Altered cisplatin pharmacokinetics during nonalcoholic steatohepatitis contributes to reduced nephrotoxicity

作     者：Joseph L.Jilek Kayla L.Frost Kevyn A.Jacobus Wenxi He Erica L.Toth Michael Goedken Nathan J.Cherrington Joseph L.Jilek;Kayla L.Frost;Kevyn A.Jacobus;Wenxi He;Erica L.Toth;Michael Goedken;Nathan J.Cherrington

作者机构：Department of Pharmacology&ToxicologyCollege of PharmacyUniversity of ArizonaTucsonAZ 85724USA Rutgers Translational SciencesRutgers UniversityPiscatawayNJ 08901USA 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2021年第11卷第12期

页      面：3869-3878页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 1004[医学-公共卫生与预防医学(可授医学、理学学位)] 100706[医学-药理学] 1001[医学-基础医学(可授医学、理学学位)] 100602[医学-中西医结合临床] 10[医学] 

基　　金：supported by the National Institutes of Health(R01ES028668 P30ES006694 and T32ES007091 USA) 

主　　题：Nonalcoholic steatohepatitis NASH Cisplatin Drug transporter Nephrotoxicity 

摘      要：Disease-mediated alterations to drug disposition constitute a significant source of adverse drug ***(CDDP)elicits nephrotoxicity due to exposure in proximal tubule cells during renal *** to renal drug transporter expression have been discovered during nonalcoholic steatohepatitis(NASH),however,associated changes to substrate toxicity is *** test this,a methionine-and choline-deficient diet-induced rat model was used to evaluate NASH-associated changes to CDDP pharmacokinetics,transporter expression,and *** rats administered CDDP(6 mg/kg,i.p.)displayed 20%less nephrotoxicity than healthy ***,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 *** copper transporter-1 expression decreased,and organic cation transporter-2 and ATPase copper transporting protein-7 b increased slightly,reducing CDDP *** CDDP accumulation increased 250%in NASH rats relative to healthy *** 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 *** data provide a link between NASH-induced hepatic and renal transporter expression changes and CDDP renal clearance,which may alter nephrotoxicity.