Cytochrome P450 and flavin-containing monooxygenase enzymes are responsible for differential oxidation of the anti-thyroid-cancer drug vandetanib by human and rat hepatic microsomal systems
Jazyk angličtina Země Nizozemsko Médium print-electronic
Typ dokumentu časopisecké články
PubMed
31837525
DOI
10.1016/j.etap.2019.103310
PII: S1382-6689(19)30185-1
Knihovny.cz E-zdroje
- Klíčová slova
- Anti-thyroid-cancer drug, Cytochromes P450, Flavin-containing monoxygenases, Metabolism, Tyrosine kinase inhibitor, Vandetanib,
- MeSH
- chinazoliny metabolismus MeSH
- jaterní mikrozomy MeSH
- krysa rodu Rattus MeSH
- lidé MeSH
- oxidace-redukce MeSH
- oxygenasy metabolismus MeSH
- piperidiny metabolismus MeSH
- protinádorové látky metabolismus MeSH
- systém (enzymů) cytochromů P-450 metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- chinazoliny MeSH
- dimethylaniline monooxygenase (N-oxide forming) MeSH Prohlížeč
- oxygenasy MeSH
- piperidiny MeSH
- protinádorové látky MeSH
- systém (enzymů) cytochromů P-450 MeSH
- vandetanib MeSH Prohlížeč
We studied the in vitro metabolism of the anti-thyroid-cancer drug vandetanib in a rat animal model and demonstrated that N-desmethylvandetanib and vandetanib N-oxide are formed by NADPH- or NADH-mediated reactions catalyzed by rat hepatic microsomes and pure biotransformation enzymes. In addition to the structural characterization of vandetanib metabolites, individual rat enzymes [cytochrome P450 (CYP) and flavin-containing monooxygenase (FMO)] capable of oxidizing vandetanib were identified. Generation of N-desmethylvandetanib, but not that of vandetanib N-oxide, was attenuated by CYP3A and 2C inhibitors while inhibition of FMO decreased formation of vandetanib N-oxide. These results indicate that liver microsomal CYP2C/3A and FMO1 are major enzymes participating in the formation of N-desmethylvandetanib and vandetanib N-oxide, respectively. Rat recombinant CYP2C11 > >3A1 > 3A2 > 1A1 > 1A2 > 2D1 > 2D2 were effective in catalyzing the formation of N-desmethylvandetanib. Results of the present study explain differences between the CYP- and FMO-catalyzed vandetanib oxidation in rat and human liver reported previously and the enzymatic mechanisms underlying this phenomenon.
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