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Purpose <p>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.</p> Methods <p>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).</p> Results <p>Patients enrolled were intermediate to extensive metabolizers by <i>CYP2D6</i> 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 (<i>n</i> = 22) or citalopram (<i>n</i> = 18) (median − 14.7 and − 14.4%, respectively) but not with gabapentin (<i>n</i> = 14) (median − 2.3%). A reduction in Z-endoxifen concentrations below the 5.9&#xa0;ng/ml threshold associated with tamoxifen efficacy was observed in 12% of patients.</p> Conclusion <p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年2月27日

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  • 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,
  • Kostantinos Sideras,
  • Matthew M. Ames,
  • Joel M. Reid,
  • Charles L. Loprinzi,
  • John L. Black,
  • Richard M. Weinshilboum,
  • Matthew P. Goetz

摘要

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.