

    Development of submodels of organs within physiologically-based pharmacokinetic (PBPK) principles and beyond simple perfusion limitations may be challenging because of underdeveloped in vitro-in vivo extrapolation approaches or lack of suitable clinical data for model refinement. However, advantage of such models in predicting clinical observations in divergent patient groups is now commonly acknowledged. Mechanistic understanding of altered renal secretion in renal impairment is one area that may benefit from such models, despite knowledge gaps in renal pathophysiology. In the current study, a PBPK kidney model was developed for digoxin, accounting for the roles of organic anion transporting peptide 4C1 (OATP4C1) and P-glycoprotein (P-gp) in its tubular secretion, with the aim to investigate the impact of age and renal impairment (moderate to severe) on renal drug disposition. Initial PBPK simulations based on changes in glomerular filtration rate (GFR) underestimated the observed reduction in digoxin renal excretion clearance (CLR) in subjects with moderately impaired renal function relative to healthy. Reduction in either proximal tubule cell number or the OATP4C1 abundance in the mechanistic kidney model successfully predicted 59% decrease in digoxin CLR, in particular when these changes were proportional to reduction in GFR. In contrast, predicted proximal tubule concentration of digoxin was only sensitive to changes in the transporter expression/ million proximal tubule cells. Based on the mechanistic modeling, reduced proximal tubule cellularity and OATP4C1 abundance, and inhibition of OATP4C1-mediated transport, are proposed as possible causes of reduced digoxin renal secretion in renally impaired patients. PMID:28057840

  18. The Role of Hydrogen Sulfide in Renal System

    Science.gov (United States)

    Cao, Xu; Bian, Jin-Song

    2016-01-01

    Hydrogen sulfide has gained recognition as the third gaseous signaling molecule after nitric oxide and carbon monoxide. This review surveys the emerging role of H2S in mammalian renal system, with emphasis on both renal physiology and diseases. H2S is produced redundantly by four pathways in kidney, indicating the abundance of this gaseous molecule in the organ. In physiological conditions, H2S was found to regulate the excretory function of the kidney possibly by the inhibitory effect on sodium transporters on renal tubular cells. Likewise, it also influences the release of renin from juxtaglomerular cells and thereby modulates blood pressure. A possible role of H2S as an oxygen sensor has also been discussed, especially at renal medulla. Alternation of H2S level has been implicated in various pathological conditions such as renal ischemia/reperfusion, obstructive nephropathy, diabetic nephropathy, and hypertensive nephropathy. Moreover, H2S donors exhibit broad beneficial effects in renal diseases although a few conflicts need to be resolved. Further research reveals that multiple mechanisms are underlying the protective effects of H2S, including anti-inflammation, anti-oxidation, and anti-apoptosis. In the review, several research directions are also proposed including the role of mitochondrial H2S in renal diseases, H2S delivery to kidney by targeting D-amino acid oxidase/3-mercaptopyruvate sulfurtransferase (DAO/3-MST) pathway, effect of drug-like H2S donors in kidney diseases and understanding the molecular mechanism of H2S. The completion of the studies in these directions will not only improves our understanding of renal H2S functions but may also be critical to translate H2S to be a new therapy for renal diseases.

  19. The role of hydrogen sulfide in renal system

    Directory of Open Access Journals (Sweden)

    Xu Cao

    2016-10-01

    Full Text Available Hydrogen sulfide (H2S has gained recognition as the third gaseous signaling molecule after nitric oxide (NO and carbon monoxide (CO. This review surveys the emerging role of H2S in mammalian renal system, with emphasis on both renal physiology and diseases. H2S is produced redundantly by four pathways in kidney, indicating the abundance of this gaseous molecule in the organ. In physiological conditions, H2S was found to regulate the excretory function of the kidney possibly by the inhibitory effect on sodium transporters on renal tubular cells. Likewise, it also influences the release of renin from juxtaglomerular (JG cells and thereby modulates blood pressure. A possible role of H2S as an oxygen sensor has also been discussed, especially at renal medulla. Alternation of H2S level has been implicated in various pathological conditions such as renal ischemia/reperfusion, obstructive nephropathy, diabetic nephropathy and hypertensive nephropathy. Moreover, H2S donors exhibit broad beneficial effects in renal diseases although a few conflicts need to be resolved. Further research reveals that multiple mechanisms are underlying the protective effects of H2S, including anti-inflammation, anti-oxidation and anti-apoptosis. In the review, several research directions are also proposed including the role of mitochondrial H2S in renal diseases, H2S delivery to kidney by targeting D-amino acid oxidase/3-mercaptopyruvate sulfurtransferase (DAO/3-MST pathway, effect of drug-like H2S donors in kidney diseases and understanding the molecular mechanism of H2S. The completion of the studies in these directions will not only improves our understanding of renal H2S functions but may also be critical to translate H2S to be a new therapy for renal diseases.

