Minimal contribution of desmethyl-gefitinib, the major human plasma metabolite of gefitinib, to epidermal growth factor receptor (EGFR)-mediated tumour growth inhibition

摘要: Desmethyl-gefitinib is a major metabolite of gefitinib observed in human plasma at concentrations similar to those gefitinib. The epidermal growth factor receptor (EGFR)-related inhibitory effects and desmethyl-gefitinib have been compared both vitro, using enzyme kinase assays tumour cell inhibition, vivo by assessment xenografts inhibition the mouse. Both (IC50 = 0.022 µM) its desmethyl (0.036 µM) inhibited subcellular EGFR tyrosine activity with potency selectivity. However, (IC50 = 0.76 µM) was 15 times less active than (0.049 µM) against EGF-stimulated KB whole assay. Following preliminary pharmacokinetic study compare apparent oral bioavailability, (75 mg kg−1) (150 mg kg−1) were administered orally for days female nude mice bearing LoVo xenografts. Tumour (AUC = 300 µ...