Metabolite profiling of the multiple tyrosine kinase inhibitor lenvatinib: a cross-species comparison
| Autor: | Hitoshi Mizuo, Jos H. Beijnen, Robert S. Jansen, A. C. Dubbelman, David Critchley, Shinki Kawaguchi, Hilde Rosing, Jan H.M. Schellens, C.M. Nijenhuis, Robert Shumaker |
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| Rok vydání: | 2016 |
| Předmět: |
Male
medicine.drug_class Glucuronidation Administration Oral Antineoplastic Agents Urine Mass balance Pharmacology 030226 pharmacology & pharmacy Mass Spectrometry Tyrosine-kinase inhibitor Rats Sprague-Dawley Hydroxylation 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Species Specificity Pharmacokinetics medicine Lenvatinib Animals Humans Pharmacology (medical) Protein Kinase Inhibitors Phenylurea Compounds Metabolite identification Metabolism Rats Macaca fascicularis Oncology chemistry Biochemistry 030220 oncology & carcinogenesis Quinolines Clinical pharmacology Drug metabolism Chromatography Liquid |
| Zdroj: | Investigational New Drugs, 34(3), 300. Kluwer Academic Publishers |
| ISSN: | 1573-0646 0167-6997 |
| DOI: | 10.1007/s10637-016-0342-y |
| Popis: | Lenvatinib is an oral, multiple receptor tyrosine kinase inhibitor. Preclinical drug metabolism studies showed unique metabolic pathways for lenvatinib in monkeys and rats. A human mass balance study demonstrated that lenvatinib related material is mainly excreted via feces with a small fraction as unchanged parent drug, but little is reported about its metabolic fate. The objective of the current study was to further elucidate the metabolic pathways of lenvatinib in humans and to compare these results to the metabolism in rats and monkeys. To this end, we used plasma, urine and feces collected in a human mass balance study after a single 24 mg (100 μCi) oral dose of (14)C-lenvatinib. Metabolites of (14)C-lenvatinib were identified using liquid chromatography (high resolution) mass spectrometry with off-line radioactivity detection. Close to 50 lenvatinib-related compounds were detected. In humans, unchanged lenvatinib accounted for 97 % of the radioactivity in plasma, and comprised 0.38 and 2.5 % of the administered dose excreted in urine and feces, respectively. The primary biotransformation pathways of lenvatinib were hydrolysis, oxidation and hydroxylation, N-oxidation, dealkylation and glucuronidation. Various combinations of these conversions with modifications, including hydrolysis, gluthathione/cysteine conjugation, intramolecular rearrangement and dimerization, were observed. Some metabolites seem to be unique to the investigated species (human, rat, monkey). Because all lenvatinib metabolites in human plasma were at very low levels compared to lenvatinib, only lenvatinib is expected to contribute to the pharmacological effects in humans. |
| Databáze: | OpenAIRE |
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