PharmGKB summary: tamoxifen pathway, pharmacokinetics.
PharmGKB summary: tamoxifen pathway, pharmacokinetics.
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DOI：
10.1097/fpc.0b013e3283656bc1
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发表时间：
2013-11
影响因子：
2.6
通讯作者：
Klein TE
中科院分区：
文献类型：
--
作者：
Klein DJ;Thorn CF;Desta Z;Flockhart DA;Altman RB;Klein TE
他莫昔芬是一种选择性雌激素受体调节剂，对于治疗和预防雌激素受体（ER）阳性乳腺癌具有重要意义。它已被证明可以将疾病复发率和死亡率分别降低 50% 和 30%，并且还被用作乳腺癌高危人群的预防性治疗 [1-6]。对他莫昔芬的反应具有高度的个体差异，其部分原因可能是由于其体内代谢的差异[2]（图1）。潮热是他莫昔芬最常见的副作用，影响高达 80% 的女性 [7-9]。接受他莫昔芬治疗的患者似乎也有 B2 水平。患子宫内膜癌的风险增加 5 倍 [3,10,11]。此外，他莫昔芬可能会增加血栓栓塞事件和临床抑郁症的风险[3, 8]。选择性血清素再摄取抑制剂（SSRI）通常用于治疗潮热和抑郁症；然而，临床医生在决定开哪种 SSRI 处方时需要谨慎选择，因为许多 SSRI 药物可能会降低他莫昔芬治疗的疗效 [8, 9, 12–14]。他莫昔芬用作 ER 拮抗剂，竞争性抑制癌性 ER 阳性细胞获得生长所需的雌激素 [10, 15, 16]。然而，长期以来人们一直认为他莫昔芬实际上是一种前药，其代谢物可能是他莫昔芬治疗成功的原因[17, 18]。有关他莫昔芬开创性研究的更多信息，请参阅 Jordan 的这篇精彩评论 [19]。除了作为选择性雌激素受体调节剂外，最近发现他莫昔芬的一些代谢物在体外还可作为芳香酶抑制剂[20, 21]。芳香酶将类固醇（例如睾酮）转化为雌二醇，其抑制会严重减少体内可用雌激素的量。以前未被认识的他莫昔芬代谢物去甲诺多昔芬是他莫昔芬代谢物最有效的芳香酶抑制剂。它与来曲唑（一种专门作为芳香酶抑制剂销售的药物）在体外引起芳香酶活性的降低相同[21]。
Tamoxifen, a selective estrogen receptor modulator, is important for the treatment and prevention of estrogen receptor (ER)-positive breast cancer. It has been shown to decrease disease recurrence and mortality rates by as much as 50 and 30%, respectively, and has also been used as a prophylactic treatment for those at high risk of developing breast cancer [1–6]. The response to tamoxifen has a high degree of interindividual variability, the cause of which may partly be due to differences in its metabolism in vivo [2](Fig. 1). Hot flashes, the most common side effect of tamoxifen, affect up to 80% of women [7–9]. Patients receiving tamoxifen also seem to have a B2. 5 times higher risk of developing endometrial cancer [3, 10, 11]. In addition, tamoxifen may contribute to an increased risk for thromboembolic events and clinical depression [3, 8]. Selective serotonin reuptake inhibitors (SSRIs) are commonly used to treat both hot flashes and depression; however, clinicians need to choose carefully when deciding which SSRI to prescribe, as many may have the capacity to decrease the efficacy of tamoxifen treatment [8, 9, 12–14].Tamoxifen is used as an ER antagonist, which competitively inhibits cancerous ER-positive cells from obtaining the estrogen required for growth [10, 15, 16]. However, it has long been thought that tamoxifen is actually a prodrug and that its metabolites are likely to be the causative factors for the success seen in tamoxifen therapy [17, 18]. For more information on the seminal works on tamoxifen, please see this excellent review by Jordan [19]. Apart from acting as selective estrogen receptor modulators, it has recently been found that some of tamoxifen’s metabolites also act as aromatase inhibitors in vitro [20, 21]. Aromatase converts steroids, for example, testosterone to estradiol, the inhibition of which severely decreases the amount of available estrogen in the body. A previously unrecognized metabolite of tamoxifen, norendoxifen, is the most potent aromatase inhibitor of the tamoxifen metabolites. It causes the same decrease in vitro in aromatase activity as does letrozole, a drug that is exclusively marketed as an aromatase inhibitor [21].