© 2004 by Oxford University Press
© 2004 Oxford University Press
CORRESPONDENCE |
RESPONSE: Re: Active Tamoxifen Metabolite Plasma Concentrations After Coadministration of Tamoxifen and the Selective Serotonin Reuptake Inhibitor Paroxetine
Affiliations of authors: Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN (DAF, ZD); Breast Cancer Program, University of Michigan, Ann Arbor (JMR, DFH); and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD (VS); Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC (MDJ, AN, PB)
Correspondence to: David A. Flockhart, MD, PhD, Division of Clinical Pharmacology, Indiana University School of Medicine, 1001 W. 10th St., Rm. OPD 320, Indianapolis, IN 46203 ( e-mail: dflockha{at}iupui.edu)
We thank all three correspondents for their useful insights into our work. The data we presented demonstrate that the tamoxifen metabolite 4-hydroxy-N-desmethyl-tamoxifen (endoxifen) is equipotent to 4-hydroxy-tamoxifen in inhibiting estradiol-stimulated growth of MCF-7 cells (1) and that endoxifen concentrations were reduced in women who carried a genetic variant of CYP2D6 or in women with a wild-type CYP2D6 after coprescription with the CYP2D6 inhibitor paroxetine. The role of the parent drug tamoxifen, each of its metabolites, or a profile of the metabolites in inhibiting breast cancer progression remains unclear and is a critical area for future research. We thank Ratliff et al. for their elegant review of tamoxifen effects and agree that tamoxifen's mechanism of action is complex and that the high concentration of the parent drug and its primary metabolites may mean that they contribute to tamoxifen effects. Tamoxifen and its metabolites are concentrated in breast tissue, but determining which concentrations are active at the effect site remains elusive. The drug behaves as a weak anti-estrogen in clinical trials, suggesting that its effects may be modulated by changes in its concentration or in concentrations of estradiol and other active species at the effect site. As we stated in the discussion of our paper, we agree that the implications of a reduction in endoxifen concentrations are unknown and should not affect current prescribing practices.
We agree with Dr. Ponzone and colleagues that the minimal active dose of tamoxifen is not known. These authors have reported that tamoxifen administered in doses lower than 20 mg/day demonstrated a similar effect on surrogate markers such as circulating insulin growth factor and tissue proliferation index Ki-67 (2,3). However, studies to correlate serum and tissue surrogate markers with clinical outcomes such as disease-free or overall survival in women with breast cancer or a reduction in the incidence of breast cancer in those at high risk are not available. It is important to evaluate the metabolic profiles of tamoxifen with lower than standard does, and this is an area of continuing research.
In our study, we separated, purified, and identified the tamoxifen metabolite 4-hydroxy-N-desmethyl-tamoxifen, which we designated endoxifen, as a metabolite whose concentration was decreased when patients were coprescribed paroxetine, a CYP2D6 inhibitor. The presence of the metabolite was apparent in the 1980s and, as Lien and colleagues report, was previously designated BX. We were asked by the reviewers of JNCI to name this metabolite to reduce the difficulty of reading the article. We thank these investigators for pointing out their earlier work, which is consistent with our own and enhances the potential clinical relevance of our work. In a second paper that specifically focused on comprehensive pharmacological characterization of 4-hydroxy-N-desmethyl-tamoxifen, we have referred in detail to the work conducted in the 1980s (4). Lien et al. quantified 4-hydroxy-N-desmethyl tamoxifen in rat and human tissues in 1991 (5). Although their data differ from ours in that BX was detected in only five of 11 human serum samples tested, it had a mean concentration in those samples that was 5.3-fold greater than that of B (4-hydroxy-tamoxifen), consistent with our data. In the interaction study between tamoxifen and aminoglutethimide reported by these authors, they showed a two- to threefold reduction in the area under the curve (AUC) concentrations of tamoxifen, N-desmethyl-tamoxifen, and 4-hydroxy-tamoxifen, and a 15-fold reduction in the AUC of 4-hydroxy-N-desmethyl-tamoxifen (6). They speculated that these changes might be responsible for the documented lack of benefit seen in clinical trials when tamoxifen was coprescribed with aminoglutethimide, suggesting that the marked reduction in active metabolite concentrations seen in our study may also be important.
Given the proven benefits of tamoxifen in reducing mortality in patients with established invasive breast cancer and in reducing recurrences and new breast cancers in women with in situ lesions or other high-risk features, it will be difficult to address the effects of pharmacogenomics on these outcomes in a placebo-controlled trial. However, we are currently evaluating drug–gene interactions in a prospective cohort registry study of women who are taking tamoxifen for routine indications, and we hope that this study will provide further insights into the effects of pharmacogenetics on secondary endpoints, such as measures of estrogenic and/or anti-estrogenic activity.
REFERENCES
1 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 Inst2003;95:1758–64.
2 Decensi A, Gandini S, Guerrieri-Gonzaga A, Johansson H, Manetti L, Bonanni B, et al. Effect of blood tamoxifen concentrations on surrogate biomarkers in a trial of dose reduction in healthy women. J Clin Oncol1999;17:2633–8.
3 Decensi A, Robertson C, Viale G, Pigatto F, Johansson H, Kisanga ER, et al. A randomized trial of low-dose tamoxifen on breast cancer proliferation and blood estrogenic biomarkers. J Natl Cancer Inst2003;95:779–90.
4 Johnson MD, Zou H, Lee KH, Trebley J, Rae JM, Weatherman RV, et al. Pharmacological characterization of 4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen. Breast Cancer Res Treat2004,85:151–9.[CrossRef][Medline]
5 Lien EA, Soheim E, Ueland PM. Distribution of tam and its metabolites in rat and human tissues during steady-state treatment. Cancer Res1991; 51:4837–44.
6 Lien EA, Anker G, Lonning PE, Solheim E, Ueland PM. Decreased serum concentrations of tam and its metabolites induced by aminoglutethimide. Cancer Res1990;50:5851–7.
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J Natl Cancer Inst 2004 96: 883.
J Natl Cancer Inst 2004 96: 883-884.
J Natl Cancer Inst 2004 96: 884.
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