基于药动学探究替芬泰与替诺福韦酯的药物-药物相互作用  

Investigation of drug-drug interactions between bentysrepinine and tenofovir disoproxil fumarate based on pharmacokinetic

作　　者：张玉凤 张晨晨 滕云华 梁博涵 王玲梅 王鹏 董世奇 张爱杰 樊慧蓉[2] ZHANG Yufeng;ZHANG Chenchen;TENG Yunhua;LIANG Bohan;WANG Lingmei;WANG Peng;DONG Shiqi;ZHANG Aijie;FAN Huirong(Tianjin University of Traditional Chinese Medicine,Tianjin 301617,China;Institute of Radiation Medicine,Chinese Academy of Medical Science,Tianjin 300192,China;Tianjin Hankang Medicinal&Biological Technology Co.,Ltd.,Tianjin 300409,China)

机构地区：[1]天津中医药大学,天津301617 [2]中国医学科学院放射医学研究所,天津300192 [3]天津市汉康医药生物技术有限公司,天津300409

出　　处：《药物评价研究》2024年第11期2597-2606,共10页Drug Evaluation Research

基　　金：国家自然科学基金青年基金项目(82104284)。

摘　　要：目的建立替诺福韦酯(TDF)的代谢产物替诺福韦(TFV)、替芬泰(Y101)及其代谢物M8的LC-MS/MS分析方法,基于大鼠体内药动学、肾排泄及体外肾切片摄取模型研究Y101与TDF的药物-药物相互作用(DDI)。方法①药动学实验:SD雄性大鼠随机分为3组,分别单次ig给药Y101(60 mg·kg^(−1))、TDF(30 mg·kg^(−1))及TDF(30 mg·kg^(−1))+Y101(60 mg·kg^(−1)),通过LC-MS/MS方法测定给药后血浆中Y101、M8、TFV浓度,并采用非房室模型统计矩法计算药动学参数。②肾排泄实验:SD雄性大鼠随机分为3组,分别单次iv给药Y101(25 mg·kg^(−1))、TDF(30 mg·kg^(−1))及TDF(30 mg·kg^(−1))+Y101(25 mg·kg^(−1))。利用LC-MS/MS方法测定尿样中Y101、M8、TFV浓度,分析药物及代谢物的累积排泄率;③肾切片实验:大鼠肾切片分别在含有M8(5.0μmol·L^(−1))、TFV(10μmol·L^(−1))、TFV(10μmol·L^(−1))+Y101(2.0μmol·L^(−1))和TFV(10μmol·L^(−1))+M8(5.0μmol·L^(−1))的药液中孵育一定时间后,收集样品经适当处理后利用LC-MS/MS方法测定肾脏对TFV、Y101、M8的摄取量。结果①药动学实验:对Y101及M8开展部分方法学验证,对TFV开展全面的方法学验证,验证结果表明LC-MS/MS方法专属性强、灵敏度高。采用LC-MS/MS方法测定大鼠血浆中的TFV、Y101和M8,发现与单独用药组相比,Y101+TDF组大鼠血浆中TFV、Y101和M8药时曲线下面积(AUC_(0-t)和AUC_(0-∞))显著性增加,血浆清除率(CLP)显著性减小。②肾排泄实验:Y101+TDF组的尿累积排泄分数低于单独用药组,且TFV、M8均出现显著性降低。③肾切片实验:TFV+M8组与单独孵育组相比,肾切片对TFV或M8的摄取量均显著性下降。结论TDF的代谢产物TFV与Y101的代谢产物M8可能通过竞争性抑制有机阴离子转运体3(OAT3),对TFV、M8的血药浓度及肾排泄造成影响,提示临床合用需要进行剂量调整。Objective To establish LC-MS/MS methods for the analysis of tenofovir(TFV),bentysrepinine(Y101)and its metabolite M8.The drug-drug interactions between Y101 and tenofovir disoproxil fumarate(TDF)and its mechanism were studied by using the model of in vivo pharmacokinetics,renal excretion and in vitro uptake in kidney slices.Methods①Pharmacokinetic experiments:SD male rats were randomly divided into three groups:rats were orally given Y101(60 mg·kg^(−1)),TDF(30 mg·kg^(−1))or TDF(30 mg·kg^(−1))+Y101(60 mg·kg^(−1)),respectively.Plasma concentrations of Y101,M8 and TFV were determined by LC-MS/MS methods,and pharmacokinetic parameters were calculated by Phenix WinNonlin with non-compartmental analysis.②Renal excretion experiments:SD male rats were randomly divided into three groups:Rats via tail vein were injected with Y101(25 mg·kg^(−1)),TDF(30 mg·kg^(−1))or TDF(30 mg·kg^(−1))+Y101(25 mg·kg^(−1)),respectively.The concentrations of Y101,M8 and TFV in urine samples were determined by LC-MS/MS methods,and the cumulative excretion rates of drugs and their metabolites were calculated.③Kidney slices experiments:Rat kidney slices were incubated in buffer containing M8(5.0μmol·L^(−1)),TFV(10μmol·L^(−1)),TFV(10μmol·L^(−1))+Y101(2.0μmol·L^(−1))or TFV(10μmol·L^(−1))+M8(5.0μmol·L^(−1))for a certain period of time,respectively.The samples were collected and properly treated,and then the renal uptakes of TFV,Y101 and M8 were determined by LC-MS/MS methods.Results①Pharmacokinetic experiments:A full validation of TFV and a partial validation of Y101 and M8 were carried out.These results showed that the LC-MS/MS methods were highly specific and sensitive.The concentrations of TFV,Y101 and M8 in rat plasma were determined by validated LC-MS/MS methods.It was found that compared with the Y101 or TDF treatment group,the area under the curve(AUC_(0-t) and AUC_(0-∞))of TFV,Y101 and M8 in rat plasma increased significantly and the plasma clearance rate(CLP)decreased significantly i

关 键 词：替芬泰 替诺福韦酯 替诺福韦 药物相互作用 肾排泄 有机阴离子转运体3 

分 类 号：R969.2[医药卫生—药理学]