  20. Chemotherapeutic drugs sensitize human renal cell carcinoma cells to ABT-737 by a mechanism involving the Noxa-dependent inactivation of Mcl-1 or A1

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    Zantl Niko

    2010-06-01

    Full Text Available Abstract Background Human renal cell carcinoma (RCC is very resistant to chemotherapy. ABT-737 is a novel inhibitor of anti-apoptotic proteins of the Bcl-2 family that has shown promise in various preclinical tumour models. Results We here report a strong over-additive pro-apoptotic effect of ABT-737 and etoposide, vinblastine or paclitaxel but not 5-fluorouracil in cell lines from human RCC. ABT-737 showed very little activity as a single agent but killed RCC cells potently when anti-apoptotic Mcl-1 or, unexpectedly, A1 was targeted by RNAi. This potent augmentation required endogenous Noxa protein since RNAi directed against Noxa but not against Bim or Puma reduced apoptosis induction by the combination of ABT-737 and etoposide or vinblastine. At the level of mitochondria, etoposide-treatment had a similar sensitizing activity and allowed for ABT-737-induced release of cytochrome c. Conclusions Chemotherapeutic drugs can overcome protection afforded by Mcl-1 and A1 through endogenous Noxa protein in RCC cells, and the combination of such drugs with ABT-737 may be a promising strategy in RCC. Strikingly, A1 emerged in RCC cell lines as a protein of similar importance as the well-established Mcl-1 in protection against apoptosis in these cells.

  1. Neuronal and non-neuronal GABA transporters as targets for antiepileptic drugs

    DEFF Research Database (Denmark)

    Madsen, Karsten K; White, H Steve; Schousboe, Arne

    2010-01-01

    of such transporters pointing in particular to an interesting role of the transporters located extrasynaptically. It is suggested that the betaine-GABA transporter BGT1 should receive particular interest in this context as the GABA analogue EF 1502 (N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-4-(methylamino)-4...

  2. Recent advances in the understanding of the interaction of antidepressant drugs with serotonin and norepinephrine transporters

    DEFF Research Database (Denmark)

    Andersen, Jacob; Kristensen, Anders Skov; Bang-Andersen, Benny;

    2009-01-01

    and amphetamine. Seminal advances in the understanding of the structure and function of this transporter family have recently been accomplished by structural studies of a bacterial transporter, as well as medicinal chemistry and pharmacological studies of mammalian transporters. This feature article focuses...

  3. Phytochemical screening, and assessment of ameliorating effect of aqueous and ethanolic extracts of Gmelina arborea on drug induced hepatic and renal insufficiency in rats.

    Science.gov (United States)

    Anthony, Ogbonnaya Enyinnaya; Mbuh, Awah Francis; Emmanuel, Mounmbegna Philippe

    2012-04-01

    Phytochemical screening of stem bark and leaves of Gmelina arborea; and effect of aqueous and ethanolic extracts of Gmelina arborea stembark on hepatic and renal insufficiency in rats was assessed in this study. Phytochemical screening was carried out on the air-dried leaf, oven-dried leaf, air-dried stembark and oven-dried stembark samples. Sixty five (65) wister albino rats, (50.7-117.5 g) were divided into thirteen groups of five animals each. Three groups serve as Controls and were administered Cisplatin (5mg/kg b.w; i.p), Paracetamol (200mg/kg b.w; i.p) and Normal saline (0.002 ml/kg b.w; oral). Other groups were administered, either, cisplatin and extracts (1g/kg b.w; oral); Paracetamol and extracts (1g/kg b.w; oral); extracts alone; or drugs and combination of extracts. Animals were starved, 24 hours prior to sacrifice and sacrificed on the 9th day after commencement of treatment. Phytochemical screening results show the presence of alkaloid, flavonoid, tannin, saponin, cyanogenic glycoside, phytate, and carbohydrate. Saponin and carbohydrate were shown to be much higher in concentration than other phytochemicals. The percentage composition of cyanogenic glycoside and phytate were highest in air-dried stembark and oven-dried leaf samples, respectively. All the Gmelina arborea extracts and extract mixture administered to both paracetamol and cisplatin treated animals, significantly, lowers both the activities of the SGOT and SGPT, and the levels of serum creatinine and urea. When administered alone, the aqueous and ethanolic extracts show little or no sign of toxicity. Thus Gmelina arborea extracts may have ameliorating effect on hepatic and renal insufficiency caused by paracetamol and cisplatin respectively, and any inherent toxicity may be reduced or eliminated through adequate heat treatment.

  4. 3-Halo Chloroquine Derivatives Overcome Plasmodium falciparum Chloroquine Resistance Transporter-Mediated Drug Resistance in P. falciparum.

    Science.gov (United States)

    Edaye, Sonia; Tazoo, Dagobert; Bohle, D Scott; Georges, Elias

    2015-12-01

    Polymorphism in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) was shown to cause chloroquine resistance. In this report, we examined the antimalarial potential of novel 3-halo chloroquine derivatives (3-chloro, 3-bromo, and 3-iodo) against chloroquine-susceptible and -resistant P. falciparum. All three derivatives inhibited the proliferation of P. falciparum; with 3-iodo chloroquine being most effective. Moreover, 3-iodo chloroquine was highly effective at potentiating and reversing chloroquine toxicity of drug-susceptible and -resistant P. falciparum.

  5. Novel experimental design for steady-state processes: a systematic Bayesian approach for enzymes, drug transport, receptor binding, continuous culture and cell transport kinetics.

    Science.gov (United States)

    Crabbe, M James C; Murphy, Emma F; Gilmour, Steven G

    2005-01-01

    We demonstrate that a Bayesian approach (the use of prior knowledge) to the design of steady-state experiments can produce major gains quantifiable in terms of information, productivity and accuracy of each experiment. Developing the use of Bayesian utility functions, we have used a systematic method to identify the optimum experimental designs for a number of kinetic model data sets. This has enabled the identification of trends between kinetic model types, sets of design rules and the key conclusion that such designs should be based on some prior knowledge of the kinetic model. We suggest an optimal and iterative method for selecting features of the design such as the substrate range, number of measurements and choice of intermediate points. The final design collects data suitable for accurate modelling and analysis and minimises the error in the parameters estimated. It is equally applicable to enzymes, drug transport, receptor binding, microbial culture and cell transport kinetics.

