CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment
CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment
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DOI：
10.1093/jnci/dji005
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发表时间：
2005-01-05
影响因子：
10.3
通讯作者：
Flockhart, DA
中科院分区：
文献类型：
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作者：
Jin, Y;Desta, Z;Flockhart, DA
背景：他莫昔芬治疗乳腺癌的疗效在个体间差异很大。他莫昔芬活性代谢物内昔芬的血浆浓度与细胞色素P450（CYP）2D 6基因型相关。我们检查了合并使用选择性5-羟色胺再摄取抑制剂抗抑郁药（通常用于治疗服用他莫昔芬的女性潮热的CYP 2D 6酶抑制剂）和编码他莫昔芬代谢酶的基因的基因型对他莫昔芬及其代谢物血浆浓度的影响。研究方法：80例新诊断的乳腺癌患者开始接受他莫昔芬治疗（20 mg/d口服），其中24例正在服用CYP 2D 6抑制剂，对CYP 2D 6、CYP 2C 9、CYP 3A 5和磺基转移酶（SULT）1A 1基因的常见等位基因进行基因分型。在他莫昔芬治疗1个月和4个月后测量他莫昔芬及其代谢物的血浆浓度。通过Wilcoxon秩和检验分析基因型组之间他莫昔芬及其代谢产物的血浆浓度差异。所有统计学检验均为双侧检验。结果如下：在所有女性中，CYP 2D 6纯合变异基因型受试者接受他莫昔芬治疗4个月后，血浆内昔芬浓度显著降低，（20.0 nM，95%置信区间[CI] = 11.1 - 28.9 nM）或杂合基因型（43.1 nM，95% CI = 33.3至52.9 nM）比纯合野生型基因型（78.0 nM，95% CI = 65.9至90.1 nM）（均P = 0.003）。在携带纯合野生型基因型的受试者中，使用CYP 2D 6抑制剂的受试者的平均血浆内昔芬浓度比未使用CYP 2D 6抑制剂的受试者低58%（38.6 nM vs 91.4 nM，差异= -52.8 nM，95% CI = -86.1 to -19.5 nM，P = 0.0025）。服用CYP 2D 6弱抑制剂文拉法辛的女性血浆内昔芬浓度略有降低，而服用帕罗西汀（CYP 2D 6强效抑制剂）的受试者血浆内昔芬浓度大幅降低。CYP 2C 9、CYP 3A 5或SULT 1A 1的遗传变异与他莫昔芬或其代谢产物的血浆浓度无统计学显著相关性。结论：CYP 2D 6多态性与联合使用抗抑郁药和其他CYP 2D 6抑制剂药物之间的相互作用可能与他莫昔芬活性改变有关。
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 wildtype 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% Cl = -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. Conclusion: Interactions between CYP2D6 polymorphisms and coadministered antidepressants and other drugs that are CYP2D6 inhibitors may be associated with altered tamoxifen activity.