title: Metabolite profiling of the multiple tyrosine kinase inhibitor lenvatinib: a cross-species comparison.
abstract: 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.
authors.affiliation: The Netherlands Cancer Institute, Division of Clinical Pharmacology, Department of Medical Oncology, Amsterdam, The Netherlands. a.c.dubbelman@gmail.com.|Antoni van Leeuwenhoek / The Netherlands Cancer Institute and MC Slotervaart, Department of Pharmacy & Pharmacology, Louwesweg 6, 1066 CE, Amsterdam, The Netherlands. a.c.dubbelman@gmail.com.|Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands. a.c.dubbelman@gmail.com.
authors.forename: Anne-Charlotte
authors.initials: AC
authors.lastname: Dubbelman
authors.affiliation: Antoni van Leeuwenhoek / The Netherlands Cancer Institute and MC Slotervaart, Department of Pharmacy & Pharmacology, Louwesweg 6, 1066 CE, Amsterdam, The Netherlands. cynthia.nijenhuis@slz.nl.
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Nijenhuis
authors.affiliation: Antoni van Leeuwenhoek / The Netherlands Cancer Institute and MC Slotervaart, Department of Pharmacy & Pharmacology, Louwesweg 6, 1066 CE, Amsterdam, The Netherlands.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Jansen
authors.affiliation: Antoni van Leeuwenhoek / The Netherlands Cancer Institute and MC Slotervaart, Department of Pharmacy & Pharmacology, Louwesweg 6, 1066 CE, Amsterdam, The Netherlands.
authors.forename: Hilde
authors.initials: H
authors.lastname: Rosing
authors.affiliation: Eisai Co. Ltd., Drug metabolism and Pharmacokinetics Japan, Tsukuba, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Mizuo
authors.affiliation: Eisai Co. Ltd., Drug metabolism and Pharmacokinetics Japan, Tsukuba, Japan.
authors.forename: Shinki
authors.initials: S
authors.lastname: Kawaguchi
authors.affiliation: Eisai Ltd., Chief Clinical Officer Department, Clinical Pharmacology, Hatfield, UK.
authors.forename: David
authors.initials: D
authors.lastname: Critchley
authors.affiliation: Eisai Inc., Oncology Product Creation Unit, Clinical Pharmacology and Translational Medicine, Woodcliff Lake, NJ, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Shumaker
authors.affiliation: The Netherlands Cancer Institute, Division of Clinical Pharmacology, Department of Medical Oncology, Amsterdam, The Netherlands.|Division of Pharmacoepidemiology and Clinical Pharmacology, Faculty of Science, Department of Pharmaceutical Sciences Utrecht, Utrecht University, Utrecht, The Netherlands.
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.affiliation: Antoni van Leeuwenhoek / The Netherlands Cancer Institute and MC Slotervaart, Department of Pharmacy & Pharmacology, Louwesweg 6, 1066 CE, Amsterdam, The Netherlands.|Division of Pharmacoepidemiology and Clinical Pharmacology, Faculty of Science, Department of Pharmaceutical Sciences Utrecht, Utrecht University, Utrecht, The Netherlands.
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D002853:Chromatography, Liquid; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D013058:Mass Spectrometry; D010671:Phenylurea Compounds / Q000493:pharmacokinetics*; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics*; D011804:Quinolines / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C531958:lenvatinib
keywords: Clinical pharmacology; Lenvatinib; Mass balance; Metabolism; Metabolite identification; Pharmacokinetics