title: Investigation of Endogenous Compounds Applicable to Drug-Drug Interaction Studies Involving the Renal Organic Anion Transporters, OAT1 and OAT3, in Humans.
abstract: This study was a comprehensive analysis of metabolites in plasma and urine specimens from subjects who received probenecid, a potent inhibitor of renal organic anion transporters (OATs). Taurine and glycochenodeoxycholate sulfate (GCDCA-S) could be identified using authentic standards. Probenecid had no effect on the area under the plasma-concentration time curves of taurine and GCDCA-S, whereas it significantly inhibited their urinary excretion in a dose-dependent manner. Probenecid at 500, 750, and 1500 mg orally decreased the renal clearance (CLR) values of taurine and GCDCA-S by 45% and 60%, 59% and 79%, and 70% and 88%, respectively. The CLRvalues correlated strongly (r > 0.96) between the test compounds (benzylpenicillin, 6β-hydroxycortisol, taurine, and GCDCA-S). Taurine and GCDCA-S were substrates of OAT1 and OAT3, with Kmvalues of 379 ± 58 and 64.3 ± 3.9 μM, respectively. The Kivalues of probenecid for the OAT1- and OAT3-mediated uptake of taurine and GCDCA-S (9.49 ± 1.27 and 7.40 ± 0.70 μM, respectively) were similar to those of their typical substrate drugs. The magnitude of the reduction in the CLRof taurine and GCDCA-S by probenecid could be reasonably explained using the geometric mean values of unbound probenecid concentration and Kivalues. These results suggest that taurine and GCDCA-S can be used as probes for evaluating pharmacokinetic drug-drug interactions involving OAT1 and OAT3, respectively, in humans.
authors.affiliation: Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan (Y.T., Y.Sa., K.M., H.K.); Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan (K.K.); Drug Metabolism and Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co. Ltd., Tokyo, Japan (Y.I.); Clinical Trial Center, Kitasato University Hospital, Kanagawa, Japan (Y.K.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.Su.).
authors.forename: Yuri
authors.initials: Y
authors.lastname: Tsuruya
authors.affiliation: Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan (Y.T., Y.Sa., K.M., H.K.); Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan (K.K.); Drug Metabolism and Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co. Ltd., Tokyo, Japan (Y.I.); Clinical Trial Center, Kitasato University Hospital, Kanagawa, Japan (Y.K.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.Su.).
authors.forename: Koji
authors.initials: K
authors.lastname: Kato
authors.affiliation: Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan (Y.T., Y.Sa., K.M., H.K.); Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan (K.K.); Drug Metabolism and Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co. Ltd., Tokyo, Japan (Y.I.); Clinical Trial Center, Kitasato University Hospital, Kanagawa, Japan (Y.K.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.Su.).
authors.forename: Yamato
authors.initials: Y
authors.lastname: Sano
authors.affiliation: Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan (Y.T., Y.Sa., K.M., H.K.); Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan (K.K.); Drug Metabolism and Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co. Ltd., Tokyo, Japan (Y.I.); Clinical Trial Center, Kitasato University Hospital, Kanagawa, Japan (Y.K.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.Su.).
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Imamura
authors.affiliation: Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan (Y.T., Y.Sa., K.M., H.K.); Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan (K.K.); Drug Metabolism and Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co. Ltd., Tokyo, Japan (Y.I.); Clinical Trial Center, Kitasato University Hospital, Kanagawa, Japan (Y.K.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.Su.).
authors.forename: Kazuya
authors.initials: K
authors.lastname: Maeda
authors.affiliation: Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan (Y.T., Y.Sa., K.M., H.K.); Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan (K.K.); Drug Metabolism and Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co. Ltd., Tokyo, Japan (Y.I.); Clinical Trial Center, Kitasato University Hospital, Kanagawa, Japan (Y.K.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.Su.).
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kumagai
authors.affiliation: Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan (Y.T., Y.Sa., K.M., H.K.); Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan (K.K.); Drug Metabolism and Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co. Ltd., Tokyo, Japan (Y.I.); Clinical Trial Center, Kitasato University Hospital, Kanagawa, Japan (Y.K.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.Su.).
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
authors.affiliation: Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan (Y.T., Y.Sa., K.M., H.K.); Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan (K.K.); Drug Metabolism and Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co. Ltd., Tokyo, Japan (Y.I.); Clinical Trial Center, Kitasato University Hospital, Kanagawa, Japan (Y.K.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.Su.) kusuhara@mol.f.u-tokyo.ac.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
mesh_terms: D000328:Adult; D000818:Animals; D002460:Cell Line; D004347:Drug Interactions / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D027362:Organic Anion Transport Protein 1 / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism*; D010400:Penicillin G / Q000378:metabolism / Q000494:pharmacology; D011339:Probenecid / Q000378:metabolism* / Q000494:pharmacology; D013654:Taurine / Q000378:metabolism / Q000494:pharmacology; D055815:Young Adult
chemical_list: D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; C114338:organic anion transport protein 3; D013654:Taurine; C001380:6 beta-hydroxycortisol; D011339:Probenecid; D010400:Penicillin G; D006854:Hydrocortisone