Tamoxifen’s anticancer effects blunted by paroxetine

Paroxetine, an antidepressant commonly prescribed to treat tamoxifen-associated hot flashes, may compromise the breakdown of tamoxifen into its active metabolites, new research shows. Dr. David A. Flockhart suggests that ‘doctors consider an alternative to paroxetine for hot flashes during tamoxifen treatment.’

In the body, tamoxifen is converted to 4-hydroxy-tamoxifen and other active metabolites largely by cytochrome P450 2D6 (CYP2D6), according to a paper in the December 3rd issue of the Journal of the National Cancer Institute. Selective serotonin reuptake inhibitors such as paroxetine are potent inhibitors of this enzyme. Dr. Flockhart, from Indiana University in Indianapolis, and colleagues theorized that coadministration of paroxetine and tamoxifen could dampen tamoxifen metabolism. To investigate, they measured tamoxifen and its metabolites in plasma before and after 4 weeks of concomitant paroxetine in 12 women of known CYP2D6 genotype on chronic adjuvant tamoxifen therapy. Before paroxetine administration, a previously unrecognized metabolite of tamoxifen, 4-hydroxy-N-desmethyl-tamoxifen (endoxifen), was present in plasma in substantially higher concentrations than 4-hydroxy-tamoxifen (12.4 vs 1.1 ng/mL, p < 0.001). During paroxetine coadministration, plasma concentrations of endoxifen fell significantly from 12.4 to 5.5 ng/mL (p = 0.004), whereas levels of 4-hydroxy-tamoxifen did not. In the 7 women with a normal wild-type CYP2D6 genotype, endoxifen levels fell on average 64% compared with just 24% in the 5 women with a variant CYP2D6 genotype. 'Our data suggest that CYP2D6 genotype and drug interactions should be considered in women treated with tamoxifen,' the investigators write. These preliminary findings, they add, 'raise the possibility that pharmacogenetic variation in CYP2D6 activity may influence therapeutic outcomes from tamoxifen treatment.' Dr. Flockhart told Reuters Health, 'There may be a subgroup of women who we can identify that stands to benefit most from tamoxifen.' In in vitro studies, the team found that endoxifen suppressed estradiol-stimulated proliferation of MCF7 breast cancer cells with potency comparable to 4-hydroxy-tamoxifen. 'It has been widely believed for many years that the clinical activity of tamoxifen is largely mediated by 4-hydroxy-tamoxifen,' the authors write. The current study suggests that 'endoxifen may be even more important than 4-hydroxy-tamoxifen in mediating the anticancer effects of tamoxifen,' Dr. Matthew P. Goetz and Dr. Charles L. Loprinzi from the Mayo Clinic in Rochester, Minnesota point out in an editorial. Drs. Goetz and Loprinzi agree with Dr. Flockhart and colleagues that more study is needed before definitive recommendations for or against concomitant tamoxifen and SSRI therapy can be made. (Source: J Natl Cancer Inst 2003;95:1734-1735,1758-1764: Reuters Health: Megan Rauscher: December 2, 2003: Oncolink)