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Liquid Chromatography-Tandem Mass Spectrometry Method for Ticagrelor and its Active Metabolite Determination in Human Plasma: Application to a Pharmacokinetic Study
Current Analytical Chemistry ( IF 1.8 ) Pub Date : 2020-07-08 , DOI: 10.2174/1573411015666190220144904
Niloufar Marsousi 1 , Serge Rudaz 1 , Jules A. Desmeules 1 , Youssef Daali 1
Affiliation  

Background: Ticagrelor is a highly recommended new antiplatelet agent for the treatment of patients with acute coronary syndrome at moderate or high ischemic risk. There is a real need for rapid and accurate analytical methods for ticagrelor determination in biological fluids for pharmacokinetic studies. In this study, a sensitive and specific LC-MS method was developed and validated for quantification of ticagrelor and its active metabolite (AM) in human plasma over expected clinical concentrations. Methods: Samples were handled by liquid-liquid extraction (LLE). A linear gradient was applied with a mobile phase composed of formic acid 0.1% and acetonitrile with 0.1% of formic acid using a C18 reversed-phase column. MS spectra were obtained by electrospray ionization in negative mode and optimized at 521.4→360.9 m/z, 477.2→361.2 m/z and 528.1→367.9 m/z transitions for ticagrelor, AM and ticagrelor-d7, respectively. Results: This method allowed rapid elution, in less than 4 minutes, and quantification of concentrations as low as 2 ng/mL for ticagrelor and 1 ng/mL for AM using only 100 μL of human plasma. LLE using hexane/ethyl acetate (50/50) was an optimal compromise in terms of extraction recovery and endogenous compounds interference. Trueness values of 87.8% and 89.5% and precisions of 84.1% and 93.8% were obtained for ticagrelor and AM, respectively. Finally, the usefulness of the method was assessed in a clinical trial where a single 180 mg ticagrelor was orally administered to healthy male volunteers. Pharmacokinetic parameters of ticagrelor and its active metabolite were successfully determined. Conclusion: A sensitive and specific quantification LC-MS-MS method was developed and validated for ticagrelor and its active metabolite determination in human plasma. The method was successfully applied to a clinical trial where a single ticagrelor 180 mg dose was orally administered to healthy male volunteers. The described method allows quantification of concentrations as low as 2 ng/mL of ticagrelor and 1 ng/mL of the metabolite using only 100 μL of plasma.

中文翻译:

人血浆中替格瑞洛及其活性代谢物测定的液相色谱-串联质谱法:在药代动力学研究中的应用

背景:替格瑞洛是一种强烈推荐的新型抗血小板药物,用于治疗中度或高度缺血风险的急性冠脉综合征患者。在药代动力学研究中,确实需要快速准确的分析方法来测定生物体液中的替格瑞洛。在本研究中,开发并验证了一种灵敏且特异的 LC-MS 方法,用于定量人体血浆中超过预期临床浓度的替格瑞洛及其活性代谢物 (AM)。方法:通过液液萃取 (LLE) 处理样品。使用由 0.1% 甲酸和含 0.1% 甲酸的乙腈组成的流动相,使用 C18 反相柱施加线性梯度。MS 谱是通过负模式电喷雾电离获得的,并优化为 521.4→360.9 m/z、477.2→361.2 m/z 和 528.1→367。替格瑞洛、AM 和替格瑞洛-d7 分别为 9 m/z 跃迁。结果:该方法可在不到 4 分钟的时间内实现快速洗脱,并且仅使用 100 μL 人血浆即可对替格瑞洛的浓度低至 2 ng/mL 和 AM 的浓度低至 1 ng/mL 进行定量。使用己烷/乙酸乙酯 (50/50) 的 LLE 是萃取回收率和内源性化合物干扰的最佳折衷方案。替格瑞洛和 AM 的真实度值分别为 87.8% 和 89.5%,精度分别为 84.1% 和 93.8%。最后,在一项临床试验中评估了该方法的有效性,在该试验中,健康男性志愿者口服单剂 180 毫克替格瑞洛。成功测定了替格瑞洛及其活性代谢物的药代动力学参数。结论:开发并验证了一种灵敏且特异的定量 LC-MS-MS 方法,用于测定人血浆中的替格瑞洛及其活性代谢物。该方法已成功应用于一项临床试验,其中对健康男性志愿者口服单剂量替格瑞洛 180 mg。所述方法允许仅使用 100 μL 血浆对低至 2 ng/mL 替格瑞洛和 1 ng/mL 代谢物的浓度进行量化。
更新日期:2020-07-08
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