利伐沙班在老年非瓣膜性房颤患者中的药动学研究

Pharmacokinetics Study of Rivaroxaban in Elderly Patients with Non-valvular Atrial Fibrillation

目的建立LC-MS/MS测定人血浆中利伐沙班的浓度并进行药动学研究。方法人血浆样品用乙腈沉淀蛋白后,选用ZORBAX Eclipse XDB C18色谱柱（2.1 mm×100 mm,3.5？m）,以乙腈-10 mmol醋酸铵溶液（含0.1%甲酸）为流动相梯度洗脱,流速为0.30 m L·min^-1,采用电喷雾离子化源,正离子方式,多反应监测扫描方式进行监测,用于定量分析的离子反应分别为m/z 436.2→m/z 145.2（利伐沙班）和m/z 256.1→m/z 165.2（内标苯海拉明）。结果血浆中利伐沙班的线性范围为5.0~1 000 ng·m L^-1（r=0.995 8）,定量下限为5.0 ng·m L^-1;方法回收率为94.1%~106.7%;日内、日间RSD均〈15%;提取回收率为84.4%~91.3%,无明显基质效应。结论该方法快速、灵敏、准确、专属性强、重复性好,适用于人血浆中利伐沙班的血药浓度检测和药动学研究。

OBJECTIVE To develop a LC-MS/MS method for the determination of rivaroxaban in human plasma and apply it to the pharmacokinetics study. METHODS The plasma samples were precipitated by acetonitrile. The ZORBAX Eclipse XDB C18 column（2.1 mm×100 mm, 3.5 μm） was adopted. The mobile phase was acetonitrile-10 mmol ammonium acetate（containing 0.1% formic acid） with the gradient elution at the flow rate of 0.30 m L·min^-1. Detection of the analyte was achieved by using positive ion electrospray ionization（ESI） in the multiple reaction monitoring（MRM） mode. The MS/MS ion transitions monitored were m/z 436.2→m/z 145.2 and m/z 256.1→m/z 165.2 for rivaroxaban and internal standard, respectively. RESULTS The linear range of rivaroxaban was 5.0^-1 000 ng·m L^-1（r=0.995 8）. The lower limit of quantitation was 5.0 ng·m L^-1. The recovery rate was 94.1%^-106.7%, and the intra-day and inter-day relative standard deviations were 15%. The absolute recovery was 84.4%？91.3%, and no significant matrix effect was found. CONCLUSION This method is rapid, sensitive, accurate, specific, reliable, and suitable for the determination of rivaroxaban in human plasma and pharmacokinetic study.