Metabolomics reveals the formation of aldehydes and iminium in gefitinib metabolism.

摘要: Gefitinib (GEF), an inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, is widely used for the treatment cancers, particularly non-small cell lung cancer. However, its clinical use limited by multiple adverse effects associated with GEF, such as liver and injuries, severe nausea, diarrhea. Although, exact mechanism GEF are still unknown, xenobiotic-induced bioactivation thought to play a significant role in induced toxicity. Using metabolomic approach, we investigated metabolic pathways human mouse microsomes. Thirty four metabolites adducts were identified half them novel. The potential reactive metabolites, two aldehydes one iminium, first time. previously reported GSH primary amines observed well. aldehyde iminium further confirmed using methoxylamine potassium cyanide trapping reagents. recombinant CYP450 isoforms, CYP3A4 inhibitor, S9 from Cyp3a-null mice, CYP3A major enzyme contributing formation aldehydes, adducts, liver. Multiple enzymes contribute iminium. This study provided us more knowledge involved pathways, which can be utilized understanding predicting possible drug-drug interactions. Further studies suggested determine roles these