Drug Metabolism and Pharmacokinetics Japan, Tsukuba Research Laboratories, Eisai Co., Ltd., Tokodai, Tsukuba-shi, Ibaraki, Japan (S.I., Y.N., T.K., O.T., K.K., T.Y.); Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (K.M., H.K.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Yokohama-shi, Kanagawa, Japan (Y.S.).
Drug Metab Dispos. 2013 Oct;41(10):1859-66. doi: 10.1124/dmd.113.052290. Epub 2013 Aug 6.
Organic anion transporting polypeptide (OATP) 1B1 plays an important role in the hepatic uptake of many drugs, and the evaluation of OATP1B1-mediated drug-drug interactions (DDIs) is emphasized in the latest DDI (draft) guidance documents from U.S. and E.U. regulatory agencies. It has been suggested that some OATP1B1 inhibitors show a discrepancy in their inhibitory potential, depending on the substrates used in the cell-based assay. In this study, inhibitory effects of 14 compounds on the OATP1B1-mediated uptake of the prototypical substrates [³H]estradiol-17β-glucuronide (E₂G), [³H]estrone-3-sulfate (E₁S), and [³H]sulfobromophthalein (BSP) were studied in OATP1B1-transfected cells. Inhibitory potencies of tested compounds varied depending on the substrates. Ritonavir, gemfibrozil, and erythromycin caused remarkable substrate-dependent inhibition with up to 117-, 14-, and 13-fold difference in their IC₅₀ values, respectively. Also, the clinically relevant OATP inhibitors rifampin and cyclosporin A exhibited up to 12- and 6-fold variation in their IC₅₀ values, respectively. Regardless of the inhibitors tested, the most potent OATP1B1 inhibition was observed when [³H]E₂G was used as a substrate. Mutual inhibition studies of OATP1B1 indicated that E₂G and E₁S competitively inhibited each other, whereas BSP noncompetitively inhibited E₂G uptake. In addition, BSP inhibited E₁S in a competitive manner, but E₁S caused an atypical kinetics on BSP uptake. This study showed substrate-dependent inhibition of OATP1B1 and demonstrated that E₂G was the most sensitive in vitro OATP1B1 probe substrate among three substrates tested. This will give us an insight into the assessment of clinically relevant OATP1B1-mediated DDI in vitro with minimum potential of false-negative prediction.
有机阴离子转运多肽 1B1（OATP1B1）在许多药物的肝脏摄取中发挥重要作用，因此，美国和欧盟监管机构的最新药物相互作用（DDI）指南草案强调了对 OATP1B1 介导的药物相互作用的评估。有研究表明，一些 OATP1B1 抑制剂在其抑制潜力方面存在差异，具体取决于细胞测定中使用的底物。在这项研究中，在 OATP1B1 转染细胞中研究了 14 种化合物对原型底物[³H]雌二醇-17β-葡糖苷酸（E₂G）、[³H]雌酮-3-硫酸盐（E₁S）和[³H]磺溴酞（BSP）的 OATP1B1 摄取的抑制作用。测试化合物的抑制效力因底物而异。利托那韦、吉非贝齐和红霉素分别导致高达 117、14 和 13 倍的 IC₅₀值差异，表现出明显的底物依赖性抑制。此外，临床相关的 OATP 抑制剂利福平（rifampin）和环孢素 A（cyclosporin A）的 IC₅₀值差异分别高达 12 和 6 倍。无论测试的抑制剂如何，当使用[³H]E₂G 作为底物时，观察到最强的 OATP1B1 抑制作用。OATP1B1 的相互抑制研究表明，E₂G 和 E₁S 竞争性地相互抑制，而 BSP 非竞争性地抑制 E₂G 的摄取。此外，BSP 以竞争性方式抑制 E₁S，但 E₁S 导致 BSP 摄取的非典型动力学。这项研究表明 OATP1B1 的底物依赖性抑制作用，并证明在测试的三种底物中，E₂G 是最敏感的体外 OATP1B1 探针底物。这将使我们深入了解体外评估具有最小潜在假阴性预测的临床相关 OATP1B1 介导的 DDI。
