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

Extract

The article by Stearns et al. (1) provides evidence that the tamoxifen metabolite endoxifen (4-hydroxy-N-desmethyltamoxifen) is equipotent with 4-hydroxytamoxifen in inhibiting estradiol-stimulated MCF7 cell proliferation. Further, they show that paroxetine can potentially interfere with metabolism of tamoxifen to endoxifen through an inhibition of CYP2D6. Stearns et al. (1) speculate that, as a result, coadministration of tamoxifen and paroxetine might decrease the therapeutic value of tamoxifen treatment. Because paroxetine has a valuable role in controlling hot flashes, a common side effect of tamoxifen treatment, the article by Stearns et al. (1) provides important information for the many women taking tamoxifen and taking or considering paroxetine or other selective serotonin reuptake inhibitors (SSRIs).

Tamoxifen is a selective estrogen receptor modulator used in the treatment of estrogen receptor–positive breast cancer in both metastatic and adjuvant settings. The breast cancer prevention trial showed that women who received tamoxifen had a 45% reduction in breast cancer occurrence (2). Although tamoxifen is an active agent against breast cancer, its exact mechanism(s) of action is still unknown. Tamoxifen appears to have both cytostatic and cytotoxic activity. The “classic” mechanism of estrogen and anti-estrogen action requires that the ligand–receptor complex binds to defined promoter elements and modulates transcription. This mechanism appears to have cytostatic effects (3). Tamoxifen has also been shown to be cytotoxic, initiating apoptosis in estrogen receptor–positive breast cancer cells and acutely damaged, estrogen receptor–poor normal human breast epithelial cells in vitro (4,5). We have recently shown that apoptosis induced by tamoxifen is independent of the classic pathway of tamoxifen action, involved plasma membrane–mediated regulation of AKT, mitochondrial depolarization, and caspase activation (5,6).