The liver plays a central role in the pharmacokinetics of drugs through drug metabolizing enzymes and transporters.Non-alcoholic steatohepatitis(NASH)causes disease-specific alterations to the absorption,distribution,...The liver plays a central role in the pharmacokinetics of drugs through drug metabolizing enzymes and transporters.Non-alcoholic steatohepatitis(NASH)causes disease-specific alterations to the absorption,distribution,metabolism,and excretion(ADME)processes,including a decrease in protein expression of basolateral uptake transporters,an increase in efflux transporters,and modifications to enzyme activity.This can result in increased drug exposure and adverse drug reactions(ADRs).Our goal was to predict drugs that pose increased risks for ADRs in NASH patients.Bibliographic research identified 71 drugs with reported ADRs in patients with liver disease,mainly non-alcoholic fatty liver disease(NAFLD),54 of which are known substrates of transporters and/or metabolizing enzymes.Since NASH is the progressive form of NAFLD but is most frequently undiagnosed,we identified other drugs at risk based on NASH-specific alterations to ADME processes.Here,we present another list of 71 drugs at risk of pharmacokinetic disruption in NASH,based on their transport and/or metabolism processes.It encompasses drugs from various pharmacological classes for which ADRs may occur when used in NASH patients,especially when eliminated through multiple pathways altered by the disease.Therefore,these results may inform clinicians regarding the selection of drugs for use in NASH patients.展开更多
Variations in drug metabolism may alter drug efficacy and cause toxicity;better understanding of the mechanisms and risks shall help to practice precision medicine.At the 21 st International Symposium on Microsomes an...Variations in drug metabolism may alter drug efficacy and cause toxicity;better understanding of the mechanisms and risks shall help to practice precision medicine.At the 21 st International Symposium on Microsomes and Drug Oxidations held in Davis,California,USA,in October 2-6,2016,a number of speakers reported some new findings and ongoing studies on the regulation mechanisms behind variable drug metabolism and toxicity,and discussed potential implications to personalized medications.A considerably insightful overview was provided on genetic and epigenetic regulation of gene expression involved in drug absorption,distribution,metabolism,and excretion(ADME) and drug response.Altered drug metabolism and disposition as well as molecular mechanisms among diseased and special populations were presented.In addition,the roles of gut microbiota in drug metabolism and toxicology as well as long non-coding RNAs in liver functions and diseases were discussed.These findings may offer new insights into improved understanding of ADME regulatory mechanisms and advance drug metabolism research.展开更多
Disease-mediated alterations to drug disposition constitute a significant source of adverse drug reactions.Cisplatin(CDDP)elicits nephrotoxicity due to exposure in proximal tubule cells during renal secretion.Alterati...Disease-mediated alterations to drug disposition constitute a significant source of adverse drug reactions.Cisplatin(CDDP)elicits nephrotoxicity due to exposure in proximal tubule cells during renal secretion.Alterations to renal drug transporter expression have been discovered during nonalcoholic steatohepatitis(NASH),however,associated changes to substrate toxicity is unknown.To test this,a methionine-and choline-deficient diet-induced rat model was used to evaluate NASH-associated changes to CDDP pharmacokinetics,transporter expression,and toxicity.NASH rats administered CDDP(6 mg/kg,i.p.)displayed 20%less nephrotoxicity than healthy rats.Likewise,CDDP renal clearance decreased in NASH rats from 7.39 to 3.83 mL/min,renal secretion decreased from 6.23 to 2.80 mL/min,and renal CDDP accumulation decreased by 15%,relative to healthy rats.Renal copper transporter-1 expression decreased,and organic cation transporter-2 and ATPase copper transporting protein-7 b increased slightly,reducing CDDP secretion.Hepatic CDDP accumulation increased 250%in NASH rats relative to healthy rats.Hepatic organic cation transporter-1 induction and multidrug and toxin extrusion protein-1 and multidrug resistance-associated protein-4 reduction may contribute to hepatic CDDP sequestration in NASH rats,although no drug-related toxicity was observed.These data provide a link between NASH-induced hepatic and renal transporter expression changes and CDDP renal clearance,which may alter nephrotoxicity.展开更多
基金supported by National Institutes of Health(R01ES028668 and P30ES006694,USA)。
文摘The liver plays a central role in the pharmacokinetics of drugs through drug metabolizing enzymes and transporters.Non-alcoholic steatohepatitis(NASH)causes disease-specific alterations to the absorption,distribution,metabolism,and excretion(ADME)processes,including a decrease in protein expression of basolateral uptake transporters,an increase in efflux transporters,and modifications to enzyme activity.This can result in increased drug exposure and adverse drug reactions(ADRs).Our goal was to predict drugs that pose increased risks for ADRs in NASH patients.Bibliographic research identified 71 drugs with reported ADRs in patients with liver disease,mainly non-alcoholic fatty liver disease(NAFLD),54 of which are known substrates of transporters and/or metabolizing enzymes.Since NASH is the progressive form of NAFLD but is most frequently undiagnosed,we identified other drugs at risk based on NASH-specific alterations to ADME processes.Here,we present another list of 71 drugs at risk of pharmacokinetic disruption in NASH,based on their transport and/or metabolism processes.It encompasses drugs from various pharmacological classes for which ADRs may occur when used in NASH patients,especially when eliminated through multiple pathways altered by the disease.Therefore,these results may inform clinicians regarding the selection of drugs for use in NASH patients.
