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Review
. 2010 Jun 1;28(16):2768-76.
doi: 10.1200/JCO.2009.23.8931. Epub 2010 May 3.

Coprescription of tamoxifen and medications that inhibit CYP2D6

Kostandinos Sideras  1 , James N Ingle, Matthew M Ames, Charles L Loprinzi, David P Mrazek, John L Black, Richard M Weinshilboum, John R Hawse, Thomas C Spelsberg, Matthew P Goetz
Affiliations
Review

Coprescription of tamoxifen and medications that inhibit CYP2D6

Kostandinos Sideras et al. J Clin Oncol. .

Erratum in

  • J Clin Oncol. 2010 Jul 20;28(21):3543

Abstract

Evidence has emerged that the clinical benefit of tamoxifen is related to the functional status of the hepatic metabolizing enzyme cytochrome P450 2D6 (CYP2D6). CYP2D6 is the key enzyme responsible for the generation of the potent tamoxifen metabolite, endoxifen. Multiple studies have examined the relationship of CYP2D6 status to breast cancer outcomes in tamoxifen-treated women; the majority of studies demonstrated that women with impaired CYP2D6 metabolism have lower endoxifen concentrations and a greater risk of breast cancer recurrence. As a result, practitioners must be aware that some of the most commonly prescribed medications coadministered with tamoxifen interfere with CYP2D6 function, thereby reducing endoxifen concentrations and potentially increasing the risk of breast cancer recurrence. After reviewing the published data regarding tamoxifen metabolism and the evidence relating CYP2D6 status to breast cancer outcomes in tamoxifen-treated patients, we are providing a guide for the use of medications that inhibit CYP2D6 in patients administered tamoxifen.

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Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.
Fig 1.
Schematic representation of the primary and secondary metabolism of tamoxifen by the cytochrome P450 system. The relative contribution of each pathway to the overall oxidation of tamoxifen is shown by the thickness of the arrow. Adapted from Borges et al.
Fig 2.
Fig 2.
Endoxifen concentration according to CYP2D6 activity. (A) Endoxifen concentrations (nmol/L) in tamoxifen-treated women based on CYP2D6 functional alleles. (B) Endoxifen concentrations in tamoxifen-treated women who are CYP2D6 extensive metabolizers and who were coprescribed venlafaxine (not a CYP2D6 inhibitor), sertraline and citalopram (weak CYP2D6 inhibitors), or fluoxetine and paroxetine (potent CYP2D6 inhibitors). Modified with permission.
Fig 3.
Fig 3.
Effects of clinically relevant concentrations of tamoxifen and its metabolites on the estrogen-stimulated proliferation of MCF-7 cells. Estrogen-stimulated growth of MCF-7 cells is inhibited minimally by clinically relevant concentrations of tamoxifen and its metabolites (without endoxifen), but growth is blocked completely in the presence of increasing concentrations of endoxifen (1,000 nmol/L). Note that 20 nmol/L endoxifen is observed in poor metabolizers while 100 nmol/L is observed in extensive metabolizers. E2, estradiol; TAM, tamoxifen; 4HT, 4-hydroxytamoxifen; NDT, N-desmethyltamoxifen. Data adapted and modified.
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References

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