RT Journal Article
SR Electronic
T1 Oxidative Metabolic Pathway of Lenvatinib Mediated by Aldehyde Oxidase
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1326
OP 1333
DO 10.1124/dmd.114.058073
VO 42
IS 8
A1 Kazuko Inoue
A1 Hitoshi Mizuo
A1 Shinki Kawaguchi
A1 Katsuyuki Fukuda
A1 Kazutomi Kusano
A1 Tsutomu Yoshimura
YR 2014
UL http://dmd.aspetjournals.org/content/42/8/1326.abstract
AB Lenvatinib is a multityrosine kinase inhibitor that inhibits vascular endothelial growth factor receptors, and is being developed as an anticancer drug. P450s are involved in one of the elimination pathways of lenvatinib, and mono-oxidized metabolites, such as N-oxide (M3) and desmethylated metabolite (M2), form in rats, dogs, monkeys, and humans. Meanwhile, two other oxidative metabolites are produced only in monkey and human liver S9 fractions, and their structures have been identified using high-resolution mass spectrometry as a quinolinone form of lenvatinib (M3′) and a quinolinone form of desmethylated lenvatinib (M2′). The formation of M3′ from lenvatinib occurred independently of NADPH and was effectively inhibited by typical inhibitors of aldehyde oxidase, indicating the involvement of aldehyde oxidase, but not P450s, in this pathway. M2′ was a dioxidized metabolite arising from a combination of mono-oxidation and desmethylation and could only be produced from M2 in a NADPH-independent manner; M2′ could not be generated from M3 or M3′. These results suggested that M2′ is formed from lenvatinib by a unique two-step pathway through M2. Although both lenvatinib and M2 were substrates for aldehyde oxidase, an enzyme kinetic study indicated that M2 was a much more favorable substrate than lenvatinib. No inhibitory activities of lenvatinib, M2′, or M3′ and no significant inhibitory activities of M2 or M3 on aldehyde oxidase were observed, suggesting a low possibility of drug-drug interactions in combination therapy with substrates of aldehyde oxidase.