液相色谱-质谱联用法测定人血浆氯吡格雷及其代谢产物药物浓度及应用

发布时间：2019-07-25 07:01

【摘要】：目的:建立测定人血浆中氯吡格雷及其活性和非活性代谢产物浓度的超高效液相色谱-串联质谱检测方法,并将其应用于氯吡格雷在中国健康人群的药代动力学特征研究。方法:采用液液萃取法和蛋白沉淀法处理血浆样品,测定原药、活性代谢产物和非活性代谢产物浓度。液相色谱-质谱条件:采用Thermo C18(100 mm×2.1 mm,5μm)色谱柱,以乙腈(含0.1%甲酸)-水(含0.1%甲酸)(9∶1)为流动相,流速200μL·min-1;正离子模式多反应监测扫描分析,离子通道分别为氯吡格雷m/z 321.7→211.9,活性代谢产物m/z 503.6→353.8,非活性代谢产物m/z 307.7→197.8,内标氯雷他定m/z382.8→336.9和卡马西平m/z 237.1→194.1。11例健康受试者口服300 mg负荷剂量的氯吡格雷,于不同时间点分别采集静脉血进行药代动力学分析。结果:血浆中氯吡格雷及其活性和非活性代谢产物线性范围分别为0.1~20、1~200和25~10 000 ng·m L-1,定量下限分别为0.1、1和25 ng·m L-1,回收率分别在49.2%~53.7%、50.9%~54.3%和95.5%~103.5%之间,批内、批间精密度RSD均小于11%,内标氯雷他定的提取回收率为58.9%,卡马西平的提取回收率为105.9%。稳定性试验中,在各种贮存条件下氯吡格雷、活性代谢产物、非活性代谢产物均稳定性良好。药动学结果显示,健康受试者口服300 mg氯吡格雷后,氯吡格雷、活性代谢产物及非活性代谢产物在人体内平均Cmax分别为(3.84±1.26)、(90.75±44.75)和(15 423.31±5 960.89)ng·m L-1,平均tmax分别为(1.02±0.43)、(0.82±0.28)和(0.98±0.31)h,平均t1/2分别为(6.22±4.00)、(0.46±0.12)和(7.16±0.92)h,平均AUC0-∞分别为(12.88±4.72)、(102.47±38.13)和(52 797.00±17 854.92)ng·m L-1·h。结论:该方法操作简便快速,重复性好,特异性强,灵敏度高,可用于氯吡格雷的药动学研究。
[Abstract]:Objective: to establish an ultra-high performance liquid chromatography-tandem mass spectrometry (HPLC-MS) method for the determination of clopidogrel and its active metabolites in human plasma and to study the pharmacokinetics of clopidogrel in healthy Chinese population. Methods: plasma samples were treated by liquid-liquid extraction and protein precipitation method, and the concentrations of raw drugs, active metabolites and non-active metabolites were determined. The conditions of liquid chromatography-mass spectrometry were as follows: Thermo C18 (100 mm 脳 2.1 mm, 5 渭 m) column was used, the mobile phase was acetonitrile (containing 0.1% formic acid)-water (containing 0.1% formic acid) (9:1), and the flow rate was 200 渭 L 路min-1. Positive ion mode multi-reaction scanning analysis showed that the ion channels were clopidogrel m 鈮，

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