Metalloporphyrin-Catalyzed
Oxidation of Sunitinib
and Pazopanib, Two Anticancer Tyrosine Kinase Inhibitors: Evidence
for New Potentially Toxic Metabolites
Marie-Noëlle Paludetto
Christian Bijani
Florent Puisset
Vania Bernardes-Génisson
Cécile Arellano
Anne Robert
10.1021/acs.jmedchem.8b00812.s002
https://acs.figshare.com/articles/dataset/Metalloporphyrin-Catalyzed_Oxidation_of_Sunitinib_and_Pazopanib_Two_Anticancer_Tyrosine_Kinase_Inhibitors_Evidence_for_New_Potentially_Toxic_Metabolites/7007888
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 <i>in vitro</i> with amines. A similar reaction is expected to
occur <i>in vivo</i> and may be at the origin of the potentially
severe hepatotoxicity of these TKIs.
2018-08-13 00:00:00
Such biomimetic oxidation
HLM
aldehyde derivatives
TKI-type drugs
tyrosine kinase inhibitors
Toxic Metabolites Oxidation
anticancer drugs
Metalloporphyrin-Catalyzed Oxidation
Anticancer Tyrosine Kinase Inhibitors
liver microsomes
metabolite
cytochrome P 450 type oxidation
hepatic metabolism