Lehmann David, Nelsen Jamie, Ramanath Vijay, Newman Nancy, Duggan David, Smith Adrienne
SUNY Upstate Medical University, Syracuse, USA.
J Clin Pharmacol. 2004 Aug;44(8):861-5. doi: 10.1177/0091270004266618.
Tamoxifen is a selective estrogen receptor modulator used in estrogen receptor-positive breast cancer. Tamoxifen is metabolized to an extremely potent antiestrogen by cytochrome P450 (CYP) 2D6, 2C9, and 3A isoforms. The selective serotonin reuptake inhibitors (SSRIs) are potent inhibitors of these CYPs. Since the prevalence of depression in breast cancer patients is nearly triple that of the general population, it is likely that a subgroup of breast cancer patients will receive long-term treatment with both an SSRI and tamoxifen. A case control design was used to investigate the possibility that a resultant decrease in production of the 4-hydroxy metabolite from chronic inhibition results in the attenuation of the antitumor effect of tamoxifen. Twenty-eight patients without recurrences of breast cancer (controls) were matched to an equal number of cases (recurrences) by cancer stage and year of diagnosis. Data were analyzed on all chronic medication exposure (> 3 months) in both cases and controls classified as to their status as CYP 2D6, 2C9, and 3A inhibitors, substrates, or inducers. No significant difference was found for CYP inhibitor or substrate exposure between cases and controls. Indeed, controls showed a slightly greater exposure to inhibitors of the relevant CYP isoforms compared to cases. These results suggested a trend toward the null hypothesis. It is unlikely that the effect of chronic exposure to potent CYP isoform inhibitors affects the antitumor effect of tamoxifen and its 4-hydroxy metabolite, supporting the safety of the continued practice of concomitant SSRI administration to breast cancer patients with depression.
他莫昔芬是一种用于雌激素受体阳性乳腺癌的选择性雌激素受体调节剂。他莫昔芬通过细胞色素P450（CYP）2D6、2C9和3A同工酶代谢为一种极具活性的抗雌激素。选择性5-羟色胺再摄取抑制剂（SSRI）是这些CYP的强效抑制剂。由于乳腺癌患者中抑郁症的患病率几乎是普通人群的三倍，很可能有一部分乳腺癌患者会同时接受SSRI和他莫昔芬的长期治疗。采用病例对照设计来研究慢性抑制导致4-羟基代谢物生成减少是否会削弱他莫昔芬的抗肿瘤作用。28例无乳腺癌复发的患者（对照组）按癌症分期和诊断年份与同等数量的病例（复发组）进行匹配。对病例组和对照组中所有分类为CYP 2D6、2C9和3A抑制剂、底物或诱导剂的慢性药物暴露（>3个月）数据进行分析。病例组和对照组之间在CYP抑制剂或底物暴露方面未发现显著差异。实际上，与病例组相比，对照组显示出对相关CYP同工酶抑制剂的暴露略多。这些结果表明倾向于零假设。长期暴露于强效CYP同工酶抑制剂不太可能影响他莫昔芬及其4-羟基代谢物的抗肿瘤作用，这支持了对患有抑郁症的乳腺癌患者继续同时给予SSRI的安全性。
