title: Comparison of the Predictability of Human Hepatic Clearance for Organic Anion Transporting Polypeptide Substrate Drugs Between Different In Vitro-In Vivo Extrapolation Approaches.
abstract: Prediction of human pharmacokinetic profiles of drug candidates is an essential step toward first-in-human studies. However, it remains difficult to quantitatively predict hepatic clearance, particularly when hepatic uptake is mediated by transporter(s). Using 15 organic anion transporting polypeptide (OATP) substrate drugs, we tested 3 in vitro-in vivo extrapolation (IVIVE) approaches to predict overall hepatic intrinsic clearance in vivo (CLint,all,vivo). IVIVE approaches involved metabolic intrinsic clearance in human liver microsomes (CLint,met) with or without hepatocyte-to-buffer maximum unbound concentration ratio (Kp,uu,max) correction and uptake intrinsic clearance at 37°C (PSinf,37°C) in human hepatocyte suspensions. Kp,uu,maxand PSinf,37°Cvalues were determined in 2 hepatocyte batches, and all tested compounds showed temperature-dependent uptake, consistent with the fact of transporter-mediated uptake. CLint,metsubstantially underestimated CLint,all,vivo. By multiplying CLint,metby Kp,uu,maxvalues, the prediction performance was much improved; however, in vitro-in vivo correlation was poor. Among the IVIVE approaches, PSinf,37°Cshowed the most robust correlation with CLint,all,vivo, and one of the hepatocyte batches could predict CLint,all,vivowith a minimal empirical scaling factor. These results suggested IVIVE with hepatic uptake clearance determined in hepatocyte suspensions as one of the most practical approaches for predicting CLint,all,vivoof OATP substrate drugs.
authors.affiliation: Drug Metabolism and Pharmacokinetics Tsukuba, Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
authors.forename: Saki
authors.initials: S
authors.lastname: Izumi
authors.affiliation: Drug Metabolism and Pharmacokinetics Tsukuba, Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan. Electronic address: y2-nozaki@hhc.eisai.co.jp.
authors.forename: Yoshitane
authors.initials: Y
authors.lastname: Nozaki
authors.affiliation: Drug Metabolism and Pharmacokinetics Tsukuba, Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Komori
authors.affiliation: Modeling & Simulation, Clinical Pharmacology, Eisai Co., Ltd., 4-6-10 Koishikawa, Bunkyo-ku, Tokyo 112-8088, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Takenaka
authors.affiliation: Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Maeda
authors.affiliation: Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
authors.affiliation: Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, 1-6 Suehiro-cho, Tsurumi-ku, Yokohama-shi, Kanagawa 230-0045, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D001692:Biological Transport; D014453:Glucuronosyltransferase / Q000378:metabolism; D022781:Hepatocytes; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000378:metabolism*; D008954:Models, Biological; D027361:Organic Anion Transporters / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D053719:Tandem Mass Spectrometry / Q000379:methods; D013696:Temperature
chemical_list: D027361:Organic Anion Transporters; D010455:Peptides; D014453:Glucuronosyltransferase
keywords: active transport; cytochrome P450; glucuronosyltransferase (UGT); hepatic clearance; hepatic transport; hepatocytes; membrane transport/transporters; organic anion transporting polypeptide transporters; transporters