Metalloporphyrin-Catalyzed Oxidation of Sunitinib and Pazopanib, Two Anticancer Tyrosine Kinase Inhibitors: Evidence for New Potentially Toxic Metabolites

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.