  6. Renal Osteodystrophy

    Directory of Open Access Journals (Sweden)

    Aynur Metin Terzibaşoğlu

    2004-12-01

    Full Text Available Chronic renal insufficiency is a functional definition which is characterized by irreversible and progressive decreasing in renal functions. This impairment is in collaboration with glomeruler filtration rate and serum creatinine levels. Besides this, different grades of bone metabolism disorders develop in chronic renal insufficiency. Pathologic changes in bone tissue due to loss of renal paranchyme is interrelated with calcium, phosphorus vitamine-D and parathyroid hormone. Clinically we can see high turnover bone disease, low turnover bone disease, osteomalacia, osteosclerosis and osteoporosis in renal osteodystropy. In this article we aimed to review pathology of bone metabolism disorders due to chronic renal insufficiency, clinic aspects and treatment approaches briefly.

  7. Drug-protein hydrogen bonds govern the inhibition of the ATP hydrolysis of the multidrug transporter P-glycoprotein.

    Science.gov (United States)

    Chufan, Eduardo E; Kapoor, Khyati; Ambudkar, Suresh V

    2016-02-01

    P-glycoprotein (P-gp) is a member of the ATP-binding cassette transporter superfamily. This multidrug transporter utilizes energy from ATP hydrolysis for the efflux of a variety of hydrophobic and amphipathic compounds including anticancer drugs. Most of the substrates and modulators of P-gp stimulate its basal ATPase activity, although some inhibit it. The molecular mechanisms that are in play in either case are unknown. In this report, mutagenesis and molecular modeling studies of P-gp led to the identification of a pair of phenylalanine-tyrosine structural motifs in the transmembrane region that mediate the inhibition of ATP hydrolysis by certain drugs (zosuquidar, elacridar and tariquidar), with high affinity (IC50's ranging from 10 to 30nM). Upon mutation of any of these residues, drugs that inhibit the ATPase activity of P-gp switch to stimulation of the activity. Molecular modeling revealed that the phenylalanine residues F978 and F728 interact with tyrosine residues Y953 and Y310, respectively, in an edge-to-face conformation, which orients the tyrosines in such a way that they establish hydrogen-bond contacts with the inhibitor. Biochemical investigations along with transport studies in intact cells showed that the inhibitors bind at a high affinity site to produce inhibition of ATP hydrolysis and transport function. Upon mutation, they bind at lower affinity sites, stimulating ATP hydrolysis and only poorly inhibiting transport. These results also reveal that screening chemical compounds for their ability to inhibit the basal ATP hydrolysis can be a reliable tool to identify modulators with high affinity for P-gp.

  8. Staphylococcus aureus and Lipopolysaccharide Modulate Gene Expressions of Drug Transporters in Mouse Mammary Epithelial Cells Correlation to Inflammatory Biomarkers

    Science.gov (United States)

    Yagdiran, Yagmur; Tallkvist, Jonas; Artursson, Karin

    2016-01-01

    Inflammation in the mammary gland (mastitis) is the most common disease in dairy herds worldwide, often caused by the pathogens Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli). Little is known about the effects of mastitis on drug transporters and the impact on transporter-mediated excretion of drugs into milk. We used murine mammary epithelial HC11 cells, after lactogenic differentiation into a secreting phenotype, and studied gene expressions of ABC- and SLC- transporters after treatment of cells with S. aureus and lipopolysaccharide, an endotoxin secreted by E. coli. The studied transporters were Bcrp, Mdr1, Mrp1, Oatp1a5, Octn1 and Oct1. In addition, Csn2, the gene encoding β-casein, was analyzed. As biomarkers of the inflammatory response, gene expressions of the cytokines Il6 and Tnfα and the chemokine Cxcl2 were determined. Our results show that S. aureus and LPS treatment of cells, at non-cytotoxic concentrations, induced an up-regulation of Mdr1 and of the inflammatory biomarkers, except that Tnfα was not affected by lipopolysaccharide. By simple regression analysis we could demonstrate statistically significant positive correlations between each of the transporters with each of the inflammatory biomarkers in cells treated with S. aureus. The coefficients of determination (R2) were 0.7–0.9 for all but one correlation. After treatment of cells with lipopolysaccharide, statistically significant correlations were only found between Mdr1 and the two parameters Cxcl2 and Il6. The expression of Csn2 was up-regulated in cells treated with S. aureus, indicating that the secretory function of the cells was not impaired. The strong correlation in gene expressions between transporters and inflammatory biomarkers may suggest a co-regulation and that the transporters have a role in the transport of cytokines and chemokines. Our results demonstrate that transporters in mammary cells can be affected by infection, which may have an impact on

  9. Perioperative acute renal failure.

    LENUS (Irish Health Repository)

    Mahon, Padraig

    2012-02-03

    PURPOSE OF REVIEW: Recent biochemical evidence increasingly implicates inflammatory mechanisms as precipitants of acute renal failure. In this review, we detail some of these pathways together with potential new therapeutic targets. RECENT FINDINGS: Neutrophil gelatinase-associated lipocalin appears to be a sensitive, specific and reliable biomarker of renal injury, which may be predictive of renal outcome in the perioperative setting. For estimation of glomerular filtration rate, cystatin C is superior to creatinine. No drug is definitively effective at preventing postoperative renal failure. Clinical trials of fenoldopam and atrial natriuretic peptide are, at best, equivocal. As with pharmacological preconditioning of the heart, volatile anaesthetic agents appear to offer a protective effect to the subsequently ischaemic kidney. SUMMARY: Although a greatly improved understanding of the pathophysiology of acute renal failure has offered even more therapeutic targets, the maintenance of intravascular euvolaemia and perfusion pressure is most effective at preventing new postoperative acute renal failure. In the future, strategies targeting renal regeneration after injury will use bone marrow-derived stem cells and growth factors such as insulin-like growth factor-1.

