Down‐Regulation of OATP1B1‐Mediated Transport by Mammalian Target of Rapamycin (mTOR) Inhibitors Everolimus and Sirolimus: Potential Mechanism and Implication in OATP‐Mediated Drug‐Drug Interactions

作者：Taleah Farasyn, Sonia Pahwa, Xueying Wang, Pengyue Zhang, Kai Ding, Lang Li, Wei Lee Yue · 发表于：The FASEB Journal · 年份：2017 · DOI：10.1096/fasebj.31.1_supplement.1062.9 · 研究领域：Drug Transport and Resistance Mechanisms、Pharmacological Effects and Toxicity Studies、Amino Acid Enzymes and Metabolism

Purpose Organic anion transporting polypeptides (OATP) 1B1 is an important determinant of transporter‐mediated drug‐drug interactions (DDIs). The OATP substrates statins are often co‐administered with immunosuppressants including mammalian target of rapamycin (mTOR) inhibitors everolimus (EV) and sirolimus (SIR) to reduce cardiovascular risks in transplant recipients. OATP1B1 has putative phosphorylation sites by the mTOR kinase. The aim of this study is to determine the effects of mTOR inhibitors on OATP1B1‐mediated transport and to elucidate the potential underlying mechanism and implication in OATP‐mediated DDIs. Methods Phosphorylation of OATP1B1 was determined by P32‐orthophosphate labeling. Effects of EV and SIR on accumulation of [ 3 H]E 2 17G, [ 3 H]estrone sulfate and [ 3 H]rosuvastatin were determined in HEK293‐OATP1B1 cells. The effects of EV and SIR on wild‐type (WT) OATP1B1‐ and mTOR kinase‐dead mutant (MT) OATP1B1‐mediated transport were compared. The IC 50 of EV and SIR against OATP1B1 was determined with or without pre‐incubation with EV or SIR. The maximum plasma concentration (C max )/IC 50 and plasma concentration‐time curve (AUC) ratio [AUCR=1+(f u × I in,max /IC 50 )] were calculated based on the FDA draft guidance for OATP‐inhibition tree. The FDA Adverse Events Reporting System (FAERS) was used for pharmacoepidemiological studies to assess whether concurrent usage of EV or SIR with metabolically stable statins, pitavastatin, rosuvastatin and pravastatin...