In vitro metabolism of gefitinib in human liver microsomes

摘要: The in vitro metabolism of gefitinib was investigated by incubating [14C]-gefitinib, as well M537194, M387783 and M523595 (the main metabolites observed man), at a concentration 100 microM with human liver microsomes (4 mg ml(-1)) for 120 min. These relatively high substrate microsomal protein concentrations were used an effort to generate sufficient quantities identification. HPLC ultraviolet light, radiochemical mass spectral analysis, together the availability authentic standards, enabled quantification structural identification large number metabolites. Although 16 identified, restricted three regions molecule. major pathway involved morpholine ring-opening step-wise removal ring propoxy side chain. O-demethylation quinazoline methoxy group quantitatively less important pathway, contrast clinical situation, where O-desmethyl (M523595) is predominant plasma metabolite. third metabolic route, oxidative defluorination, only minor route metabolism. Some formed combination these processes, but no other parts Incubation produced ten identified metabolites, use vivo additional substrates more comprehensive be constructed this has been valuable supporting limited data available from study.