Unique metabolic pathway of [(14)C]lenvatinib after oral administration to male cynomolgus monkey.
Lenvatinib, a potent inhibitor of multiple tyrosine kinases, including vascular endothelial growth factor receptors 2 and 3, generated unique metabolites after oral administration of [(14)C]lenvatinib (30 mg/kg) to a male cynomolgus monkey. Lenvatinib was found to be transformed to a GSH conjugate, through displacement of an O-aryl moiety, at the quinoline part of the molecule in the liver and kidneys. The GSH conjugate underwent further hydrolysis by γ-glutamyltranspeptidase and dipeptidases, followed by intramolecular rearrangement, to form N-cysteinyl quinoline derivatives, which were dimerized to form disulfide dimers and also formed an N,S-cysteinyl diquinoline derivative. In urine, a thioacetic acid conjugate of the quinoline was also observed as one of the major metabolites of lenvatinib. Lenvatinib is a 4-O-aryl quinoline derivative, and such compounds have been known to undergo conjugation with GSH, accompanied by release of the O-aryl moiety. Because of intramolecular rearrangement in the case of lenvatinib, hydrolysis of the GSH conjugate yielded N-cysteinylglycine and N-cysteine conjugates instead of the corresponding S-conjugates. Because the N-substituted derivatives possess free sulfhydryl groups, dimerization through disulfide bonds and another nucleophilic substitution reaction with lenvatinib resulted in the formation of disulfanyl dimers and an N,S-cysteinyl diquinoline derivative, respectively. Characteristic product ions at m/z 235 and m/z 244, which were associated with thioquinoline and N-ethylquinoline derivatives, respectively, were used to differentiate S- and N-derivatives in this study. On the basis of accurate mass and NMR measurements, a unique metabolic pathway for lenvatinib in monkey and the proposed formation mechanism have been elucidated.
Drug Metabolism and Pharmacokinetics Japan, Eisai Product Creation Systems, Eisai Co., 5-1-3, Tokodai, Tsukuba, Ibaraki, 300-2635, Japan. k12-inoue@hhc.eisai.co.jp
Kazuko
K
Inoue
Naoki
N
Asai
Hitoshi
H
Mizuo
Katsuyuki
K
Fukuda
Kazutomi
K
Kusano
Tsutomu
T
Yoshimura
D000284:Administration, Oral; D000818:Animals; D001646:Bile / Q000737:chemistry; D001711:Biotransformation; D002250:Carbon Radioisotopes; D002853:Chromatography, Liquid; D005704:Gallbladder / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D008252:Macaca fascicularis; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D053858:Metabolic Networks and Pathways; D015394:Molecular Structure; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000097:blood / Q000378:metabolism* / Q000652:urine; D011804:Quinolines / Q000008:administration & dosage* / Q000097:blood / Q000378:metabolism* / Q000652:urine; D051381:Rats; D013997:Time Factors
D002250:Carbon Radioisotopes; D010671:Phenylurea Compounds; D011804:Quinolines; C531958:lenvatinib