Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: implication for optimization of breast cancer treatment.
OBJECTIVE
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).


CONCLUSIONS
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.
Borges
Silvana
S
Department of Medicine, Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, 46202, USA. siborges@iupui.edu
Desta
Zeruesenay
Z
Li
Lang
L
Skaar
Todd C
TC
Ward
Bryan A
BA
Nguyen
Anne
A
Jin
Yan
Y
Storniolo
Anna Maria
AM
Nikoloff
D Michele
DM
Wu
Lin
L
Hillman
Grant
G
Hayes
Daniel F
DF
Stearns
Vered
V
Flockhart
David A
DA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D005260:Female; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D010641:Phenotype; D011446:Prospective Studies; D013629:Tamoxifen / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use*
D018931:Antineoplastic Agents, Hormonal; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D013629:Tamoxifen; D019389:Cytochrome P-450 CYP2D6