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

Breast Cancer Res Treat. 2025 May;211(1):261-270. doi: 10.1007/s10549-025-07644-3. Epub 2025 Feb 27.

Abstract

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 patients.

Conclusion: The addition of venlafaxine and citalopram but not gabapentin during tamoxifen treatment decreases plasma Z-endoxifen concentrations. SSRIs/SNRIs affecting tamoxifen biotransformation pathways, but with less potent CYPi potential, should be used cautiously in tamoxifen-treated patients and non-CYP inhibiting medications considered when possible.

Keywords: CYP2D6; Citalopram; Gabapentin; Tamoxifen; Venlafaxine; Z-endoxifen.

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents, Hormonal* / pharmacokinetics
  • Breast Neoplasms* / drug therapy
  • Breast Neoplasms* / genetics
  • Breast Neoplasms* / pathology
  • Citalopram* / administration & dosage
  • Cytochrome P-450 CYP2D6 / genetics
  • Cytochrome P-450 CYP2D6 / metabolism
  • Cytochrome P-450 CYP2D6 Inhibitors
  • Drug Interactions
  • Female
  • Gabapentin / administration & dosage
  • Humans
  • Middle Aged
  • Prospective Studies
  • Tamoxifen* / administration & dosage
  • Tamoxifen* / analogs & derivatives
  • Tamoxifen* / blood
  • Tamoxifen* / metabolism
  • Tamoxifen* / pharmacokinetics
  • Tamoxifen* / therapeutic use
  • Venlafaxine Hydrochloride* / administration & dosage

Substances

  • Tamoxifen
  • Gabapentin
  • Venlafaxine Hydrochloride
  • Citalopram
  • Cytochrome P-450 CYP2D6
  • Antineoplastic Agents, Hormonal
  • 4-hydroxy-N-desmethyltamoxifen
  • Cytochrome P-450 CYP2D6 Inhibitors