Cytochrome P450
Mediated Bioactivation of Saracatinib
Jiaming Chen
Ying Peng
Jiang Zheng
10.1021/acs.chemrestox.6b00242.s001
https://acs.figshare.com/articles/journal_contribution/Cytochrome_P450_Mediated_Bioactivation_of_Saracatinib/4203126
Saracatinib is a highly selective
Src kinase inhibitor against
all Src kinase family members and has demonstrated anticancer effects
in preclinical models. Unfortunately, it has shown multiple adverse
effects during its clinical trials, along with time-dependent inhibition
of P450 enzymes. The major objective of this study was to identify
reactive metabolites of saracatinib <i>in vitro</i> and <i>in vivo</i>. Four oxidative metabolites (M1–M4) were
detected in rat and human liver microsomal incubation systems after
exposure to saracatinib. An <i>ortho</i>-quinone-derived
reactive metabolite existing as a GSH conjugate (M5) was found in
microsomes fortified with GSH as a trapping agent. The formation of
the metabolites detected was NADPH dependent. Metabolites M2–M4
were also observed in bile and urine of rats given saracatinib, and
M5 was only detected in bile. Inhibition and recombinant P450 enzyme
incubation studies demonstrated that P450 3A4 was the primary enzyme
responsible for the metabolic activation of saracatinib. The metabolism
study facilitates the understanding of correlation between saracatinib-induced
hepatotoxicity and bioactivation.
2016-10-21 00:00:00
oxidative metabolites
Src kinase inhibitor
metabolism study
P 450 enzyme incubation studies
Src kinase family members
P 450 enzymes
Saracatinib Saracatinib
quinone-derived reactive metabolite
NADPH
saracatinib-induced hepatotoxicity
bile
M 5
GSH conjugate
Cytochrome P 450 Mediated Bioactivation
time-dependent inhibition
reactive metabolites
anticancer effects
incubation systems
P 450 3