© 2003 by Oxford University Press
© 2003 Oxford University Press
ARTICLE |
Active Tamoxifen Metabolite Plasma Concentrations After Coadministration of Tamoxifen and the Selective Serotonin Reuptake Inhibitor Paroxetine
Affiliations of authors: The Breast Cancer Program, Departments of Medicine and Oncology, Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC (VS, MDJ, AN, PB, DFH); and Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN (JMR, AM, PB, ZD, DAF).
Correspondence to: David A. Flockhart, MD, PhD, Division of Clinical Pharmacology, Indiana University School of Medicine, 1001 West 10th St., Myers Bldg. W7123, Indianapolis, IN 46203 (e-mail: dflockha{at}iupui.edu)
Background: Tamoxifen, a selective estrogen receptor modulator (SERM), is converted to 4-hydroxy-tamoxifen and other active metabolites by cytochrome P450 (CYP) enzymes. Selective serotonin reuptake inhibitors (SSRIs), which are often prescribed to alleviate tamoxifen-associated hot flashes, can inhibit CYPs. In a prospective clinical trial, we tested the effects of coadministration of tamoxifen and the SSRI paroxetine, an inhibitor of CYP2D6, on tamoxifen metabolism. Methods: Tamoxifen and its metabolites were measured in the plasma of 12 women of known CYP2D6 genotype with breast cancer who were taking adjuvant tamoxifen before and after 4 weeks of coadministered paroxetine. We assessed the inhibitory activity of pure tamoxifen metabolites in an estradiol-stimulated MCF7 cell proliferation assay. To determine which CYP isoforms were involved in the metabolism of tamoxifen to specific metabolites, we used CYP isoform-specific inhibitors. All statistical tests were two-sided. Results: We separated, purified, and identified the metabolite 4-hydroxy-N-desmethyl-tamoxifen, which we named endoxifen. Plasma concentrations of endoxifen statistically significantly decreased from a mean of 12.4 ng/mL before paroxetine coadministration to 5.5 ng/mL afterward (difference = 6.9 ng/mL, 95% confidence interval [CI] = 2.7 to 11.2 ng/mL) (P = .004). Endoxifen concentrations decreased by 64% (95% CI = 39% to 89%) in women with a wild-type CYP2D6 genotype but by only 24% (95% CI = 23% to 71%) in women with a variant CYP2D6 genotype (P = .03). Endoxifen and 4-hydroxy-tamoxifen inhibited estradiol-stimulated MCF7 cell proliferation with equal potency. In vitro, troleandomycin, an inhibitor of CYP3A4, inhibited the demethylation of tamoxifen to N-desmethyl-tamoxifen by 78% (95% CI = 65% to 91%), and quinidine, an inhibitor of CYP2D6, reduced the subsequent hydroxylation of N-desmethyl-tamoxifen to endoxifen by 79% (95% CI = 50% to 108%). Conclusions: Endoxifen is an active tamoxifen metabolite that is generated via CYP3A4-mediated N-demethylation and CYP2D6-mediated hydroxylation. Coadministration of paroxetine decreased the plasma concentration of endoxifen. Our data suggest that CYP2D6 genotype and drug interactions should be considered in women treated with tamoxifen.
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Correspondence about this Article
- Re: Active Tamoxifen Metabolite Plasma Concentrations After Coadministration of Tamoxifen and the Selective Serotonin Reuptake Inhibitor Paroxetine
- Brooke Ratliff, Eric C. Dietze, Gregory R. Bean, Cassandra Moore, Sam Wanko, and Victoria L. Seewaldt
J Natl Cancer Inst 2004 96: 883.[Extract] [Full Text] [PDF]
- Re: Active Tamoxifen Metabolite Plasma Concentrations After Coadministration of Tamoxifen and the Selective Serotonin Reuptake Inhibitor Paroxetine
- Riccardo Ponzone, Nicoletta Biglia, and Piero Sismondi
J Natl Cancer Inst 2004 96: 883-884.[Extract] [Full Text] [PDF]
- Re: Active Tamoxifen Metabolite Plasma Concentrations After Coadministration of Tamoxifen and the Selective Serotonin Reuptake Inhibitor Paroxetine
- Ernst A. Lien, Per M. Ueland, and Per E. Lønning
J Natl Cancer Inst 2004 96: 884.[Extract] [Full Text] [PDF]
- RESPONSE: Re: Active Tamoxifen Metabolite Plasma Concentrations After Coadministration of Tamoxifen and the Selective Serotonin Reuptake Inhibitor Paroxetine
- Vered Stearns, Michael D. Johnson, James M. Rae, Antonella Novielli, Pankaj Bhargava, Daniel F. Hayes, Zeruesenay Desta, and David A. Flockhart
J Natl Cancer Inst 2004 96: 884-885.[Extract] [Full Text] [PDF]
Editorial about this Article
- A Hot Flash on Tamoxifen Metabolism
- Matthew P. Goetz and Charles L. Loprinzi
J Natl Cancer Inst 2003 95: 1734-1735.[Extract] [Full Text] [PDF]
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