title: Stereoselective hydroxylation by CYP2C19 and oxidation by ADH4 in the in vitro metabolism of tivantinib.
abstract: 1. In prior studies, it has been shown that tivantinib is extensively metabolized in humans to many oxidative metabolites and glucuronides. In order to identify the responsible enzymes, we investigated the in vitro metabolism of tivantinib and its four major circulating metabolites. 2. The primary isoforms involved in the elimination of tivantinib were CYP2C19 and CYP3A4/5. CYP2C19 showed catalytic activity for the formation of M5 (hydroxylated metabolite), but not for M4 (a stereoisomer of M5), whereas CYP3A4/5 catalyzed the formation of both metabolites. For the elimination of M4, M5 and M8 (keto-metabolite), CYP3A4/5 was the major cytochrome P450 isoform and UGT1A9 was mainly involved in the glucuronidation of M4 and M5. 3. ADH4 was identified as one of the major alcohol dehydrogenase isoforms contributing to the formation of M6 (sequential keto-metabolite of M4 and M5) and M8. The substrate preference of ADH for M4, and not M5, was observed in the formation of M6. 4. In conclusion, CYP2C19, CYP3A4/5, UGT1A9 and ADH4 were the primary drug metabolizing enzymes involved in the in vitro metabolism of tivantinib and its metabolites. The stereoselective hydroxylation by CYP2C19 and substrate stereoselectivity of ADH4-catalyzed oxidation in the in vitro metabolism of tivantinib was discovered.
authors.affiliation: a Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd. , Tokyo , Japan .
authors.forename: Yumi
authors.initials: Y
authors.lastname: Nishiya
authors.affiliation: a Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd. , Tokyo , Japan .
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nakai
authors.affiliation: a Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd. , Tokyo , Japan .
authors.forename: Yoko
authors.initials: Y
authors.lastname: Urasaki
authors.affiliation: a Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd. , Tokyo , Japan .
authors.forename: Hideo
authors.initials: H
authors.lastname: Takakusa
authors.affiliation: b Organic Synthesis Department, Daiichi Sankyo RD Novare Co., Ltd. , Tokyo , Japan .
authors.forename: Satoru
authors.initials: S
authors.lastname: Ohsuki
authors.affiliation: b Organic Synthesis Department, Daiichi Sankyo RD Novare Co., Ltd. , Tokyo , Japan .
authors.forename: Yuji
authors.initials: Y
authors.lastname: Iwano
authors.affiliation: b Organic Synthesis Department, Daiichi Sankyo RD Novare Co., Ltd. , Tokyo , Japan .
authors.forename: Takanori
authors.initials: T
authors.lastname: Yasukochi
authors.affiliation: c Discovery Science and Technology Department, Daiichi Sankyo RD Novare Co., Ltd. , Tokyo , Japan .
authors.forename: Tomoko
authors.initials: T
authors.lastname: Takayama
authors.affiliation: c Discovery Science and Technology Department, Daiichi Sankyo RD Novare Co., Ltd. , Tokyo , Japan .
authors.forename: Shohei
authors.initials: S
authors.lastname: Bazyo
authors.affiliation: c Discovery Science and Technology Department, Daiichi Sankyo RD Novare Co., Ltd. , Tokyo , Japan .
authors.forename: Chikahiro
authors.initials: C
authors.lastname: Oza
authors.affiliation: a Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd. , Tokyo , Japan .
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kurihara
authors.affiliation: d ArQule, Inc. , Woburn , MA , USA , and.
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Savage
authors.affiliation: e Research Function, Daiichi Sankyo Co., Ltd. , Tokyo , Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Izumi
mesh_terms: D000426:Alcohol Dehydrogenase / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000378:metabolism*; D065731:Cytochrome P-450 CYP2C19 / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D010084:Oxidation-Reduction; D011760:Pyrrolidinones / Q000378:metabolism*; D011804:Quinolines / Q000378:metabolism*
chemical_list: C551661:ARQ 197; D000970:Antineoplastic Agents; D011760:Pyrrolidinones; D011804:Quinolines; D000426:Alcohol Dehydrogenase; C105552:alcohol dehydrogenase IV; D065731:Cytochrome P-450 CYP2C19
keywords: Alcohol dehydrogenase; UDP-glucuronosyltransferase; c-Met inhibitor; cytochrome P450; enzyme identification; human