  10. Antagonistic changes in sensitivity to antifungal drugs by mutations of an important ABC transporter gene in a fungal pathogen.

    Directory of Open Access Journals (Sweden)

    Wenjun Guan

    Full Text Available Fungal pathogens can be lethal, especially among immunocompromised populations, such as patients with AIDS and recipients of tissue transplantation or chemotherapy. Prolonged usage of antifungal reagents can lead to drug resistance and treatment failure. Understanding mechanisms that underlie drug resistance by pathogenic microorganisms is thus vital for dealing with this emerging issue. In this study, we show that dramatic sequence changes in PDR5, an ABC (ATP-binding cassette efflux transporter protein gene in an opportunistic fungal pathogen, caused the organism to become hypersensitive to azole, a widely used antifungal drug. Surprisingly, the same mutations conferred growth advantages to the organism on polyenes, which are also commonly used antimycotics. Our results indicate that Pdr5p might be important for ergosterol homeostasis. The observed remarkable sequence divergence in the PDR5 gene in yeast strain YJM789 may represent an interesting case of adaptive loss of gene function with significant clinical implications.

  11. Eligibility for renal denervation

    DEFF Research Database (Denmark)

    Persu, Alexandre; Jin, Yu; Baelen, Marie;

    2014-01-01

    -resistant hypertension (ENCOReD). The analysis included 731 patients. Age averaged 61.6 years, office blood pressure at screening was 177/96 mm Hg, and the number of blood pressure-lowering drugs taken was 4.1. Specialists referred 75.6% of patients. The proportion of patients eligible for renal denervation according......Based on the SYMPLICITY studies and CE (Conformité Européenne) certification, renal denervation is currently applied as a novel treatment of resistant hypertension in Europe. However, information on the proportion of patients with resistant hypertension qualifying for renal denervation after...... undetected secondary causes of hypertension (11.1%). In conclusion, after careful screening and treatment adjustment at hypertension expert centers, only ≈40% of patients referred for renal denervation, mostly by specialists, were eligible for the procedure. The most frequent cause of ineligibility...

  12. Comparison of the Ability of Various Imaging Modalities (CT & Plain X- Ray in Detecting Drug Transport in Body Packers

    Directory of Open Access Journals (Sweden)

    Morteza Sanei

    2009-01-01

    Full Text Available "ndrugs within the human body. In our country due to vast common border with Afghanistan which is the biggest Opium producer in the world and has the second place in Heroine production, drug smuggling has potential national threat and besides it has a global impact as using our territory as the major smuggling route to the west. Furthermore, in recent years new generations of African smugglers of new types of drugs are using our country as a transit route to transport drugs to Europe or Africa. In this way handmade or automatically produced packets are swallowed, rectally or vaginally inserted, and then transported. The first choice modality is plain x-ray of the abdomen in upright and supine positions. Recently abdominal and pelvic CT without contrast has shown a great success rate in the detection of body packers with changing window modality to detect different types of drugs. "nMaterials and Methods: Plain x-ray and abdominal and pelvic CT without contrast were performed for 12 cases who confessed to drug packet ingestion. The presence, number and location of the packets were evaluated in different modalities and the density of the packets were also measured in Hounsfield units (HU. "nResults: The mean age of our cases was 28.2±5.9 years (range, 17-35 years. Eleven (91.6 % patients were male and only one case was female. All patients had characteristic findings in plain x-ray and also all packets were visualized in all patients "nConclusion: Plain x-ray has a distinctive position in detecting packets in intestines especially when oral contrast materials are used. It is cheaper and more accessible than CT, but using different Hounsfield units in CT windows can even characterize different types of drugs even before extracting them.  

  13. Nuclear Receptor 4A1 (NR4A1 as a Drug Target for Renal Cell Adenocarcinoma.

    Directory of Open Access Journals (Sweden)

    Erik Hedrick

    Full Text Available The orphan nuclear receptor NR4A1 exhibits pro-oncogenic activity in cancer cell lines. NR4A1 activates mTOR signaling, regulates genes such as thioredoxin domain containing 5 and isocitrate dehydrogenase 1 that maintain low oxidative stress, and coactivates specificity protein 1 (Sp1-regulated pro-survival and growth promoting genes. Transfection of renal cell carcinoma (RCC ACHN and 786-O cells with oligonucleotides that target NR4A1 results in a 40-60% decrease in cell proliferation and induction of apoptosis. Moreover, knockdown of NR4A1 in RCC cells decreased bcl-2, survivin and epidermal growth factor receptor expression, inhibited of mTOR signaling, induced oxidative and endoplasmic reticulum stress, and decreased TXNDC5 and IDH1. We have recently demonstrated that selected 1,1-bis(3'-indolyl-1-(p-substituted phenylmethane (C-DIM compounds including the p-hydroxyphenyl (DIM-C-pPhOH and p-carboxymethyl (DIM-C-pPhCO2Me analogs bind NR4A1 and act as antagonists. Both DIM-C-pPhOH and DIM-C-pPhCO2Me inhibited growth and induced apoptosis in ACHN and 786-O cells, and the functional and genomic effects of the NR4A1 antagonists were comparable to those observed after NR4A1 knockdown. These results indicate that NR4A1 antagonists target multiple growth promoting and pro-survival pathways in RCC cells and in tumors (xenograft and represent a novel chemotherapy for treating RCC.

