Sato Toshihiro, Mishima Eikan, Mano Nariyasu, Abe Takaaki, Yamaguchi Hiroaki
Department of Pharmaceutical Sciences, Tohoku University Hospital (T.S., N.M., H.Y.); Division of Nephrology, Endocrinology, and Vascular Medicine, Graduate School of Medicine (E.M., T.A.); Division of Medical Science, Graduate School of Biomedical Engineering (T.A.); Department of Clinical Biology and Hormonal Regulation, Graduate School of Medicine (T.A.), Tohoku University, Sendai, Japan.
Department of Pharmaceutical Sciences, Tohoku University Hospital (T.S., N.M., H.Y.); Division of Nephrology, Endocrinology, and Vascular Medicine, Graduate School of Medicine (E.M., T.A.); Division of Medical Science, Graduate School of Biomedical Engineering (T.A.); Department of Clinical Biology and Hormonal Regulation, Graduate School of Medicine (T.A.), Tohoku University, Sendai, Japan
J Pharmacol Exp Ther. 2017 Aug;362(2):271-277. doi: 10.1124/jpet.117.241703. Epub 2017 May 26.
Organic anion-transporting polypeptide 4C1 (OATP4C1) is an organic anion transporter expressed in the basolateral membrane of the renal proximal tubules. It plays a major role in the urinary excretion of both exogenous drugs and endogenous compounds. Our previous studies have indicated the importance of OATP4C1 in pathologic and physiologic conditions; however, the majority of its pharmacologic characteristics remained unclear. Therefore, to provide essential information for clinical drug therapy decisions and drug development, we clarified drug interactions mediated by OATP4C1. To elucidate potential drug interactions via OATP4C1, we screened 53 representative drugs commonly used in clinical settings. Next, we evaluated the IC values of drugs that inhibited OATP4C1 by more than 50%. To apply our results to clinical settings, we calculated the drug-drug interaction (DDI) indices. The screening analysis using an OATP4C1-expressing cell system demonstrated that 22 out of 53 therapeutic drugs inhibited OATP4C1-mediated triiodothyronine transport. In particular, OATP4C1-mediated transport was strongly inhibited by 10 drugs. The IC values of 10 drugs-nicardipine, spironolactone, fluvastatin, crizotinib, levofloxacin, clarithromycin, ritonavir, saquinavir, quinidine, and verapamil-obtained in this study were 51, 53, 41, 24, 420, 200, 8.5, 4.3, 100, and 110 M, respectively. The IC values of these drugs were higher than the plasma concentrations obtained in clinical practice. However, ritonavir showed the highest DDI index (1.9) for OATP4C1, suggesting that it may strongly influence this transporter and thus cause drug interactions seen in clinical settings. Our finding gives new insight into the role of OATP4C1 in clinical DDIs.
有机阴离子转运多肽4C1（OATP4C1）是一种在肾近端小管基底外侧膜表达的有机阴离子转运体。它在外源性药物和内源性化合物的尿排泄中起主要作用。我们之前的研究表明了OATP4C1在病理和生理条件下的重要性；然而，其大部分药理学特性仍不清楚。因此，为了为临床药物治疗决策和药物开发提供重要信息，我们阐明了由OATP4C1介导的药物相互作用。为了阐明通过OATP4C1的潜在药物相互作用，我们筛选了53种临床常用的代表性药物。接下来，我们评估了抑制OATP4C1超过50%的药物的IC值。为了将我们的结果应用于临床，我们计算了药物相互作用（DDI）指数。使用表达OATP4C1的细胞系统进行的筛选分析表明，53种治疗药物中有22种抑制OATP4C1介导的三碘甲状腺原氨酸转运。特别是，10种药物强烈抑制OATP4C1介导的转运。本研究中获得的10种药物——尼卡地平、螺内酯、氟伐他汀、克唑替尼、左氧氟沙星、克拉霉素、利托那韦、沙奎那韦、奎尼丁和维拉帕米——的IC值分别为51、53、41、24、420、200、8.5、4.3、100和110μM。这些药物的IC值高于临床实践中获得的血浆浓度。然而，利托那韦对OATP4C1的DDI指数最高（1.9），表明它可能强烈影响该转运体，从而导致临床中出现的药物相互作用。我们的发现为OATP4C1在临床药物相互作用中的作用提供了新的见解。
