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

Xenobiotica; the Fate of Foreign Compounds in Biological Systems
D McKillopM Hutchison

Abstract

Desmethyl-gefitinib is a major metabolite of gefitinib observed in human plasma at concentrations similar to those of gefitinib. The epidermal growth factor receptor (EGFR)-related inhibitory effects of gefitinib and desmethyl-gefitinib have been compared both in vitro, using enzyme kinase assays and tumour cell growth inhibition, and in vivo by assessment of tumour xenografts growth inhibition in the mouse. Both gefitinib (IC(50) = 0.022 microM) and its desmethyl metabolite (0.036 microM) inhibited subcellular EGFR tyrosine kinase activity with a similar potency and selectivity. However, desmethyl-gefitinib (IC(50) = 0.76 microM) was 15 times less active than gefitinib (0.049 microM) against EGF-stimulated KB cell growth in a whole cell assay. Following a preliminary pharmacokinetic study to compare apparent oral bioavailability, gefitinib (75 mg kg(-1)) and desmethyl-gefitinib (150 mg kg(-1)) were administered orally for 15 days to female nude mice bearing LoVo tumour xenografts. Tumour concentrations of gefitinib (AUC = 300 microg h g(-1)) were much higher than those of desmethyl-gefitinib (44.3 microg h g(-1)), although plasma concentrations of gefitinib (48.4 microg h ml(-1)) and desmethyl-gefitinib (39.0 microg h ml(-1)) ...Continue Reading

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Citations

May 11, 2011·Clinical Pharmacokinetics·Matthias SchefflerUwe Fuhr
Nov 19, 2010·Bioanalysis·Dennis A Smith, R Scott Obach
Jun 28, 2013·Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer·Eunyoung LeeDae Seog Heo
Aug 21, 2009·Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer·Tatsuya KatayamaTetsuya Mitsudomi
Aug 22, 2009·British Journal of Clinical Pharmacology·Stephanie ChhunStephane Mouly
Apr 29, 2015·Cancer Chemotherapy and Pharmacology·Wei LiYong Liu
May 14, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Jean-Sébastien GuillamoMarc Peschanski

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