The impact of coadministration of venlafaxine, citalopram or gabapentin on the metabolic activation of tamoxifen

作者：Stephanie L. Safgren, Vera J. Suman, Roberto A. Leon Ferre, Matthew L. Kosel, Vered Stearns, N. Lynn Henry, Neelima Denduluri, William Irvin, James N. Ingle, Kostandinos Sideras, Matthew M. Ames, Joel M. Reid, Charles L. Loprinzi, John L. Black, Richard M. Weinshilboum, Matthew P. Goetz · 发表于：Breast Cancer Research and Treatment · 年份：2025 · DOI：10.1007/s10549-025-07644-3 · 被引用次数：2 · 研究领域：Pharmacogenetics and Drug Metabolism、Menopause: Health Impacts and Treatments、Estrogen and related hormone effects

PURPOSE: Tamoxifen undergoes metabolic activation by cytochrome P450 (CYP) enzymes to metabolites with more potent anti-estrogenic effects. Numerous studies demonstrate decreased tamoxifen efficacy associated with reduced CYP2D6 activity or lower Z-endoxifen concentrations. Women taking tamoxifen frequently experience vasomotor symptoms (VMS) that may require medical treatment. Many medications used for VMS or depression are CYP substrates that may reduce Z-endoxifen concentrations. While the drug-drug interactions (DDI) from potent CYP2D6 inhibitors (CYPi) on tamoxifen metabolism has been studied, the impact of less potent CYPi including drugs used to treat VMS remains largely unknown. METHODS: We performed a prospective trial to evaluate the impact of gabapentin or non-potent CYPi (venlafaxine citalopram) on plasma concentrations of tamoxifen and its metabolites (Z-endoxifen, N-desmethyl-tamoxifen (NDMT) and 4-hydroxy-tamoxifen (4HT). RESULTS: Patients enrolled were intermediate to extensive metabolizers by CYP2D6 genotyping. While tamoxifen and NDMT plasma concentrations were not significantly altered, the percent decrease in plasma Z-endoxifen concentration was statistically significant with the addition of venlafaxine (n = 22) or citalopram (n = 18) (median - 14.7 and - 14.4%, respectively) but not with gabapentin (n = 14) (median - 2.3%). A reduction in Z-endoxifen concentrations below the 5.9 ng/ml threshold associated with tamoxifen efficacy was observed in 12% of pat...