title: Metabolism and disposition of [(14)C]tivantinib after oral administration to humans, dogs and rats.
abstract: 1. The biotransformation and disposition of tivantinib in humans, dogs and rats was examined after a single oral administration of [(14)C]tivantinib. Tivantinib constituted no more than one-third of the plasma radioactivity in all species, demonstrating significant contribution of the metabolites to plasma radioactivity. The major circulating metabolites in all species were M4 and M5, hydroxylated metabolites at the benzyl position of the tricyclic ring, accounting for 19.3 and 12.2% of the AUC of the total radioactivity, respectively, in humans. 2. The majority of radioactivity was excreted to the feces via bile. Tivantinib was detected at trace levels in urine, feces and bile, demonstrating extensive metabolism prior to biliary excretion and nearly complete tivantinib absorption under fed conditions. 3. Seven metabolic pathways were identified for tivantinib and included six oxidations (M4, M5, M7, M8, M9 and M11) and one glucuronidation (M23). The major metabolic and excretory pathways were found to be common among all species. Species differences in the metabolic pathways included lactam metabolite (M8) formation in humans and dehydrogenated metabolite (M11) formation in animals. 4. None of the metabolites identified in this work are believed to significantly impact the efficacy or toxicity of tivantinib in humans.
authors.affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd. , Hiromachi, Shinagawa-ku, Tokyo , Japan .
authors.forename: Takahiro
authors.initials: T
authors.lastname: Murai
authors.forename: Hideo
authors.initials: H
authors.lastname: Takakusa
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nakai
authors.forename: Emi
authors.initials: E
authors.lastname: Kamiyama
authors.forename: Tomoe
authors.initials: T
authors.lastname: Taira
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kimura
authors.forename: Takeshi
authors.initials: T
authors.lastname: Jimbo
authors.forename: Mohinder
authors.initials: M
authors.lastname: Bathala
authors.forename: Fraser
authors.initials: F
authors.lastname: Pickersgill
authors.forename: Hamim
authors.initials: H
authors.lastname: Zahir
authors.forename: Taro
authors.initials: T
authors.lastname: Tokui
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Savage
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ashwell
authors.forename: Takashi
authors.initials: T
authors.lastname: Izumi
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000818:Animals; D001646:Bile; D001711:Biotransformation; D002250:Carbon Radioisotopes / Q000032:analysis; D045744:Cell Line, Tumor; D002648:Child; D004285:Dogs; D005243:Feces; D006801:Humans; D006900:Hydroxylation; D008297:Male; D053858:Metabolic Networks and Pathways; D055442:Metabolome; D008875:Middle Aged; D011760:Pyrrolidinones / Q000378:metabolism* / Q000493:pharmacokinetics*; D011804:Quinolines / Q000378:metabolism* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014556:Urine; D055815:Young Adult
chemical_list: C551661:ARQ 197; D002250:Carbon Radioisotopes; D011760:Pyrrolidinones; D011804:Quinolines
keywords: ADME; Absorption; excretion; metabolite identification; oncology; pharmacokinetics; species comparison; tivantinib