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