Cell-to-Medium Concentration Ratio Overshoot in the Uptake of Statins by Human Hepatocytes in Suspension, but Not in Mon
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Research Article Cell-to-Medium Concentration Ratio Overshoot in the Uptake of Statins by Human Hepatocytes in Suspension, but Not in Monolayer: Kinetic Analysis Suggesting a Partial Loss of Functional OATP1Bs Wooin Lee,1 Satoshi Koyama,2 Kiyoe Morita,2 Aya Kiriake,2 Ryota Kikuchi,3 Xiaoyan Chu,4 Nora Lee,5 Renato J. Scialis,6 Hong Shen,6 Emi Kimoto,7 Larry Tremaine,8 Naoki Ishiguro,9 Ralf Lotz,10 Kazuya Maeda,11 Hiroyuki Kusuhara,11 and Yuichi Sugiyama2,12
Received 24 June 2020; accepted 15 September 2020 Abstract. Suspended human hepatocytes (SHH) have long been used in assessing hepatic drug uptake, while plated human hepatocytes in short-term monolayer culture (PHH) have gained use in recent years. This study aimed to cross-evaluate SHH and PHH in measuring the hepatic uptake mediated by organic anion transporting polypeptide 1Bs (OATP1Bs). We compared the time courses of cell-to-medium (C/M) concentration ratios and initial uptake clearance values of the OATP1B substrates (pitavastatin, rosuvastatin, cerivastatin, pravastatin, dehydropravastatin, and SC-62807) between SHH and PHH. For all compounds except cerivastatin, the C/M ratios in SHH displayed an apparent overshoot (an initial increase followed by a decrease) during the 180-min uptake experiment, but not in PHH. Based on the literature evidence suggesting the possible internalization of OATP1Bs in primary hepatocytes, separate experiments measured the drug uptake after varying lengths of pre-incubation in the drug-free medium. The initial uptake clearances of pitavastatin and
Electronic supplementary material The online version of this article (https://doi.org/10.1208/s12248-020-00512-6) contains supplementary material, which is available to authorized users. 1
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, South Korea. 2 Sugiyama Laboratory, RIKEN Cluster for Science, Technology and Innovation Hub, 1-7-22 Suehiro-cho, Tsurumi, Yokohama, Kanagawa, Japan. 3 AbbVie Inc, North Chicago, Illinois, USA. 4 Merck & Co., Inc, North Wales, Pennsylvania, USA. 5 Daewoong Pharmaceutical Co., Ltd, Seoul, South Korea. 6 Bristol Myers Squibb, Princeton, New Jersey, USA. 7 ADME Sciences, Medicine Design, Worldwide Research and Development, Pfizer Inc, Groton, Connecticut, USA. 8 Tremaine DMPK Consulting LLC, Merritt Island, Florida, USA. 9 Pharmacokinetics and Non-Clinical Safety Department, Nippon Boehringer Ingelheim Co., Ltd, Kobe, Hyogo, Japan. 10 Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany. 11 Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan. 12 To whom correspondence should be addressed. (e–mail: [email protected]) Abbreviations: SHH, Suspended human hepatocytes; PHH, Plated human hepatocytes; SCHH, Sandwich-cultured human hepatocytes; OATP, Organic anion transporting polypeptide; C/M ratio, Cell-tomedium concentration ratio; Kp,uu, Unbound
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