BACKGROUND Tamoxifen is considered a prodrug of its active metabolite endoxifen, which is dependent on the CYP2D6 and CYP3A enzymes. Tamoxifen pharmacokinetic variability influences endoxifen exposure and, consequently, its clinical outcome. This study investigated the impact of hormonal status on the pharmacokinetics of tamoxifen and its metabolites in TAM-treated breast cancer patients. METHODS TAM-treated breast cancer patients (n = 40) previously believed to have CYP3A activity within the normal range based on oral midazolam and phenotyped as CYP2D6 normal metabolizers using oral metoprolol were divided into two groups according to premenopausal (n = 20; aged 35-50 years) or postmenopausal (n = 20; aged 60-79 years) status. All patients were treated with 20 mg/day tamoxifen for at least three months. Serial plasma samples were collected within the 24 h dose interval for analysis of unchanged tamoxifen, endoxifen, 4-hydroxytamoxifen and N-desmethyltamoxifen quantified by LC-MS/MS. CYP activities were assessed using midazolam apparent clearance (CYP3A) and the metoprolol/alfa-hydroxymetoprolol plasma metabolic ratio (CYP2D6). CYP3A4, CYP3A5 and CYP2D6 SNPs and copy number variation were investigated using TaqMan assays. RESULTS Postmenopausal status increased steady-state plasma concentrations (Css) of tamoxifen (116.95 vs 201.23 ng/mL), endoxifen (8.01 vs 18.87 ng/mL), N-desmethyltamoxifen (485.16 vs 843.88 ng/mL) and 4-hydroxytamoxifen (2.67 vs 4.11 ng/mL). The final regression models included hormonal status as the only predictor for Css of tamoxifen [β-coef ± SE, p-value (75.03 ± 17.71, p = 0.0001)] and 4-hydroxytamoxifen (1.7822 ± 0.4385, p = 0.0002), while endoxifen Css included hormonal status (8.578 ± 3.402, p = 0.02) and race (11.945 ± 2.836, p = 0.007). For N-desmethyltamoxifen Css, the final model was correlated with hormonal status (286.259 ± 76.766, p = 0.0007) and weight (- 8.585 ± 3.060, p = 0.008). CONCLUSION The premenopausal status was associated with decreased endoxifen plasma concentrations by 135% compared to postmenopausal status. Thus, the endoxifen plasma concentrations should be monitored mainly in the premenopausal period to maintain plasma levels above the efficacy threshold value. TRIAL REGISTRATION RBR-7tqc7k.

中文翻译：

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激素状态会影响他莫昔芬治疗的乳腺癌患者的他莫昔芬及其主要代谢产物的血浆暴露。

背景技术他莫昔芬被认为是其活性代谢物endoxifen的前药，其依赖于CYP2D6和CYP3A酶。他莫昔芬的药代动力学变异性会影响Endoxifen的暴露量，进而影响其临床疗效。这项研究调查了激素状态对他莫昔芬及其代谢产物在TAM治疗的乳腺癌患者中的药代动力学的影响。方法根据经口服咪达唑仑并经口服美托洛尔表型定为CYP2D6正常代谢者的表型，经TAM治疗的乳腺癌患者（n = 40）以前被认为具有正常范围的CYP3A活性，根据绝经前分为n组（n = 20； 35岁） -50岁）或绝经后（n = 20；年龄60-79岁）。所有患者均接受20 mg /天他莫昔芬治疗至少三个月。在24 h剂量间隔内收集系列血浆样品，以分析通过LC-MS / MS定量的未改变的他莫昔芬，内皮西芬，4-羟基他莫昔芬和N-去甲基他莫昔芬。使用咪达唑仑表观清除率（CYP3A）和美托洛尔/α-羟基美托洛尔血浆代谢率（CYP2D6）评估CYP活性。CYP3A4，CYP3A5和CYP2D6 SNPs和拷贝数变异使用TaqMan分析法进行了研究。结果绝经后状态增加了他莫昔芬的稳态血浆浓度（Css）（116.95 vs 201.23 ng / mL），endoxifen（8.01 vs 18.87 ng / mL），N-去甲基他莫昔芬（485.16 vs 843.88 ng / mL）和4-羟基他莫昔芬（2.67） vs 4.11 ng / mL）。最终的回归模型包括激素状态是他莫昔芬Css的唯一预测指标[β-coef±SE，p值（75.03±17.71，p = 0.0001）]和4-羟基他莫昔芬（1.7822±0.4385，p = 0.0002），而endoxifen Css包括荷尔蒙状态（8.578±3.402，p = 0.02）和种族（11.945±2.836，p = 0.007）。对于N-去甲基他莫昔芬Css，最终模型与荷尔蒙状态（286.259±76.766，p = 0.0007）和体重（-8.585±3.060，p = 0.008）相关。结论与绝经后状态相比，绝经前状态与内皮西芬血浆浓度降低135％有关。因此，应主要在绝经前监测内皮西芬的血浆浓度，以使血浆水平维持在功效阈值以上。试用注册RBR-7tqc7k。585±3.060，p = 0.008）。结论与绝经后状态相比，绝经前状态与内皮西芬血浆浓度降低135％有关。因此，应主要在绝经前监测内皮西芬的血浆浓度，以使血浆水平维持在功效阈值以上。试用注册RBR-7tqc7k。585±3.060，p = 0.008）。结论与绝经后状态相比，绝经前状态与内皮西芬血浆浓度降低135％有关。因此，应主要在绝经前监测内皮西芬的血浆浓度，以使血浆水平维持在功效阈值以上。试用注册RBR-7tqc7k。