Metabolism and disposition of [(14)C]tivantinib after oral administration to humans, dogs and rats
| Autor: | Fraser Pickersgill, Mohinder S. Bathala, Hideo Takakusa, Daisuke Nakai, Mark A. Ashwell, Takashi Izumi, Tomoko Kimura, Ronald E. Savage, Taro Tokui, Emi Kamiyama, Jimbo Takeshi, Tomoe Taira, Takahiro Murai, Hamim Zahir |
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| Rok vydání: | 2014 |
| Předmět: |
Adult
Male Adolescent Health Toxicology and Mutagenesis Metabolite Glucuronidation Administration Oral Pharmacology Urine Toxicology Hydroxylation Biochemistry Excretion Rats Sprague-Dawley chemistry.chemical_compound Feces Young Adult Dogs Pharmacokinetics Oral administration Cell Line Tumor Metabolome Animals Bile Humans Carbon Radioisotopes Tivantinib Child Biotransformation ADME General Medicine Middle Aged Pyrrolidinones Rats chemistry Quinolines Metabolic Networks and Pathways |
| Zdroj: | Xenobiotica; the fate of foreign compounds in biological systems. 44(11) |
| ISSN: | 1366-5928 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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