P10 Effect of CYP2D6 and SULT1A1 genotypes on the serum concentration of 4-hydroxytamoxifen and 4-hydroxy-N-demethyltamoxifen during steady state treatment of breast cancer patients

The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen

“…The CYP2D6 gene is highly polymorphic, with at least 46 major polymorphic alleles and four well-defined phenotypes: poor, intermediate, extensive, and ultra-rapid metabolizers. To date, pharmacokinetic data have demonstrated that common and important CYP2D6 genetic variants that either abolish (e.g., *3, *4, *5) or decrease (*10) CYP2D6 activity significantly decrease plasma endoxifen concentrations in tamoxifen-treated women [14,17,29]. Based on these data, comprehensive genotyping will be necessary in order to account for all CYP2D6 genetic variants which affect CYP2D6 metabolism.…”

“…A series of studies carried out to characterize endoxifen pharmacology have demonstrated that it has equivalent potency in vitro to 4-hydroxytamoxifen in ER-alpha (ERa) and -beta (ERb) binding [10], in suppression of ER-dependent human breast cancer cell line proliferation [10,11] and in global ER-responsive gene expression [12]. In women chronically receiving 20 mg/day tamoxifen, plasma endoxifen steady-state concentrations are, on average, 6-10 times higher (but can reach up to 20-fold higher) than 4-hydroxytamoxifen [13][14][15] and are directly related to cytochrome P450 (CYP) 2D6 genetic variation and inhibition of the enzyme system [14][15][16][17]. In a prospective tamoxifen trial, co-administration of CYP2D6 inhibitors was associated with a significant reduction in the mean plasma endoxifen concentrations, with the reduction in endoxifen concentrations directly related to inhibitor potency [14].…”

A Multidisciplinary Approach to the Management of Breast Cancer, Part 2: Therapeutic Considerations

“…[55][56][57][58][59][60] 4-Hydroxy-N-desmethyl tamoxifen, which is formed by the CYP2D6-mediated oxidation of N-desmethyl tamoxifen, is the most important of the 2 hydroxylated metabolites, given that steady-state concentrations range up to 20-fold higher than 4-hydroxytamoxifen. [61][62][63] Jin et al and others [62][63][64][65] have demonstrated in a prospective trial that both CYP2D6 genetic variation and inhibition of the enzyme system significantly affect the plasma concentrations of 4-hydroxy-N-desmethyl tamoxifen.…”