title: Investigation of the impact of substrate selection on in vitro organic anion transporting polypeptide 1B1 inhibition profiles for the prediction of drug-drug interactions.
abstract: The risk assessment of organic anion transporting polypeptide (OATP) 1B1-mediated drug-drug interactions (DDIs) is an indispensable part of drug development. We previously reported that in vitro inhibitory potencies of several inhibitors on OATP1B1 depend on the substrates when prototypical substrates, estradiol-17β-glucuronide (E₂G), estrone-3-sulfate, and sulfobromophthalein were used as test substrates. The purpose of this study was to comprehensively investigate this substrate-dependent inhibition of OATP1B1 using clinically relevant OATP1B1 inhibitors and substrate drugs. Effects of cyclosporine A (CsA), rifampin, and gemfibrozil on OATP1B1-mediated uptake of 12 substrate drugs were examined in OATP1B1-expressing human embryonic kidney 293 cells. The Ki values (μM) for CsA varied from 0.0771 to 0.486 (6.3-fold), for rifampin from 0.358 to 1.23 (3.4-fold), and for gemfibrozil from 9.65 to 252 (26-fold). Except for the inhibition of torasemide uptake by CsA and that of nateglinide uptake by gemfibrozil, the Ki values were within 2.8-fold of those obtained using E₂G as a substrate. Preincubation potentiated the inhibitory effect of CsA on OATP1B1 with similar magnitude regardless of the substrates. R values calculated based on a static model showed some variation depending on the Ki values determined with various substrates, and such variability could have an impact on the DDI predictions particularly for a weak-to-moderate inhibitor (gemfibrozil). OATP1B1 substrate drugs except for torasemide and nateglinide, or E₂G as a surrogate, is recommended as an in vitro probe in the inhibition experiments, which will help mitigate the risk of false-negative DDI predictions potentially caused by substrate-dependent Ki variation.
authors.affiliation: Drug Metabolism and Pharmacokinetics Japan, Tsukuba Research Laboratories, Eisai Co. Ltd., Ibaraki, Japan (S.I., Y.N., T.K.); Pharmacokinetics and Pharmacodynamics, Morphotek Inc., Exton, Pennsylvania (O.T.); Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan (K.M., H.K.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.S.).
authors.forename: Saki
authors.initials: S
authors.lastname: Izumi
authors.affiliation: Drug Metabolism and Pharmacokinetics Japan, Tsukuba Research Laboratories, Eisai Co. Ltd., Ibaraki, Japan (S.I., Y.N., T.K.); Pharmacokinetics and Pharmacodynamics, Morphotek Inc., Exton, Pennsylvania (O.T.); Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan (K.M., H.K.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.S.).
authors.forename: Yoshitane
authors.initials: Y
authors.lastname: Nozaki
authors.affiliation: Drug Metabolism and Pharmacokinetics Japan, Tsukuba Research Laboratories, Eisai Co. Ltd., Ibaraki, Japan (S.I., Y.N., T.K.); Pharmacokinetics and Pharmacodynamics, Morphotek Inc., Exton, Pennsylvania (O.T.); Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan (K.M., H.K.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.S.).
authors.forename: Kazuya
authors.identifier: http://orcid.org/0000-0002-9174-5213
authors.initials: K
authors.lastname: Maeda
authors.affiliation: Drug Metabolism and Pharmacokinetics Japan, Tsukuba Research Laboratories, Eisai Co. Ltd., Ibaraki, Japan (S.I., Y.N., T.K.); Pharmacokinetics and Pharmacodynamics, Morphotek Inc., Exton, Pennsylvania (O.T.); Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan (K.M., H.K.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.S.).
authors.forename: Takafumi
authors.initials: T
authors.lastname: Komori
authors.affiliation: Drug Metabolism and Pharmacokinetics Japan, Tsukuba Research Laboratories, Eisai Co. Ltd., Ibaraki, Japan (S.I., Y.N., T.K.); Pharmacokinetics and Pharmacodynamics, Morphotek Inc., Exton, Pennsylvania (O.T.); Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan (K.M., H.K.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.S.).
authors.forename: Osamu
authors.initials: O
authors.lastname: Takenaka
authors.affiliation: Drug Metabolism and Pharmacokinetics Japan, Tsukuba Research Laboratories, Eisai Co. Ltd., Ibaraki, Japan (S.I., Y.N., T.K.); Pharmacokinetics and Pharmacodynamics, Morphotek Inc., Exton, Pennsylvania (O.T.); Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan (K.M., H.K.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.S.).
authors.forename: Hiroyuki
authors.identifier: http://orcid.org/0000-0002-3641-8746
authors.initials: H
authors.lastname: Kusuhara
authors.affiliation: Drug Metabolism and Pharmacokinetics Japan, Tsukuba Research Laboratories, Eisai Co. Ltd., Ibaraki, Japan (S.I., Y.N., T.K.); Pharmacokinetics and Pharmacodynamics, Morphotek Inc., Exton, Pennsylvania (O.T.); Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan (K.M., H.K.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.S.) ychi.sugiyama@riken.jp.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D000959:Antihypertensive Agents / Q000378:metabolism*; D001667:Binding, Competitive; D001692:Biological Transport / Q000187:drug effects; D003510:Cyclohexanes / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D004958:Estradiol / Q000031:analogs & derivatives / Q000378:metabolism; D015248:Gemfibrozil / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000378:metabolism*; D007700:Kinetics; D027381:Liver-Specific Organic Anion Transporter 1; D049990:Membrane Transport Modulators / Q000494:pharmacology*; D008954:Models, Biological; D000077715:Nateglinide; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012293:Rifampin / Q000494:pharmacology; D013449:Sulfonamides / Q000378:metabolism; D000077786:Torsemide
chemical_list: D000959:Antihypertensive Agents; D003510:Cyclohexanes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007004:Hypoglycemic Agents; D027381:Liver-Specific Organic Anion Transporter 1; D049990:Membrane Transport Modulators; D027361:Organic Anion Transporters; D011994:Recombinant Proteins; C503999:SLCO1B1 protein, human; D013449:Sulfonamides; C025483:estradiol-17 beta-glucuronide; D000077715:Nateglinide; D010649:Phenylalanine; D004958:Estradiol; D016572:Cyclosporine; D015248:Gemfibrozil; D012293:Rifampin; D000077786:Torsemide