  14. How to improve drug dosing for patients with renal impairment in primary care - a cluster-randomized controlled trial

    Directory of Open Access Journals (Sweden)

    Erler Antje

    2012-09-01

    Full Text Available Abstract Background Patients with chronic kidney disease (CKD are at increased risk for inappropriate or potentially harmful prescribing. The aim of this study was to examine whether a multifaceted intervention including the use of a software programme for the estimation of creatinine clearance and recommendation of individual dosage requirements may improve correct dosage adjustment of relevant medications for patients with CKD in primary care. Methods A cluster-randomized controlled trial was conducted between January and December 2007 in small primary care practices in Germany. Practices were randomly allocated to intervention or control groups. In each practice, we included patients with known CKD and elderly patients (≥70 years suffering from hypertension. The practices in the intervention group received interactive training and were provided a software programme to assist with individual dose adjustment. The control group performed usual care. Data were collected at baseline and at 6 months. The outcome measures, analyzed across individual patients, included prescriptions exceeding recommended maximum daily doses, with the primary outcome being prescriptions exceeding recommended standard daily doses by more than 30%. Results Data from 44 general practitioners and 404 patients are included. The intervention was effective in reducing prescriptions exceeding the maximum daily dose per patients, with a trend in reducing prescriptions exceeding the standard daily dose by more than 30%. Conclusions A multifaceted intervention including the use of a software program effectively reduced inappropriately high doses of renally excreted medications in patients with CKD in the setting of small primary care practices. Trial registration Current Controlled Trials ISRCTN02900734

  15. Transport rankings of non-steroidal antiinflammatory drugs across blood-brain barrier in vitro models.

    Directory of Open Access Journals (Sweden)

    Iveta Novakova

    Full Text Available The aim of this work was to conduct a comprehensive study about the transport properties of NSAIDs across the blood-brain barrier (BBB in vitro. Transport studies with celecoxib, diclofenac, ibuprofen, meloxicam, piroxicam and tenoxicam were accomplished across Transwell models based on cell line PBMEC/C1-2, ECV304 or primary rat brain endothelial cells. Single as well as group substance studies were carried out. In group studies substance group compositions, transport medium and serum content were varied, transport inhibitors verapamil and probenecid were added. Resulted permeability coefficients were compared and normalized to internal standards diazepam and carboxyfluorescein. Transport rankings of NSAIDs across each model were obtained. Single substance studies showed similar rankings as corresponding group studies across PBMEC/C1-2 or ECV304 cell layers. Serum content, glioma conditioned medium and inhibitors probenecid and verapamil influenced resulted permeability significantly. Basic differences of transport properties of the investigated NSAIDs were similar comparing all three in vitro BBB models. Different substance combinations in the group studies and addition of probenecid and verapamil suggested that transporter proteins are involved in the transport of every tested NSAID. Results especially underlined the importance of same experimental conditions (transport medium, serum content, species origin, cell line for proper data comparison.

  16. Fabrication of functional hollow microspheres constructed from MOF shells: Promising drug delivery systems with high loading capacity and targeted transport

    Science.gov (United States)

    Gao, Xuechuan; Hai, Xiao; Baigude, Huricha; Guan, Weihua; Liu, Zhiliang

    2016-11-01

    An advanced multifunctional, hollow metal-organic framework (MOF) drug delivery system with a high drug loading level and targeted delivery was designed and fabricated for the first time and applied to inhibit tumour cell growth. This hollow MOF targeting drug delivery system was prepared via a simple post-synthetic surface modification procedure, starting from hollow ZIF-8 successfully obtained for the first time via a mild phase transformation under solvothermal conditions. As a result, the hollow ZIF-8 exhibits a higher loading capacity for the model anticancer drug 5-fluorouracil (5-FU). Subsequently, 5-FU-loaded ZIF-8 was encapsulated into polymer layers (FA-CHI-5-FAM) with three components: a chitosan (CHI) backbone, the imaging agent 5-carboxyfluorescein (5-FAM), and the targeting reagent folic acid (FA). Thus, an advanced drug delivery system, ZIF-8/5-FU@FA-CHI-5-FAM, was fabricated. A cell imaging assay demonstrated that ZIF-8/5-FU@FA-CHI-5-FAM could target and be taken up by MGC-803 cells. Furthermore, the as-prepared ZIF-8/5-FU@FA-CHI-5-FAM exhibited stronger cell growth inhibitory effects on MGC-803 cells because of the release of 5-FU, as confirmed by a cell viability assay. In addition, a drug release experiment in vitro indicated that ZIF-8/5-FU@FA-CHI-5-FAM exhibited high loading capacity (51%) and a sustained drug release behaviour. Therefore, ZIF-8/5-FU@FA-CHI-5-FAM could provide targeted drug transportation, imaging tracking and localized sustained release.

