Cytochrome P-450 2D6 (CYP2D6) Genotype and Breast Cancer Recurrence in Tamoxifen-Treated Patients: Evaluating the Importance of Loss of Heterozygosity.
Background/Overview TAMOXIFEN METABOLISM Tamoxifen undergoes extensive primary and secondary metabolism, and plasma concentrations of tamoxifen and its metabolites vary widely. The metabolite 4-hydroxytamoxifen (4-OH tamoxifen) has demonstrated a 100-fold greater affinity for the estrogen receptor and 30to 100-fold greater potency in suppressing estrogen-dependent cell proliferation in vitro compared with the parent drug (summarized in Goetz et al ). Another metabolite, 4-hydroxy-N-desmethyl tamoxifen (endoxifen), has properties and potency identical to 4-OH tamoxifen. Because 4-OH tamoxifen represents less than 20% of the product of tamoxifen primary metabolism and because steady-state plasma endoxifen concentrations are on average 5to 10-fold higher than 4-OH tamoxifen plasma levels, it has been assumed that endoxifen is the major active metabolite of tamoxifen.