Department of Clinical Analysis, Toxicology and Food Science, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
Department of Gynecology and Obstetrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
BMC Pharmacol Toxicol. 2019 Dec 19;20(Suppl 1):81. doi: 10.1186/s40360-019-0358-y.
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.
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.
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).
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.
RBR-7tqc7k.
他莫昔芬被认为是其活性代谢物依西美坦的前体药物，而依西美坦的活性取决于 CYP2D6 和 CYP3A 酶。他莫昔芬药代动力学的可变性会影响依西美坦的暴露，从而影响其临床疗效。本研究调查了激素状态对 TAM 治疗的乳腺癌患者中他莫昔芬及其代谢物的药代动力学的影响。
将先前认为 CYP3A 活性处于正常范围内的 TAM 治疗的乳腺癌患者（n=40）根据口服咪达唑仑和表型为 CYP2D6 正常代谢者分为两组，根据绝经前（n=20；年龄 35-50 岁）或绝经后（n=20；年龄 60-79 岁）状态。所有患者均接受 20mg/天的他莫昔芬治疗至少三个月。在 24 小时剂量间隔内采集连续的血浆样本，通过 LC-MS/MS 分析未改变的他莫昔芬、依西美坦、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-羟美托洛尔血浆代谢比（CYP2D6）评估 CYP 活性。使用 TaqMan 测定法研究 CYP3A4、CYP3A5 和 CYP2D6 SNP 和拷贝数变异。
绝经后状态增加了他莫昔芬（116.95 对 201.23ng/mL）、依西美坦（8.01 对 18.87ng/mL）、N-去甲基他莫昔芬（485.16 对 843.88ng/mL）和 4-羟基他莫昔芬（2.67 对 4.11ng/mL）的稳态血浆浓度。最终回归模型包括激素状态作为他莫昔芬 [β-系数±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）的 Css 的唯一预测因子，而依西美坦 Css 包括激素状态（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，最终模型与激素状态（286.259±76.766，p=0.0007）和体重（-8.585±3.060，p=0.008）相关。
与绝经后状态相比，绝经前状态与依西美坦血浆浓度降低 135%相关。因此，主要应在绝经前监测依西美坦的血浆浓度，以维持高于疗效阈值的血浆水平。
RBR-7tqc7k。
