Oxidative metabolic pathway of lenvatinib mediated by aldehyde oxidase
Kazuko Inoue1, Hitoshi Mizuo2, Shinki Kawaguchi2
1Drug Metabolism and Pharmacokinetics Japan, Eisai Product Creation Systems, Eisai Co., Ltd., Tsukuba, Japan k12-inoue@hhc.eisai.co.jp.
Abstract:
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.
Insights
Lenvatinib metabolism involves aldehyde oxidase, not just P450s, forming unique quinolinone metabolites (M3
Area of Science:
- Pharmacology and Drug Metabolism
Background:
- Lenvatinib, a multityrosine kinase inhibitor targeting VEGF receptors, is an anticancer drug candidate.
- Cytochrome P450 enzymes (P450s) are implicated in lenvatinib elimination, producing N-oxide (M3) and desmethylated (M2) metabolites across species.
- Unique oxidative metabolites, quinolinone forms (M3', M2'), are identified in monkey and human liver S9 fractions.
Purpose of the Study:
- To elucidate the metabolic pathways of lenvatinib, particularly the formation of novel oxidative metabolites M3' and M2'.
- To investigate the enzymatic basis for the formation of M3' and M2', differentiating between P450s and aldehyde oxidase.
- To assess the potential for drug-drug interactions between lenvatinib metabolites and aldehyde oxidase substrates.
Main Methods:
- High-resolution mass spectrometry was employed for structural identification of metabolites.
- Enzyme inhibition studies using NADPH and specific inhibitors were conducted to determine the role of P450s and aldehyde oxidase.
- Enzyme kinetic studies were performed to compare the substrate affinity of lenvatinib and its metabolite M2 for aldehyde oxidase.
- In vitro assays assessed the inhibitory potential of lenvatinib and its metabolites on aldehyde oxidase activity.
Main Results:
- Metabolite M3' formation from lenvatinib was NADPH-independent and inhibited by aldehyde oxidase inhibitors, indicating aldehyde oxidase involvement.
- Metabolite M2' is a dioxidized metabolite formed from M2 via a unique two-step pathway, independent of NADPH.
- Aldehyde oxidase efficiently metabolized both lenvatinib and M2, with M2 being a significantly more favorable substrate.
- Lenvatinib and its metabolites M2', M3', M2, and M3 showed no significant inhibition of aldehyde oxidase activity.
Conclusions:
- Lenvatinib undergoes unique oxidative metabolism via aldehyde oxidase, in addition to P450-mediated pathways, producing quinolinone derivatives.
- A distinct two-step pathway involving aldehyde oxidase leads to the formation of metabolite M2' from M2.
- The lack of significant aldehyde oxidase inhibition by lenvatinib and its metabolites suggests a low risk of drug-drug interactions.
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