Metalloporphyrin-Catalyzed Oxidation of Sunitinib and Pazopanib, Two Anticancer Tyrosine Kinase Inhibitors: Evidence for New Potentially Toxic Metabolites.
J Med Chem
; 61(17): 7849-7860, 2018 09 13.
Article
em En
| MEDLINE
| ID: mdl-30102538
ABSTRACT
Oxidation of two tyrosine kinase inhibitors (TKIs) sunitinib and pazopanib, using a chemical catalytic system able to mimic the cytochrome P450 type oxidation, allowed us to prepare putative reactive/toxic metabolites of these anticancer drugs. Among these metabolites, aromatic aldehyde derivatives were unambiguously characterized. Such biomimetic oxidation of TKI-type drugs was essential to facilitate the identification of low amounts of aldehydes generated from these TKIs when incubated with human liver microsomes (HLM), which are classical models of human hepatic metabolism. These TKI derivative aldehydes quickly react in vitro with amines. A similar reaction is expected to occur in vivo and may be at the origin of the potentially severe hepatotoxicity of these TKIs.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirimidinas
/
Sulfonamidas
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Microssomos Hepáticos
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Inibidores de Proteínas Quinases
/
Aldeídos
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Doença Hepática Induzida por Substâncias e Drogas
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Sunitinibe
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Metaloporfirinas
Limite:
Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article