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建立LC-MS/MS法同时测定人血浆中R-华法林和S-华法林,应用于吗啉硝唑与华法林代谢相互作用的研究。采用随机双周期交叉试验设计,给予12名健康受试者华法林或同时给予吗啉硝唑和华法林,按时间点采集血样。以甲氯噻嗪为内标,经乙醚-二氯甲烷(3∶2)提取后经手性色谱柱Astec ChirobioticTMV(150 mm×4.6 mm ID,5μm)分离。流动相为5 mmol.L-1醋酸铵水溶液(pH 4.0)-乙腈(72∶28),流速为1.5 mL.min-1(柱后分流,离子源-废液体积比为1∶2)。采用电喷雾电离源,多反应监测方式(MRM)进行负离子检测。R-华法林和S-华法林的分离度为1.56,线性范围均为5～1 000 ng.mL-1,日内和日间精密度(RSD)均小于10%,准确度(RE)在-4.9%～0.7%之间。该方法快速、灵敏,适用于药物对华法林代谢相互作用的研究。结果表明,吗啉硝唑对华法林无明显的代谢相互作用。
A LC-MS / MS method was established for the simultaneous determination of R-warfarin and S-warfarin in human plasma for the study of metabolic interactions between morpholinon and warfarin. Twelve randomized, double-cycle crossover trials were designed to give warfarin to 12 healthy subjects or to both morpholinan and warfarin, and blood samples were taken at time points. Methylchlorothiazide was used as an internal standard and was separated by chiral column Astec ChirobioticTM (150 mm × 4.6 mm ID, 5 μm) after extraction with ether-dichloromethane (3: 2). The mobile phase consisted of 5 mmol·L-1 ammonium acetate aqueous solution (pH 4.0) -acetonitrile (72:28) with a flow rate of 1.5 mL · min-1 (post-column split, ion source to waste volume ratio of 1: 2). Electrospray ionization source and multi-reaction monitoring (MRM) were used to detect negative ions. The separation of R-warfarin and S-warfarin was 1.56, with a linear range of 5-1000 ng.mL-1, with an RSD of less than 10%, accuracy (RE) Between -4.9% ~ 0.7%. The method is rapid and sensitive and is suitable for the study of metabolic interactions of warfarin. The results showed that morpholinonide had no significant metabolic interaction with warfarin.