基于相对摄取清除率的有机阴离子转运多肽 1B1（OATP1B1）和 OATP1B3 介导的摄取清除率的比例因子（RAF）在人肝细胞中的研究。
Relative Activity Factor (RAF)-Based Scaling of Uptake Clearance Mediated by Organic Anion Transporting Polypeptide (OATP) 1B1 and OATP1B3 in Human Hepatocytes.
机构信息
Drug Metabolism and Pharmacokinetics Tsukuba , Tsukuba Research Laboratories, Eisai Co., Ltd. , 5-1-3 Tokodai , Tsukuba-shi , Ibaraki 300-2635 , Japan.
Laboratory of Molecular Pharmacokinetics , Graduate School of Pharmaceutical Sciences, University of Tokyo , 7-3-1 Hongo , Bunkyo-ku, Tokyo 113-003 , Japan.
出版信息
Mol Pharm. 2018 Jun 4;15(6):2277-2288. doi: 10.1021/acs.molpharmaceut.8b00138. Epub 2018 May 16.
In vitro-in vivo extrapolation based on uptake clearance determined in human hepatocytes has been used to predict in vivo hepatic clearance of organic anion transporting polypeptide (OATP) substrates. This study evaluated the relative activity factor (RAF) approach to extrapolate active uptake clearance in transporter-transfected cell systems (CL) to that in human hepatocyte suspensions (PS). RAF values for OATP1B1 and OATP1B3 were determined in two batches of cryopreserved human hepatocytes using estrone-3-sulfate and cholecystokinin octapeptide as reference substrates, respectively. Fourteen OATP1B substrate drugs selected (atorvastatin, bosentan, cerivastatin, fexofenadine, fluvastatin, glibenclamide, irbesartan, nateglinide, pitavastatin, pravastatin, rosuvastatin, telmisartan, torasemide, and valsartan) showed temperature-dependent uptake in human hepatocytes. In transporter-transfected cells, OATP1B1- and OATP1B3-mediated uptake was observed in all compounds except for telmisartan. RAF-based net CL was mainly accounted for by OATP1B1 (72.3-99.7%) and fell within the 3-fold of PS observed in human hepatocytes in 11 out of 13 compounds (excluding telmisartan). This study demonstrated that the RAF approach provides a quantitative index of OATP1B1- and OATP1B3-mediated PS in human hepatocytes, which will facilitate the optimization of the pharmacokinetic properties of OATP1B substrates at nonclinical stages of drug development.
基于人源肝细胞摄取清除率进行的体外-体内外推法已被用于预测有机阴离子转运多肽（OATP）底物的体内肝脏清除率。本研究评估了相对活性因子（RAF）方法，即将转染细胞系统中的主动摄取清除率（CL）外推至人肝细胞悬液（PS）中的情况。使用雌酮-3-硫酸盐和缩胆囊素八肽作为参考底物，在两批冷冻保存的人原代肝细胞中确定了 OATP1B1 和 OATP1B3 的 RAF 值。选择了 14 种 OATP1B 底物药物（阿托伐他汀、波生坦、西立伐他汀、非索非那定、氟伐他汀、格列本脲、厄贝沙坦、那格列奈、匹伐他汀、普伐他汀、罗苏伐他汀、替米沙坦、托拉塞米和缬沙坦），这些药物在人原代肝细胞中表现出温度依赖性摄取。在转染细胞中，除替米沙坦外，所有化合物均观察到 OATP1B1 和 OATP1B3 介导的摄取。基于 RAF 的净 CL 主要由 OATP1B1 （72.3-99.7%）解释，并且在 13 种化合物中的 11 种（不包括替米沙坦）中，观察到与人原代肝细胞中 PS 的 3 倍范围内相符。本研究表明，RAF 方法提供了人原代肝细胞中 OATP1B1 和 OATP1B3 介导的 PS 的定量指标，这将有助于在药物开发的非临床阶段优化 OATP1B 底物的药代动力学性质。
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