O-Desmethyl Gefitinib

O-Desmethyl gefitinib is the major metabolite of gefitinib (Item No. 13166) in human plasma, formed by the cytochrome P450 isoform CYP2D6.¹ It is an active metabolite that inhibits EGFR similarly to gefitinib in subcellular assays (IC₅₀s = 36 and 22 nM, respectively) but is less active in whole cell assays (IC₅₀s = 760 and 49 nM, respectively).² In a LoVo tumor mouse xenograft model, the tumor concentration of O-desmethyl gefitinib was 6.8-fold lower than that of gefitinib and did not significantly reduce tumor growth. A high plasma concentration of O-desmethyl gefitinib in patients homozygous for CYP2D6 was not associated with an increase in adverse effects.³

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1. McKillop, D., Hutchison, M., Partridge, E.A., et al. Metabolic disposition of gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in rat, dog and man. Xenobiotica 34(10), 917-934 (2004).

2. McKillop, D., Guy, S.P., Spence, M.P., et al. Minimal contribution of desmethyl-gefitinib, the major human plasma metabolite of gefitinib, to epidermal growth factor receptor (EGFR)-mediated tumour growth inhibition. Xenobiotica 36(1), 29-39 (2006).

3. Kobayashi, H., Sato, K., Niioka, T., et al. Effects of polymorphisms in CYP2D6 and ABC transporters and side effects induced by gefitinib on the pharmacokinetics of the gefitinib metabolite, O-desmethyl gefitinib. Med. Oncol. 33(6), 1-8 (2016).