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

关键词:  利伐沙班  液质联用法  血药浓度  药动学

Key words:  rivaroxaban  LC-MS/MS  blood concentration  pharmacokinetics

摘要:

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 mm)，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 mL·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·mL^-1(r=0.995 8)，定量下限为5.0 ng·mL^-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。

Abstract:

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 mL·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·mL^-1(r=0.995 8). The lower limit of quantitation was 5.0 ng·mL^-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.