Recent advances in preclinical in vitro approaches towards quantitative prediction of hepatic clearance and drug-drug interactions involving organic anion transporting polypeptide (OATP) 1B transporters |
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| Institution: | 1. Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan;2. Clinical Pharmacology Department, Daiichi Sankyo Co., Ltd, Tokyo, Japan;3. General Administration Department, Daiichi Sankyo RD Novare Co., Ltd, Tokyo, Japan;4. Biomarker & Translational Research Department, Daiichi Sankyo Co., Ltd, Tokyo, Japan;1. Chugai Pharmabody Research Pte. Ltd., Singapore;2. Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan;3. Laboratory of Clinical Pharmacology, Yokohama University of Pharmacy, Yokohama, Japan;4. Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Yokohama, Japan;1. Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA 98195, United States;2. Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS 66160, United States |
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| Abstract: | Hepatic uptake mediated by organic anion transporting polypeptide (OATP) 1B1 and 1B3 can serve as a major elimination pathway for various anionic drugs and as a site of drug-drug interactions (DDIs). This article provides an overview of the in vitro approaches used to predict human hepatic clearance (CLh) and the risk of DDIs involving OATP1Bs. On the basis of the so-called extended clearance concept, in vitro–in vivo extrapolation methods using human hepatocytes as in vitro systems have been used to predict the CLh involving OATP1B-mediated hepatic uptake. CLh can be quantitatively predicted using human donor lots possessing adequate OATP1B activities. The contribution of OATP1Bs to hepatic uptake can be estimated by the relative activity factor, the relative expression factor, or selective inhibitor approaches, which offer generally consistent outcomes. In OATP1B1 inhibition assays, substantial substrate dependency was observed. The time-dependent inhibition of OATP1B1 was also noted and may be a mechanism underlying the in vitro–in vivo differences in the inhibition constant of cyclosporine A. Although it is still challenging to quantitatively predict CLh and DDIs involving OATP1Bs from only preclinical data, understanding the utility and limitation of the current in vitro methods will pave the way for better prediction. |
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| Keywords: | Drug-drug interactions (DDIs) Extended clearance concept In vitro–in vivo extrapolation (IVIVE) Hepatic clearance Hepatocytes Organic anion transporting polypeptide (OATP) Relative activity factor (RAF) Relative expression factor (REF) Substrate-dependent inhibition Time-dependent inhibition |
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