目的 建立具有高灵敏度和高选择性测定人血浆中沙格雷酯药物浓度的液相色谱-串联质谱检测方法,并将其应用于盐酸沙格雷酯片的人体生物等效性研究。方法 血浆样品经乙腈沉淀,采用C₁₈色谱柱,在多反应监测正离子模式下,以电喷雾离子源作为电离技术扫描分析,离子通道分别为:沙格雷酯m/z 430.200→135.100,沙格雷酯-d3 m/z 433.200→138.200。采用单中心、开放、随机、单次口服、两序列、四周期、全重复试验设计,中国健康受试者分别空腹和餐后口服单剂量100 mg盐酸沙格雷酯片受试制剂及参比制剂后于不同的时间点采集血样,利用所建立的方法进行检测分析,计算2种制剂的药动学参数并进行统计分析。结果 血浆中沙格雷酯线性范围为1～1 000 ng·mL^-1,定量下限为1 ng·mL^-1,回收率在94.2%～96.2%内,批间批内精密度RSD均小于10%,内标沙格雷酯-d3的平均提取回收率为95.6%。在稳定性试验中的各种储存条件下沙格雷酯及内标沙格雷酯-d3的稳定性均良好。药动学结果显示,空腹和餐后状态下沙格雷酯受试制剂和参比制剂均具有生物等效性。高脂饮食可使沙格雷酯在体内的t_max延长和ρ_max降低。结论 所建立的方法操作简单快捷,重复性好,特异性强,灵敏度高,可用于沙格雷酯的药动学研究与血药浓度监测;空腹和餐后状态下两制剂生物等效,高脂饮食可影响沙格雷酯在体内的药动学特征。

OBJECTIVE To establish a UPLC-MS/MS method for the determination of sarpogrelate in human plasma, and to apply it to a bioequivalence study enrolling 56 Chinese volunteers administered of 100 mg sarpogrelate tablets. METHODS Plasma samples were precipitated by acetonitrile, using C₁₈ chromatographic column, in multi-reaction monitoring (MRM) positive ion mode, using electrospray ion source as ionization technology for scanning analysis.The mass transition pairs of m/z 430.200→135.100 and m/z 433.200→138.200 were used to detect sarpogrelate and d3-sarpogrelate (internal standard), respectively.A single-center, open, randomized, single dose, two-sequence, four-cycle, fully repeated trial was conducted to evaluate the pharmacokinetics and bioequivalence of sarpogrelate in healthy Chinese subjects under fasting and fed conditions. Venous blood samples for pharmacokinetic measurements were taken at different time points from 55 healthy volunteers after receiving 100 mg dose of test and reference sarpogrelate. Pharmacokinetic parameters were calculated using non-compartmental methods with WinNonlin 7.0. RESULTS The calibration curves were linear over a concentration range of 1-1 000 ng·mL^-1 for sarpogrelate and the lower limits of quantitation were 1 ng·mL^-1.The recovery rate is within the range of 94.2% to 96.2% for sarpogrelate and the relative standard deviations for intra-and inter-batch precision were all less than 10%.The average extraction recovery rates for internal standard, d3-sarpogrelate was 95.6%.In stability tests, sarpogrelate was found to be stable in plasma under various storage conditions.The test and reference are considered bioequivalent in human under fast and fed conditions. High-fat diet prolonged the time to t_max and decreased the ρ_max. CONCLUSION The method is simple and quick, with high repeatability, specificity and sensitivity, which can be used to analyze clinical samples and determine the pharmacokinetics of clopidogrel, its inactive and active metabolites. The two preparations are bioequivalent under fasting and fed conditions, and high-fat diet can affect the pharmacokinetic characteristics of sarpogrelate.