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  • To further define the importance of CYP A for


    To further define the importance of CYP3A for OSC metabolism in vivo, a strong CYP3A inhibitor ketoconazole was used to test whether CYP3A would affect its metabolism. As expected, the biotransformation of OSC to SC was significantly decreased by ketoconazole at all three substrate concentrations. However, unexpectedly, the A-769662 mg also decreased despite that the inhibitor concentration was at low (1μM) and middle (10μM) substrate concentrations. Some specific transporters may exist in the OSC transfer in the intestine, which may be affected by ketoconazole. The transformation of OSC was speculated to be transporter-mediated passive transfer.
    Author contributions
    Acknowledgements This work was supported by the Foundation for Distinguished Young Teachers in Higher Education of Guangdong (Yq2013037), Foundation for graduate education innovation project of Guangdong (Sybzzxm201224), the Foundation of science and technology of Guangdong (2014A010107012), as well as the Program for Pearl River New Stars of Science and Technology in Guangzhou (2012J2200048).
    Introduction Gefitinib (GEF) is a selective reversible inhibitor of epidermal growth factor receptor’s (EGFR) tyrosine kinase. GEF inhibits EGFR tyrosine kinase by targeting the adenosine triphosphate cleft within this receptor [1]. It has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of non-small cell lung cancer refractory to established cancer treatments [2]. Although GEF was considered well tolerated, various adverse effects associated with GEF have been reported in clinical practice, such as diarrhea (49%), rash (44%) [3], [4], life-threatening interstitial lung disease (ILD) and liver injury. The over incidences of GEF-induced ILD is about 1%, but approximately 1/3 of the cases can be fatal [5], [6], [7]. Liver injury associated with GEF accounted for 2–4% of patients, which can lead to discontinuations of therapy and even death [8], [9]. However, the exact mechanisms of the GEF-related adverse events are still unknown. At present, the reactive metabolites generated from metabolism are still regarded as an important root of drug-induced toxicity [10], [11]. In most cases, reactive metabolites are generated by phase-I metabolic pathways. The reactive metabolites, such as aldehydes, epoxides, quinones, and iminium ions, can cause various adverse effects [12], [13], [14]. For instance, the toxic atropaldehyde produced from felbamate contributes to felbamate-induced hepatotoxicity [15]. Studies indicated that atropaldehyde resulted in an accumulation of reactive species and toxicity by inhibiting the detoxifying enzymes glutathione S-transferase and aldehyde dehydrogenase [16]. The metabolism of GEF has been extensively investigated in vitro and in vivo [17], [18], [19], [20]. Most of GEF was metabolized in liver and mainly excreted in feces, less than 7% in the urine, irrespective of dose route or species. Using 14C-gefitinib, four major metabolites in human feces were identified, including O-desmethyl gefitinib, acid, morpholine opening metabolite, and ketone [18]. O-Desmethyl gefitinib is most abundant metabolite in both feces and human plasma [21]. McKillop et al. reported nine metabolites from direct incubations of 14C-gefitinib with human liver microsomes (HLM). Further incubation of major metabolites of GEF revealed additional seven metabolites related to GEF [22]. However, studies on the bioactivation of GEF are limited. To date, only glutathione-adducts were unraveled in microsomes and hepatocytes [20], [23]. In this study, we comprehensively profiled the metabolism and bioactivation of GEF in HLM and MLM using a metabolomic approach, which has proven to be a powerful tool in the study of drug metabolism [24], [25], [26]. Using this approach, we identified 34 metabolites and adducts related to GEF, in which half are novel. Three novel potential reactive metabolites were trapped and characterized, including two aldehydes and one iminium. Meanwhile, three known reactive metabolites, one quinone-imine and two primary amines, were also identified. Our studies suggested that CYP3A4 is the primary enzyme involved in the formation of aldehydes, quinone-imine, and primary amines. Iminium formation was mediated by multiple enzymes. These findings could be used for prediction of drug-drug interactions and further studies of GEF-related adverse effects from the angle of metabolic activation.