Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: Implication for optimization of breast cancer treatment

Silvana Borges, Zeruesenay Desta, Lang Li, Todd C. Skaar, Bryan A. Ward, Anne Nguyen, Yan Jin, Anna Maria Storniolo, D. Michele Nikoloff, Lin Wu, Grant Hillman, Daniel F. Hayes, Vered Stearns, David A. Flockhart

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)61-74
Number of pages14
JournalClinical Pharmacology and Therapeutics
Volume80
Issue number1
DOIs
StatePublished - Jul 2006

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Tamoxifen
Genotype
Cytochrome P-450 CYP2D6
Breast Neoplasms
Alleles
Therapeutics
4-hydroxy-N-desmethyltamoxifen
Cytochrome P-450 CYP2D6 Inhibitors
Phenotype
N-desmethyltamoxifen

ASJC Scopus subject areas

  • Pharmacology

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Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism : Implication for optimization of breast cancer treatment. / Borges, Silvana; Desta, Zeruesenay; Li, Lang; Skaar, Todd C.; Ward, Bryan A.; Nguyen, Anne; Jin, Yan; Storniolo, Anna Maria; Nikoloff, D. Michele; Wu, Lin; Hillman, Grant; Hayes, Daniel F.; Stearns, Vered; Flockhart, David A.

In: Clinical Pharmacology and Therapeutics, Vol. 80, No. 1, 07.2006, p. 61-74.

Research output: Contribution to journalArticle

Borges, S, Desta, Z, Li, L, Skaar, TC, Ward, BA, Nguyen, A, Jin, Y, Storniolo, AM, Nikoloff, DM, Wu, L, Hillman, G, Hayes, DF, Stearns, V & Flockhart, DA 2006, 'Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: Implication for optimization of breast cancer treatment', Clinical Pharmacology and Therapeutics, vol. 80, no. 1, pp. 61-74. https://doi.org/10.1016/j.clpt.2006.03.013
Borges, Silvana ; Desta, Zeruesenay ; Li, Lang ; Skaar, Todd C. ; Ward, Bryan A. ; Nguyen, Anne ; Jin, Yan ; Storniolo, Anna Maria ; Nikoloff, D. Michele ; Wu, Lin ; Hillman, Grant ; Hayes, Daniel F. ; Stearns, Vered ; Flockhart, David A. / Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism : Implication for optimization of breast cancer treatment. In: Clinical Pharmacology and Therapeutics. 2006 ; Vol. 80, No. 1. pp. 61-74.
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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.",
author = "Silvana Borges and Zeruesenay Desta and Lang Li and Skaar, {Todd C.} and Ward, {Bryan A.} and Anne Nguyen and Yan Jin and Storniolo, {Anna Maria} and Nikoloff, {D. Michele} and Lin Wu and Grant Hillman and Hayes, {Daniel F.} and Vered Stearns and Flockhart, {David A.}",
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T1 - Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism

T2 - Implication for optimization of breast cancer treatment

AU - Borges, Silvana

AU - Desta, Zeruesenay

AU - Li, Lang

AU - Skaar, Todd C.

AU - Ward, Bryan A.

AU - Nguyen, Anne

AU - Jin, Yan

AU - Storniolo, Anna Maria

AU - Nikoloff, D. Michele

AU - Wu, Lin

AU - Hillman, Grant

AU - Hayes, Daniel F.

AU - Stearns, Vered

AU - Flockhart, David A.

PY - 2006/7

Y1 - 2006/7

N2 - 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.

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