RESPONSE: Re: Active Tamoxifen Metabolite Plasma Concentrations After Coadministration of Tamoxifen and the Selective Serotonin Reuptake Inhibitor Paroxetine

Extract

We thank all three correspondents for their useful insights into our work. The data we presented demonstrate that the tamoxifen metabolite 4-hydroxy-N-desmethyl-tamoxifen (endoxifen) is equipotent to 4-hydroxy-tamoxifen in inhibiting estradiol-stimulated growth of MCF-7 cells (1) and that endoxifen concentrations were reduced in women who carried a genetic variant of CYP2D6 or in women with a wild-type CYP2D6 after coprescription with the CYP2D6 inhibitor paroxetine. The role of the parent drug tamoxifen, each of its metabolites, or a profile of the metabolites in inhibiting breast cancer progression remains unclear and is a critical area for future research. We thank Ratliff et al. for their elegant review of tamoxifen effects and agree that tamoxifen's mechanism of action is complex and that the high concentration of the parent drug and its primary metabolites may mean that they contribute to tamoxifen effects. Tamoxifen and its metabolites are concentrated in breast tissue, but determining which concentrations are active at the effect site remains elusive. The drug behaves as a weak anti-estrogen in clinical trials, suggesting that its effects may be modulated by changes in its concentration or in concentrations of estradiol and other active species at the effect site. As we stated in the discussion of our paper, we agree that the implications of a reduction in endoxifen concentrations are unknown and should not affect current prescribing practices.