Wang Chong, Huo Xiaokui, Wang Changyuan, Meng Qiang, Liu Zhihao, Sun Pengyuan, Cang Jian, Sun Huijun, Liu Kexin
Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Liaoning, China.
Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Liaoning, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Dalian Medical University, Liaoning, China.
J Pharm Sci. 2017 Sep;106(9):2515-2523. doi: 10.1016/j.xphs.2017.05.011. Epub 2017 May 20.
Cilostazol undergoes extensive liver metabolism. However, the transporter-mediated hepatic disposition of cilostazol remains unknown. The present study was performed to investigate the hepatic uptake and biliary excretion of cilostazol and its metabolites (OPC-13015 and OPC-13213) using rat liver and human transporter-transfected cells in vitro. Cilostazol uptake by rat liver slices and isolated rat hepatocytes exhibited time-, concentration-, and temperature dependency and was decreased by Oatp inhibitors, which suggested that Oatp was involved in the hepatic uptake of cilostazol. Cilostazol uptake in rat hepatocytes, OATP1B1-, and OATP1B3-HEK293 cells indicated a saturable process with K values of 2.7 μM, 17.7 μM, and 2.7 μM, respectively. Epigallocatechin gallate, cyclosporin A, rifampicin, and telmisartan inhibited cilostazol uptake in OATP1B1/1B3-HEK293 cells with K values close to their clinical plasma concentration, which suggested possible drug-drug interactions in humans via OATP1B1/1B3. Moreover, the cumulative biliary excretion of cilostazol and OPC-13015 was significantly decreased by quinidine, bilirubin, and novobiocin in perfused rat liver, but OPC-13213 biliary excretion was only inhibited by novobiocin, which suggested that the efflux transporters Mrp2, Bcrp, and P-gp were involved in the biliary excretion of cilostazol and its metabolites. Our findings indicated that multiple transporters were involved in the hepatic disposition of cilostazol and its metabolites.
西洛他唑在肝脏中经历广泛的代谢。然而，西洛他唑经转运体介导的肝脏处置情况仍不清楚。本研究旨在利用大鼠肝脏和转染了人类转运体的细胞，在体外研究西洛他唑及其代谢产物（OPC-13015和OPC-13213）的肝脏摄取和胆汁排泄情况。大鼠肝切片和分离的大鼠肝细胞对西洛他唑的摄取表现出时间、浓度和温度依赖性，并且被Oatp抑制剂所抑制，这表明Oatp参与了西洛他唑的肝脏摄取。大鼠肝细胞、OATP1B1-和OATP1B3-HEK293细胞对西洛他唑的摄取显示为一个可饱和过程，K值分别为2.7 μM、17.7 μM和2.7 μM。表没食子儿茶素没食子酸酯、环孢素A、利福平和平坦沙坦在OATP1B1/1B3-HEK293细胞中抑制西洛他唑的摄取，其K值接近它们的临床血浆浓度，这表明在人类中可能通过OATP1B1/1B3发生药物-药物相互作用。此外，在灌注的大鼠肝脏中，奎尼丁、胆红素和新生霉素显著降低了西洛他唑和OPC-13015的累积胆汁排泄，但OPC-13213的胆汁排泄仅被新生霉素抑制，这表明外排转运体Mrp2、Bcrp和P-gp参与了西洛他唑及其代谢产物的胆汁排泄。我们的研究结果表明，多种转运体参与了西洛他唑及其代谢产物的肝脏处置。