  17. Toxicological significance of renal Bcrp: Another potential transporter in the elimination of mercuric ions from proximal tubular cells

    Energy Technology Data Exchange (ETDEWEB)

    Bridges, Christy C., E-mail: bridges_cc@mercer.edu; Zalups, Rudolfs K.; Joshee, Lucy

    2015-06-01

    Secretion of inorganic mercury (Hg{sup 2+}) from proximal tubular cells into the tubular lumen has been shown to involve the multidrug resistance-associated protein 2 (Mrp2). Considering similarities in localization and substrate specificity between Mrp2 and the breast cancer resistance protein (Bcrp), we hypothesize that Bcrp may also play a role in the proximal tubular secretion of mercuric species. In order to test this hypothesis, the uptake of Hg{sup 2+} was examined initially using inside-out membrane vesicles containing Bcrp. The results of these studies suggest that Bcrp may be capable of transporting certain conjugates of Hg{sup 2+}. To further characterize the role of Bcrp in the handling of mercuric ions and in the induction of Hg{sup 2+}-induced nephropathy, Sprague–Dawley and Bcrp knockout (bcrp{sup −/−}) rats were exposed intravenously to a non-nephrotoxic (0.5 μmol·kg{sup −1}), a moderately nephrotoxic (1.5 μmol·kg{sup −1}) or a significantly nephrotoxic (2.0 μmol·kg{sup −1}) dose of HgCl{sub 2}. In general, the accumulation of Hg{sup 2+} was greater in organs of bcrp{sup −/−} rats than in Sprague–Dawley rats, suggesting that Bcrp may play a role in the export of Hg{sup 2+} from target cells. Within the kidney, cellular injury and necrosis was more severe in bcrp{sup −/−} rats than in controls. The pattern of necrosis, which was localized in the inner cortex and the outer stripe of the outer medulla, was significantly different from that observed in Mrp2-deficient animals. These findings suggest that Bcrp may be involved in the cellular export of select mercuric species and that its role in this export may differ from that of Mrp2. - Highlights: • Bcrp may mediate transport of mercury out of proximal tubular cells. • Hg-induced nephropathy was more severe in Bcrp knockout rats. • Bcrp and Mrp2 may differ in their ability to transport Hg.

  18. Interaction of human organic anion transporter 2 (OAT2) and sodium taurocholate cotransporting polypeptide (NTCP) with antineoplastic drugs.

    Science.gov (United States)

    Marada, Venkata V V R; Flörl, Saskia; Kühne, Annett; Müller, Judith; Burckhardt, Gerhard; Hagos, Yohannes

    2015-01-01

    The ability of an antineoplastic drug to exert its cytostatic effect depends largely on the balance between its uptake into and extrusion from the cancer cells. ATP driven efflux transporter proteins drive the export of antineoplastic drugs and play a pivotal role in the development of chemoresistance. As regards uptake transporters, comparably less is known on their impact in drug action. In the current study, we characterized the interactions of two uptake transporter proteins, expressed mainly in the liver; the organic anion transporter 2 (OAT2, encoded by the SLC22A7 gene) and the sodium taurocholate cotransporting polypeptide (NTCP, encoded by the SLC10A1 gene), stably transfected in human embryonic kidney cells, with some antineoplastic agents that are routinely being used in cancer chemotherapy. Whereas NTCP did not show any strong interactions with the cytostatics tested, we observed a very strong inhibition of OAT2 mediated [(3)H] cGMP uptake in the presence of bendamustine, irinotecan and paclitaxel. The Ki values of OAT2 for bendamustine, irinotecan and paclitaxel were determined to be 43.3±4.33μM, 26.4±2.34μM and 10.4±0.45μM, respectively. Incubation of bendamustine with OAT2 expressing cells increased the caspase-3 activity, and this increase was inhibited by simultaneous incubation with bendamustine and probenecid, a well-known inhibitor of OATs, suggesting that bendamustine is a substrate of OAT2. A higher accumulation of irinotecan was observed in OAT2 expressing cells compared to control pcDNA cells by HPLC analysis of cell lysates. The accumulation was diminished in the presence of cGMP, the substrate we used to functionally characterize OAT2, suggesting specificity of this uptake and the fact that OAT2 mediates uptake of irinotecan. Copyright © 2014 Elsevier Ltd. All rights reserved.

  19. A pleiotropic drug resistance transporter in Nicotiana tabacum is involved in defense against the herbivore Manduca sexta.

    Science.gov (United States)

    Bienert, Manuela D; Siegmund, Stephanie E G; Drozak, Anna; Trombik, Tomasz; Bultreys, Alain; Baldwin, Ian T; Boutry, Marc

    2012-12-01

    Pleiotropic drug resistance (PDR) transporters are a group of membrane proteins belonging to the ABCG sub-family of ATP binding cassette (ABC) transporters. There is clear evidence for the involvement of plant ABC transporters in resistance to fungal and bacterial pathogens, but not in the biotic stress response to insect or herbivore attack. Here, we describe a PDR transporter, ABCG5/PDR5, from Nicotiana tabacum. GFP fusion and subcellular fractionation studies revealed that ABCG5/PDR5 is localized to the plasma membrane. Staining of transgenic plants expressing the GUS reporter gene under the control of the ABCG5/PDR5 transcription promoter and immunoblotting of wild-type plants showed that, under standard growth conditions, ABCG5/PDR5 is highly expressed in roots, stems and flowers, but is only expressed at marginal levels in leaves. Interestingly, ABCG5/PDR5 expression is induced in leaves by methyl jasmonate, wounding, pathogen infiltration, or herbivory by Manduca sexta. To address the physiological role of ABCG5/PDR5, N. tabacum plants silenced for the expression of ABCG5/PDR5 were obtained. No phenotypic modification was observed under standard conditions. However, a small increase in susceptibility to the fungus Fusarium oxysporum was observed. A stronger effect was observed in relation to herbivory: silenced plants allowed better growth and faster development of M. sexta larvae than wild-type plants, indicating an involvement of this PDR transporter in resistance to M. sexta herbivory.

