van Nuland Merel, Hillebrand M J X, Rosing H, Schellens J H M, Beijnen J H
*Department of Pharmacy and Pharmacology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute and MC Slotervaart;†Division of Clinical Pharmacology, Department of Medical Oncology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute, Amsterdam, The Netherlands; and‡Division of Pharmacoepidemiology and Clinical Pharmacology, Faculty of Science, Department of Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.
Ther Drug Monit. 2017 Jun;39(3):243-251. doi: 10.1097/FTD.0000000000000387.
Abiraterone acetate and enzalutamide are 2 novel drugs for the treatment of metastatic castration-resistant prostate cancer. The metabolism of these drugs is extensive. Major metabolites are N-desmethyl enzalutamide, enzalutamide carboxylic acid, abiraterone N-oxide sulfate, and abiraterone sulfate; of which N-desmethyl enzalutamide is reported to possess antiandrogen capacities. A liquid chromatography-tandem mass spectrometry method for simultaneous quantification of abiraterone, enzalutamide, and the main metabolites has been developed and validated to support therapeutic drug monitoring.
Human plasma samples of patients treated with abiraterone or enzalutamide were harvested at the clinic and stored at -20°C. Proteins were precipitated by acetonitrile, and the final extract was injected on a Kinetex C18 column and separated with gradient elution. Analytes were detected by liquid chromatography-mass spectrometry (Triple Quad 6500).
The method was validated over various linear ranges: 1-100 ng/mL for abiraterone, 5-500 ng/mL for enzalutamide and enzalutamide carboxylic acid, 10-1000 ng/mL for N-desmethyl enzalutamide, 30-3000 ng/mL for abiraterone N-oxide sulfate, and 100-10,000 ng/mL for abiraterone sulfate. Intra-assay and interassay variabilities were within ±15% of the nominal concentrations for quality control samples at medium and high concentrations and within ±20% at the lower limit of quantification, respectively.
The described method for simultaneous determination of abiraterone and enzalutamide was validated successfully and provides a useful tool for therapeutic drug monitoring in patients treated with these agents.
醋酸阿比特龙和恩杂鲁胺是用于治疗转移性去势抵抗性前列腺癌的两种新型药物。这些药物的代谢广泛。主要代谢产物为N-去甲基恩杂鲁胺、恩杂鲁胺羧酸、阿比特龙N-氧化物硫酸盐和阿比特龙硫酸盐；其中据报道N-去甲基恩杂鲁胺具有抗雄激素能力。已开发并验证了一种同时定量阿比特龙、恩杂鲁胺及其主要代谢产物的液相色谱-串联质谱法，以支持治疗药物监测。
在临床采集接受阿比特龙或恩杂鲁胺治疗患者的人血浆样本，并储存在-20°C。用乙腈沉淀蛋白质，最终提取物注入Kinetex C18柱，采用梯度洗脱进行分离。通过液相色谱-质谱（三重四极杆6500）检测分析物。
该方法在不同线性范围内得到验证：阿比特龙为1-100 ng/mL，恩杂鲁胺和恩杂鲁胺羧酸为5-500 ng/mL，N-去甲基恩杂鲁胺为10-1000 ng/mL，阿比特龙N-氧化物硫酸盐为30-3000 ng/mL，阿比特龙硫酸盐为100-10,000 ng/mL。中、高浓度质量控制样品的批内和批间变异分别在标称浓度的±15%以内，在定量下限处变异在±20%以内。
所描述的同时测定阿比特龙和恩杂鲁胺的方法成功得到验证，为使用这些药物治疗的患者的治疗药物监测提供了有用工具。
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