Drug Metabolism and Pharmacokinetics Research Laboratories Department I, Mitsubishi Tanabe Pharma Corporation, Toda, Saitama, Japan (T.T., T.O., T.K.); Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Wakayama, Japan (T.Y., I.T., Y.U., M.U.); and Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, Japan (H.Y.).
Drug Metab Dispos. 2013 Oct;41(10):1875-82. doi: 10.1124/dmd.113.052753. Epub 2013 Aug 8.
Drug-drug interactions (DDIs) caused by the inhibition of hepatic uptake transporters such as organic anion transporting polypeptide (OATP) can affect therapeutic efficacy and cause adverse reactions. We investigated the potential utility of pitavastatin as an in vivo probe substrate for preclinically studying OATP-mediated DDIs using cynomolgus monkeys. Cyclosporine A (CsA) and rifampicin (RIF), typical OATP inhibitors, inhibited active uptake of pitavastatin into monkey hepatocytes with half-maximal inhibitory concentration values comparable with those in human hepatocytes. CsA and RIF increased the area under the plasma concentration-time curve (AUC) of intravenously administered pitavastatin in cynomolgus monkeys by 3.2- and 3.6-fold, respectively. In addition, there was no apparent prolongation of the elimination half-life of pitavastatin due to the decrease in both hepatic clearance and volume of distribution. These findings suggest that DDIs were caused by the inhibition of hepatic uptake of pitavastatin. CsA and RIF increased the AUC of orally administered pitavastatin by 10.6- and 14.8-fold, respectively, which was additionally caused by the effect of the CsA and RIF in the gastrointestinal tract. Hepatic contribution to the overall DDI for oral pitavastatin with CsA was calculated from the changes in hepatic availability and clearance, and it was shown that the magnitude of hepatic DDI was comparable between the present study and the clinical study. In conclusion, pharmacokinetic studies using pitavastatin as a probe in combination with drug candidates in cynomolgus monkeys are useful to support the assessment of potential clinical DDIs involving hepatic uptake transporters.
药物-药物相互作用（DDI）由有机阴离子转运多肽（OATP）等肝摄取转运体的抑制引起，可能会影响治疗效果并导致不良反应。我们使用食蟹猴研究了匹伐他汀作为体内探针底物，用于在临床前研究 OATP 介导的 DDI 的潜在应用。环孢素 A（CsA）和利福平（RIF）是典型的 OATP 抑制剂，它们抑制匹伐他汀进入猴肝细胞的主动摄取，其半最大抑制浓度值与人类肝细胞相当。CsA 和 RIF 使静脉给予食蟹猴的匹伐他汀的血浆浓度-时间曲线下面积（AUC）分别增加了 3.2 倍和 3.6 倍。此外，由于肝清除率和分布容积的降低，匹伐他汀的消除半衰期没有明显延长。这些发现表明，DDI 是由匹伐他汀肝摄取的抑制引起的。CsA 和 RIF 使口服匹伐他汀的 AUC 分别增加了 10.6 倍和 14.8 倍，这还归因于 CsA 和 RIF 在胃肠道中的作用。从肝可用性和清除率的变化计算了 CsA 对口服匹伐他汀的总体 DDI 的肝贡献，结果表明，本研究和临床研究中肝 DDI 的程度相当。总之，使用匹伐他汀作为探针与食蟹猴中的候选药物进行药代动力学研究，有助于支持对涉及肝摄取转运体的潜在临床 DDI 的评估。
