Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition).
Vol 22, No 14S (July 15 Supplement), 2004: 508
© 2004 American Society of Clinical Oncology

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Abstract

The effect of CYP 2D6 genotype and CYP2D6 inhibitors on tamoxife

Johns Hopkins School of Medicine, Baltimore, MD; University of Michigan, Ann Arbor, MI; Indiana University School of Medicine, Indianapolis, IN

508

Background: We have recently identified and characterized a potent active metabolite of tamoxifen, endoxifen. Co-administration of tamoxifen with the CYP 2D6 inhibitor paroxetine results in a significant reduction in plasma endoxifen concentrations (JNCI 2003;95:1758–64). We report preliminary data from an ongoing prospective study to confirm these findings. Methods: Wild type (Wt) or variant (Vt) genotype of CYP 2D6 (*4 & *6), 2C9 (*2 & *3), or 3A5 (*3) was determined in 80 women who were prescribed tamoxifen 20 mg/day for the adjuvant treatment of breast cancer. Plasma concentrations of tamoxifen and its metabolites N-desmethyl tamoxifen (NDM), 4-hydroxy tamoxifen (4-OH), and endoxifen, were determined 1 and 4 months after initiating tamoxifen. Results: Among subjects who carried CYP 2D6 Wt/Wt, Wt/Vt or Vt/Vt genotype, a statistically significant difference in 4-month plasma endoxifen concentrations was observed, but not in concentrations of tamoxifen or other metabolites (Table). Results were similar after 1 month of tamoxifen. Wt/Wt subjects who were not taking 2D6 inhibitors had significantly higher endoxifen concentrations than those who were Wt/Vt or Vt/Vt (P=0.007). This trend disappeared in subjects who were taking CYP 2D6 inhibitors (P=0.99). The use of CYP 2D6 inhibitors significantly decreased endoxifen concentration in Wt/Wt subjects (P=0.0001) and modestly in Wt/Vt subjects (P=0.07). The CYP 2D6 inhibitors sertraline and paroxetine, but not venlafaxine, were associated with low concentrations of endoxifen. CYP 2C9 genotype and inhibitors, and CYP 3A5 genotype did not effect plasma tamoxifen and metabolite concentrations. Conclusions: CYP 2D6 *4 and *6 genotype and the use of 2D6 inhibitors strongly influence tamoxifen conversion to endoxifen. The clinical implications of these findings are under study. Prescribing practices should not be changed at present.

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Abstract presentation from the 2004 ASCO Annual Meeting