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Cytochrome P450 Mediated Bioactivation of Saracatinib
journal contribution
posted on 2016-10-21, 00:00 authored by Jiaming Chen, Ying Peng, Jiang ZhengSaracatinib 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 in vitro and in vivo. Four oxidative metabolites (M1–M4) were
detected in rat and human liver microsomal incubation systems after
exposure to saracatinib. An ortho-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.
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oxidative metabolitesSrc kinase inhibitormetabolism studyP 450 enzyme incubation studiesSrc kinase family membersP 450 enzymesSaracatinib Saracatinibquinone-derived reactive metaboliteNADPHsaracatinib-induced hepatotoxicitybileM 5GSH conjugateCytochrome P 450 Mediated Bioactivationtime-dependent inhibitionreactive metabolitesanticancer effectsincubation systemsP 450 3
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