基金supported by grants of U01CA175315 and R01GM113888 from the U.S.National Institutes of Health(NIH)supported by grants of ES006694 and ES007091 from NIH+8 种基金supported by grants of ES021800,ES020522,and ES005022 from NIHsupported by the Robert Bosch Foundation,Stuttgart,Germanysupported by grants of ES023438 and DK083952 from NIHsupported by grant of R01HL122593 from NIH and the Searle Scholars Program,USAsupported by grant of R01ES025708 from NIHsupported by grants of CA098468 and T32DK007737 from NIHsupported by grants of R01DK33765 and R01ES024421 from NIHsupported by grants of R01DK104656,R01DK080440,R01ES025909,R21AA022482,and R21AA024935 from NIH,grant of 1I01BX002634 from VA Merit Award,USA,grant of No.81572443 from National Natural Science Foundation of China,and grant of P30 DK34989 from Yale Liver Center,USAsupported by grants of R01ES019487,R01GM087367,and R01GM118367 from NIH
文摘Variations in drug metabolism may alter drug efficacy and cause toxicity;better understanding of the mechanisms and risks shall help to practice precision medicine.At the 21 st International Symposium on Microsomes and Drug Oxidations held in Davis,California,USA,in October 2-6,2016,a number of speakers reported some new findings and ongoing studies on the regulation mechanisms behind variable drug metabolism and toxicity,and discussed potential implications to personalized medications.A considerably insightful overview was provided on genetic and epigenetic regulation of gene expression involved in drug absorption,distribution,metabolism,and excretion(ADME) and drug response.Altered drug metabolism and disposition as well as molecular mechanisms among diseased and special populations were presented.In addition,the roles of gut microbiota in drug metabolism and toxicology as well as long non-coding RNAs in liver functions and diseases were discussed.These findings may offer new insights into improved understanding of ADME regulatory mechanisms and advance drug metabolism research.
基金supported by the National Institutes of Health(R01ES028668,P30ES006694,and T32ES007091,USA)。
文摘Disease-mediated alterations to drug disposition constitute a significant source of adverse drug reactions.Cisplatin(CDDP)elicits nephrotoxicity due to exposure in proximal tubule cells during renal secretion.Alterations to renal drug transporter expression have been discovered during nonalcoholic steatohepatitis(NASH),however,associated changes to substrate toxicity is unknown.To test this,a methionine-and choline-deficient diet-induced rat model was used to evaluate NASH-associated changes to CDDP pharmacokinetics,transporter expression,and toxicity.NASH rats administered CDDP(6 mg/kg,i.p.)displayed 20%less nephrotoxicity than healthy rats.Likewise,CDDP renal clearance decreased in NASH rats from 7.39 to 3.83 mL/min,renal secretion decreased from 6.23 to 2.80 mL/min,and renal CDDP accumulation decreased by 15%,relative to healthy rats.Renal copper transporter-1 expression decreased,and organic cation transporter-2 and ATPase copper transporting protein-7 b increased slightly,reducing CDDP secretion.Hepatic CDDP accumulation increased 250%in NASH rats relative to healthy rats.Hepatic organic cation transporter-1 induction and multidrug and toxin extrusion protein-1 and multidrug resistance-associated protein-4 reduction may contribute to hepatic CDDP sequestration in NASH rats,although no drug-related toxicity was observed.These data provide a link between NASH-induced hepatic and renal transporter expression changes and CDDP renal clearance,which may alter nephrotoxicity.