Hot flash drug may hinder effectiveness of tamoxifen

December 02, 2003

An antidepressant used to ease a common side effect of the drug tamoxifen for breast cancer may conceivably reduce the effectiveness of tamoxifen by interfering with the breakdown of the drug into its active metabolites, according a new study in the December 3 issue of the Journal of the National Cancer Institute.

Hot flashes are the most common side effect of tamoxifen. New antidepressant drugs, such as the selective serotonin reuptake inhibitors (SSRIs) paroxetine and fluoxetine, are effective in treating tamoxifen-associated hot flashes. However, these drugs have also been shown to inhibit the enzyme that converts tamoxifen to its known most potent metabolite, 4-hydroxy-tamoxifen, and other active metabolites. The implication is that co-prescription of SSRIs with tamoxifen may reduce the effectiveness of tamoxifen.

Vered Stearns, M.D., now at Johns Hopkins University in Baltimore, Md., David A. Flockhart, M.D., Ph.D., of the Indiana University School of Medicine, Indianapolis, and their colleagues examined the effect of paroxetine--which inhibits CYP2D6, an enzyme that is primarily responsible for the metabolism of tamoxifen into its active metabolites--on levels of tamoxifen and its metabolites in blood samples from 12 women with breast cancer who were being treated with adjuvant tamoxifen. The women received paroxetine for 4 weeks during their standard course of tamoxifen. They were also tested to determine their CYP2D6 genotype.

The researchers identified that a previously unrecognized active metabolite, which they named endoxifen, was present in substantially higher concentrations than 4-hydroxy-tamoxifen. They observed that, after paroxetine treatment, endoxifen levels decreased, whereas levels of 4-hydroxy-tamoxifen did not. Treatment with paroxetine reduced the concentration of endoxifen from 12.4 ng/mL before paroxetine administration to 5.5 ng/mL after paroxetine administration. Endoxifen concentrations decreased by 64% in women with a normal CYP2D6 genotype but by only 24% in women with a variant CYP2D6 genotype.

The authors say that these findings "raise the possibility that pharmacogenetic variation in CYP2D6 activity may influence therapeutic outcomes from tamoxifen treatment." However, they write, "larger trials are required to evaluate the clinical implications of low circulating endoxifen concentrations and, until further data become available, the results of this small study should not alter treatment recommendations."

In an accompanying editorial, Matthew P. Goetz, M.D., and Charles L. Loprinzi, M.D., of the Mayo Clinic in Rochester, Minn., caution that the clinical implications of reduced levels of endoxifen remain unclear. Furthermore, they write, "because the newer antidepressants studied for the treatment of hot flashes (venlafaxine, fluoxetine, and paroxetine) have differing levels of CYP2D6 inhibition, the pharmacokinetic interaction between tamoxifen and these antidepressants needs to be studied."
Contact: Mary Hardin, Indiana University School of Medicine, 317-274-7722; fax: 317-278-8722,

Editorial: Mary Lawson, Mayo Clinic, 507-284-5005; fax: 507-284-8713,

Stearns V, Johnson MD, Rae JM, Morocho A, Novielli A, Bhargava P, et al. Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst 2003;95:1758-64.

Editorial: Goetz MP, Loprinzi CL. A hot flash on tamoxifen metabolism. J Natl Cancer Inst 2003;95:1734-5.

Note: The Journal of the National Cancer Institute is published by Oxford University Press and is not affiliated with the National Cancer Institute. Attribution to the Journal of the National Cancer Institute is requested in all news coverage.

Journal of the National Cancer Institute

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