OIV-B-3Quantitative assessment of the effect of CYP2D6 genotype on tamoxifen metabolism: A model for CYP2D6 genotype-phenotype studies

Abstract

BACKGROUND/AIMS N-Desmethyltamoxifen (NDM), a primary metabolite of tamoxifen, is hydroxylated by CYP2D6 to yield endoxifen, a potent antiestrogen. We hypothesized that endoxifen plasma concentration and the endoxifen/NDM plasma ratio reflect CYP2D6 activity and are associated with CYP2D6 genotype. METHODS We genotyped for 29 CYP2D6 alleles and determined plasma concentration of tamoxifen and its metabolites in 158 breast cancer patients after four months of tamoxifen therapy. RESULTS Using a mixture model approach, endoxifen plasma concentration identified two phenotypic groups, while four were defined by the endoxifen/NDM plasma ratio. All of the PM/PM, 83% of IM/PM and 75% of IM/IM genotypes belonged to the first endoxifen group, while 67% of EM/EM and 86% of UM/EM genotypes were part of the second phenotypic group. Three distinct genotype groups were identified in the distribution of endoxifen/NDM ratio: 1) low ratios composed of subjects lacking any functional allele; 2) intermediate ratios represented by subjects with one active allele; 3) high ratios composed of subjects with ≥2 functional alleles. Endoxifen/NDM plasma ratio was significantly different between groups. CONCLUSIONS CYP2D6 genotype is highly associated with endoxifen plasma concentration and endoxifen/NDM plasma ratio. The endoxifen plasma concentration may be useful as a point of care test to optimize tamoxifen treatment. This approach may be valuable in the study of other complex genotype-phenotype relationships. Clinical Pharmacology & Therapeutics (2005) 79, P34–P34; doi: 10.1016/j.clpt.2005.12.120