CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment.
BACKGROUND
The efficacy of tamoxifen therapy for the treatment of breast cancer varies widely among individuals. Plasma concentrations of the active tamoxifen metabolite endoxifen are associated with the cytochrome P450 (CYP) 2D6 genotype. We examined the effects of concomitant use of selective serotonin reuptake inhibitor antidepressants, which are CYP2D6 enzyme inhibitors commonly prescribed to treat hot flashes in women who take tamoxifen, and genotypes for genes that encode tamoxifen-metabolizing enzymes on plasma concentrations of tamoxifen and its metabolites.


METHODS
Eighty patients with newly diagnosed with breast cancer who were beginning tamoxifen therapy (20 mg/day orally), 24 of whom were taking CYP2D6 inhibitors, were genotyped for common alleles of the CYP2D6, CYP2C9, CYP3A5, and sulfotransferase (SULT) 1A1 genes. Plasma concentrations of tamoxifen and its metabolites were measured after 1 and 4 months of tamoxifen therapy. Differences in plasma concentrations of tamoxifen and its metabolites between genotype groups were analyzed by the Wilcoxon rank sum test. All statistical tests were two-sided.


RESULTS
Among all women, plasma endoxifen concentrations after 4 months of tamoxifen therapy were statistically significantly lower in subjects with a CYP2D6 homozygous variant genotype (20.0 nM, 95% confidence interval [CI] = 11.1 to 28.9 nM) or a heterozygous genotype (43.1 nM, 95% CI = 33.3 to 52.9 nM) than in those with a homozygous wild-type genotype (78.0 nM, 95%CI = 65.9 to 90.1 nM) (both P = .003). Among subjects who carried a homozygous wild-type genotype, the mean plasma endoxifen concentration for those who were using CYP2D6 inhibitors was 58% lower than that for those who were not (38.6 nM versus 91.4 nM, difference = -52.8 nM, 95% CI = -86.1 to -19.5 nM, P = .0025). The plasma endoxifen concentration was slightly reduced in women taking venlafaxine, a weak inhibitor of CYP2D6, whereas the plasma endoxifen concentration was reduced substantially in subjects who took paroxetine (a potent inhibitor of CYP2D6). Genetic variations of CYP2C9, CYP3A5, or SULT1A1 had no statistically significant associations with plasma concentrations of tamoxifen or its metabolites.


CONCLUSIONS
Interactions between CYP2D6 polymorphisms and coadministered antidepressants and other drugs that are CYP2D6 inhibitors may be associated with altered tamoxifen activity.
Jin
Yan
Y
Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Desta
Zeruesenay
Z
Stearns
Vered
V
Ward
Bryan
B
Ho
Herbert
H
Lee
Kyung-Hoon
KH
Skaar
Todd
T
Storniolo
Anna Maria
AM
Li
Lang
L
Araba
Adjei
A
Blanchard
Rebecca
R
Nguyen
Anne
A
Ullmer
Lynda
L
Hayden
Jill
J
Lemler
Suzanne
S
Weinshilboum
Richard M
RM
Rae
James M
JM
Hayes
Daniel F
DF
Flockhart
David A
DA
D000328:Adult; D000368:Aged; D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage / Q000378:metabolism*; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D015239:Arylsulfotransferase / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D017024:Chemotherapy, Adjuvant; D003511:Cyclohexanols / Q000378:metabolism; D065729:Cytochrome P-450 CYP2C9; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000378:metabolism; D020847:Estrogen Receptor Modulators / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D011446:Prospective Studies; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000378:metabolism*; D013629:Tamoxifen / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D013997:Time Factors; D000069470:Venlafaxine Hydrochloride
D018687:Antidepressive Agents, Second-Generation; D018931:Antineoplastic Agents, Hormonal; D001189:Aryl Hydrocarbon Hydroxylases; D015239:Arylsulfotransferase; D003511:Cyclohexanols; D065729:Cytochrome P-450 CYP2C9; D019389:Cytochrome P-450 CYP2D6; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D004791:Enzyme Inhibitors; D020847:Estrogen Receptor Modulators; D017367:Selective Serotonin Reuptake Inhibitors; D013629:Tamoxifen; D000069470:Venlafaxine Hydrochloride; C450260:CYP2C9 protein, human; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; C117544:SULT1A1 protein, human