Pharmacogenetics and Genomics
Clinical Pharmacology & Therapeutics (2006) 80, 61–74; doi:10.1016/j.clpt.2006.03.013
Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: Implication for optimization of breast cancer treatment*
Silvana Borges MD1,2,3,4,†, Zeruesenay Desta PhD1,2,3,4,†, Lang Li PhD1,2,3,4, Todd C Skaar PhD1,2,3,4, Bryan A Ward BSc1,2,3,4, Anne Nguyen BSc1,2,3,4, Yan Jin MD1,2,3,4, Anna Maria Storniolo MD1,2,3,4, D Michele Nikoloff PhD1,2,3,4, Lin Wu PhD1,2,3,4, Grant Hillman MSc1,2,3,4, Daniel F Hayes MD1,2,3,4, Vered Stearns MD1,2,3,4 and David A Flockhart MD, PhD1,2,3,4
- 1Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis
- 2Breast Oncology Program, University of Michigan, Ann Arbor, Mich
- 3Breast Cancer Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Md
- 4Roche Molecular Diagnostics, Pleasanton, Calif.
Correspondence: Silvana Borges, MD, Division of Clinical Pharmacology, Indiana University School of Medicine, 1001 W 10th St, WD Myers Bldg, W7123, Indianapolis, IN 46202. E-mail: siborges@iupui.edu
†Drs Borges and Desta contributed equally to this work.
*This study was supported in part by a Pharmacogenetics Research Network grant (2U-01 GM61373) (D.A.F., D.F.H., and V.S.), grant K24RR020815 (D.A.F.) from the National Center for Research Resources, Bethesda, Md, and a clinical pharmacology training grant (5T32-GM-08425) (D.A.F.) from the National Institute of General Medical Sciences, Bethesda, Md; by Damon Runyon-Lilly Clinical Investigator Award CI-3 from the Damon Runyon Cancer Research Foundation (V.S.); by the Fashion Footwear Foundation/QVC Presents Shoes on Sale (D.F.H.); and by a Merck Sharp & Dohme International Fellowship in Clinical Pharmacology (S.B.).
Accepted 28 March 2006.
Abstract
Background and Objectives: N-Desmethyltamoxifen (NDM), a major primary metabolite of tamoxifen, is hydroxylated by cytochrome P450 (CYP) 2D6 to yield endoxifen. Because of its high antiestrogenic potency, endoxifen may play an important role in the clinical activity of tamoxifen. We conducted a prospective trial in 158 patients with breast cancer who were taking tamoxifen to further understand the effect of CYP2D6 genotype and concomitant medications on endoxifen plasma concentrations.
Methods: Medication history, genotype for 33 CYP2D6 alleles, and plasma concentrations of tamoxifen and its metabolites were determined at the fourth month of tamoxifen treatment.
Results: By use of a mixture model approach, endoxifen plasma concentration identified 2 phenotypic groups, whereas 4 were defined by the endoxifen/NDM plasma concentration ratio. Three distinct genotype groups were identified in the distribution of endoxifen/NDM ratio: (1) low ratios composed of patients lacking any functional allele (mean, 0.04 
0.02); (2) intermediate ratios represented by patients with 1 active allele (mean, 0.08 0.04); and (3) high ratios composed of patients with 2 or more functional alleles (mean, 0.15 0.09). Endoxifen/NDM plasma ratios were significantly different between these groups (P < .001). The mean endoxifen plasma concentration was significantly lower in CYP2D6 extensive metabolizers who were taking potent CYP2D6 inhibitors than in those who were not taking CYP2D6 inhibitors (23.5 9.5 nmol/L versus 84.1 39.4 nmol/L, P < .001).
Conclusion: CYP2D6 genotype and concomitant potent CYP2D6 inhibitors are highly associated with endoxifen plasma concentration and may have an impact on the response to tamoxifen therapy. These iterative approaches may be valuable in the study of other complex genotype-phenotype relationships.