  20. Are lipid rafts involved in ABC transporter-mediated drug resistance of tumor cells?

    NARCIS (Netherlands)

    Kok, Jan Willem; Klappe, Karin; Hummel, Ina; Kroesen, Bart-Jan; Sietsma, Hannie; Meszaros, Peter

    2008-01-01

    Since their discovery, lipid rafts have been implicated in several cellular functions, including protein transport in polarized cells and signal transduction. Also in multidrug resistance lipid rafts may be important with regard to the localization of ATP-binding cassette (ABC) transporters in these

  1. Binding of the Multimodal Antidepressant Drug Vortioxetine to the Human Serotonin Transporter

    DEFF Research Database (Denmark)

    Andersen, Jacob; Ladefoged, Lucy Kate; Wang, Danyang

    2015-01-01

    SERT. X-ray crystal structures of the bacterial amino acid transporter LeuT and the Drosophila melanogaster dopamine transporter were used to build homology models of hSERT. Comparative modeling and ligand docking suggest that vortioxetine can adopt several distinct binding modes within the central...

  2. The secondary multidrug transporter LmrP contains multiple drug interaction sites

    NARCIS (Netherlands)

    Putman, M; Koole, LA; van Veen, HW; Konings, WN

    1999-01-01

    The secondary multidrug transporter LmrP of Lactococcus lactis mediates the efflux of Hoechst 33342 from the cytoplasmic leaflet of the membrane. Kinetic analysis of Hoechst 33342 transport in inside-out membrane vesicles of L. lactis showed that the LmrP-mediated H+/Hoechst 33342 antiport reaction

  3. Renal perfusion scintiscan

    Science.gov (United States)

    Renal perfusion scintigraphy; Radionuclide renal perfusion scan; Perfusion scintiscan - renal; Scintiscan - renal perfusion ... supply the kidneys. This is a condition called renal artery stenosis. Significant renal artery stenosis may be ...

  4. Impact of β-lactam antibiotic therapeutic drug monitoring on dose adjustments in critically ill patients undergoing continuous renal replacement therapy.

    Science.gov (United States)

    Economou, Caleb J P; Wong, Gloria; McWhinney, Brett; Ungerer, Jacobus P J; Lipman, Jeffrey; Roberts, Jason A

    2017-05-01

    The objective of this study was to describe the effect of therapeutic drug monitoring (TDM) and dose adjustments of β-lactam antibiotics administered to critically ill patients undergoing continuous renal replacement therapy (CRRT) in a 30-bed tertiary intensive care unit (ICU). β-Lactam TDM data in our tertiary referral ICU were retrospectively reviewed. Clinical, demographic and dosing data were collected for patients administered β-lactam antibiotics while undergoing CRRT. The target trough concentration range was 1-10× the minimum inhibitory concentration (MIC). A total of 111 TDM samples from 76 patients (46 male) with a mean ± standard deviation age of 56.6 ± 15.9 years and weight of 89.1 ± 25.8 kg were identified. The duration of antibiotic therapy was between 2 days and 42 days. TDM identified a need for dose modification of β-lactam antibiotics in 39 (35%) instances; in 27 (24%) samples, TDM values resulted in decreasing the prescribed dose of β-lactam antibiotic whereas an increase in the prescribed dose occurred in 12 (11%) cases. In patients treated for hospital-acquired pneumonia and primary or secondary bacteraemia, the dose was required to be decreased in 10/25 (40%) and 7/46 (15%) cases, respectively, to attain target concentrations. β-Lactam TDM is a useful tool for guiding drug dosing in complex patients such as those receiving CRRT. Although over one-third of patients manifested concentrations outside the therapeutic range, most of these CRRT patients had excessive β-lactam concentrations. Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

  5. Chinese Drugs That Invigorate Spleen to Remove Dampness and Activate Blood Circulation to Eliminate Turbid for Retarding Progression of Chronic Renal Failure

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective: To investigate the effect of Chinese drugs (CD) that invigorate Spleen to remove Dampness and activate the blood circulation to eliminate Turbid for retarding progression of chronic renal failure (CRF). Methods: Thirty-nine patients with CRF were divided into two groups at random: the 18 patients in group A (the control group) were treated with low protein diet and controlling blood pressure and 21 patients in group B (the treatment group) were treated similarly with that of the control group and additional CD. Levels of serous creatinine (SCr), blood urea nitrogen (BUN), blood albumin (Alb), total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL) and hemoglobin (Hb) were checked every two months and the rate of progression of CRF was estimated by slope of the creatinine reciprocal (1/SCr) with time (months). Results: Levels of SCr and BUN in group B were lower and HDL higher than those in group A significantly, P<0.05. Mean slopes of the creatinine reciprocal with time in the two groups were markedly different, P<0.01. Conclusion: Additional CD treatment based upon the low protein diet and controlling blood pressure could retard the rate of progression of CRF evidently.

