NEW YORK (Reuters Health) - Patients with breast cancer who receive selective serotonin reuptake inhibitors (SSRIs) may have a lower response to tamoxifen therapy, depending on their genotype. Specifically, women with cytochrome P450 (CYP) 2D6 polymorphisms had lower concentrations of the tamoxifen metabolite endoxifen, US researchers report.
Tamoxifen metabolite concentrations “are very variable, but they’re a lot less variable if doctors take into account genetics and drug interactions” in women being treated for breast cancer, senior investigator Dr. David A. Flockhart told Reuters Health.
Dr. Flockhart, at Indiana University in Indianapolis, and his associates previously showed that plasma concentrations of endoxifen (4-hydroxy-N-desmethyltamoxifen), a potent estrogen antagonist, depend on a patient’s CYP2D6 genotype.
They also found that plasma endoxifen concentrations were lower in patients taking the SSRI antidepressant paroxetine, an inhibitor of CYP2D6.
To follow-up, they conducted an open-label, prospective observational study among 80 women being treated with tamoxifen 20 mg/day. Forty-eight were homozygous for the wild-type allele (CYP2D6*1, Wt/Wt), 29 carried one nonfunctional variant allele (Wt/Vt), and three subjects carried two nonfunctional variant alleles (Vt/Vt).
Twenty-three were taking an SSRI for treatment of hot flashes.
Among patients who carried the Wt/Wt genotype, the mean plasma endoxifen concentration was 58% lower among the patients using an SSRI, they report in the January 5th issue of the Journal of the National Cancer Institute. The concentration was 38% lower in the Wt/Vt group taking an SSRI.
The authors point out that the most potent inhibitor of CYP2D6 was paroxetine, followed by fluoxetine, sertraline, and citalopram. Venlafaxine was the least potent inhibitor. In fact, venlafaxine had very little effect on plasma endoxifen concentration, the authors found.
“These data suggest that women taking tamoxifen should avoid potent inhibitors of this enzyme, including paroxetine and fluoxetine,” Dr. Flockhart noted.
But before his group can make wider recommendations regarding genotype analysis or measurement of metabolite levels, they must await results of ongoing studies analyzing mortality outcomes and breast cancer recurrence rates, he added.
Source: J Natl Cancer Inst 2005;97:30-39. [ Google search on this article ]
MeSH Headings:Cytochrome P-450: Cytochromes: Enzymes, Coenzymes, and Enzyme Inhibitors: Hydroxylases: Cytochrome P-450 CYP2D6: Chemicals and DrugsCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