  6. Latenciação e formas avançadas de transporte de fármacos Latentiation and advanced drug transport forms

    Directory of Open Access Journals (Sweden)

    Man-Chin Chung

    2005-06-01

    Full Text Available O processo de modificação molecular denominado latenciação é revisto, apresentando formas avançadas no transporte de fármacos, utilizando macromoléculas como transportadores e sistemas de liberação sítio-específica como: CDS (Chemical Delivery System, ADEPT (Antibody-Directed Enzyme Prodrug Therapy, GDEPT/VDEPT (Gene-Directed Enzyme Prodrug Therapy/Vírus-Directed Enzyme Prodrug Therapy, ODDS (Osteotropic Drug Delivery System, PDEPT (Polymer-Directed Enzyme Prodrug Therapy, PELT (Polymer-Enzyme Liposome Therapy e LEAPT (Lectin-Directed Enzyme-Activated Prodrug Therapy.This is a review about the molecular modification process, called latentiation, or prodrug design, focusing the progress in the prodrug approach using macromolecules as carriers and drug target systems as: PDEPT ( Polymer-Directed Enzyme Prodrug Therapy; PELT (Polymer-Enzyme Liposome Therapy; CDS (Chemical Delivery System; ADEPT(Antibody-Directed Enzyme Prodrug Therapy; GDEPT/VDEPT (Gene-Directed Enzyme Prodrug Therapy/Virus-Directed Enzyme Prodrug Therapy and ODDS (Osteotropic Drug Delivery System and LEAPT (Lectin-Directed Enzyme-Activated Prodrug Therapy.

  7. Multiphoton imaging for assessing renal disposition in acute kidney injury

    Science.gov (United States)

    Liu, Xin; Liang, Xiaowen; Wang, Haolu; Roberts, Darren M.; Roberts, Michael S.

    2016-11-01

    Estimation of renal function and drug renal disposition in acute kidney injury (AKI), is important for appropriate dosing of drugs and adjustment of therapeutic strategies, but is challenging due to fluctuations in kidney function. Multiphoton microscopy has been shown to be a useful tool in studying drug disposition in liver and can reflect dynamic changes of liver function. We extend this imaging technique to investigate glomerular filtration rate (GFR) and tubular transporter functional change in various animal models of AKI, which mimic a broad range of causes of AKI such as hypoxia (renal ischemia- reperfusion), therapeutic drugs (e.g. cisplatin), rhabdomyolysis (e.g. glycerol-induced) and sepsis (e.g. LPSinduced). The MPM images revealed acute injury of tubular cells as indicated by reduced autofluorescence and cellular vacuolation in AKI groups compared to control group. In control animal, systemically injected FITC-labelled inulin was rapidly cleared from glomerulus, while the clearance of FITC-inulin was significantly delayed in most of animals in AKI group, which may reflect the reduced GFR in AKI. Following intravenous injection, rhodamine 123, a fluorescent substrate of p-glycoprotein (one of tubular transporter), was excreted into urine in proximal tubule via p-glycoprotein; in response to AKI, rhodamine 123 was retained in tubular cells as revealed by slower decay of fluorescence intensity, indicating P-gp transporter dysfunction in AKI. Thus, real-time changes in GFR and transporter function can be imaged in rodent kidney with AKI using multiphoton excitation of exogenously injected fluorescent markers.

  8. Evaluation of drug-drug interaction between henagliflozin, a novel sodium-glucose co-transporter 2 inhibitor, and metformin in healthy Chinese males.

    Science.gov (United States)

    Wang, Liupeng; Wu, Chunyong; Shen, Lu; Liu, Haiyan; Chen, Ying; Liu, Fang; Wang, Youqun; Yang, Jin

    2016-08-01

    1. Henagliflozin is a novel sodium-glucose transporter 2 inhibitor and presents a complementary therapy to metformin for patients with T2DM due to its insulin-independent mechanism of action. This study evaluated the potential pharmacokinetic drug-drug interaction between henagliflozin and metformin in healthy Chinese male subjects. 2. In open-label, single-center, single-arm, two-period, three-treatment self-control study, 12 subjects received 25 mg henagliflozin, 1000 mg metformin or the combination. Lack of PK interaction was defined as the ratio of geometric means and 90% confidence interval (CI) for combination: monotherapy being within the range of 0.80-1.25. 3. Co-administration of henagliflozin with metformin had no effect on henagliflozin area under the plasma concentration-time curve (AUC0-24) (GRM: 1.08; CI: 1.05, 1.10) and peak plasma concentration (Cmax) (GRM: 0.99; CI: 0.92, 1.07). Reciprocally, co-administration of metformin with henagliflozin had no clinically significant on metformin AUC0-24 (GRM: 1.09, CI: 1.02, 1.16) although there was an 11% increase in metformin Cmax (GRM 1.12; CI 1.02, 1.23). All monotherapies and combination therapy were well tolerated. 4. Henagliflozin can be co-administered with metformin without dose adjustment of either drug.

  9. Moving out: from sterol transport to drug resistance - the ABCG subfamily of efflux pumps.

    Science.gov (United States)

    Moitra, Karobi; Silverton, Latoya; Limpert, Katy; Im, Kate; Dean, Michael

    2011-01-01

    The ATP binding cassette (ABC) proteins are typically ATP-driven transmembrane pumps that have been evolutionarily conserved from bacteria to humans. In humans these transporters are subdivided into seven subfamilies, ranging from A to G. The ABCG subfamily of transporters is the primary focus of this review. This subfamily of proteins has been conserved throughout evolution and plays a central role in several cellular processes, such as sterol homeostasis and multidrug resistance. Functional polymorphisms/mutations in some of these G-subfamily transporters have clinical consequences in humans.

  10. Toxicological Significance of Renal Bcrp: Another Potential Transporter in the Elimination of Mercuric Ions from Proximal Tubular Cells

    Science.gov (United States)

    Bridges, Christy C.; Zalups, Rudolfs K.; Joshee, Lucy

    2015-01-01

    Secretion of inorganic mercury (Hg2+) from proximal tubular cells into the tubula