摘要
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。
To study the drug-drug interaction of morinidazole and warfarin and its application, a sensitive and rapid liquid chromatography-tandem mass spectrometric （LC-MS/MS） method was developed for the determination of R-warfarin/S-warfarin in human plasma. In a random, two-period crossover study, 12 healthy volunteers received a single oral dose of 5 mg racemic warfarin in the absence and presence of morinidazole. Blood samples were collected according to a pre-designed time schedule. R-warfarin, S-warfarin and methyclothiazide were extracted with ethylether ： methylenechloride （3 ： 2）, then separated on a Astec ChirobioticTM V （150 mm × 4.6 mm ID, 5 gin） column using 5 mmol.L-1 ammonium acetate （pH 4.0） - acetonitrile as mobile phase at a flow-rate of 1.5 mL.min-1. The mobile phase was splitted and 0.5 mLmin- 1 was introduced into MS. A tandem mass spectrometer equipped with electrospray ionization source was used as detector and operated in the negative ion mode. Quantification was performed using multiple reaction monitoring （MRM）. The resolution of warfarin enantiomers is 1.56. The linear calibration curves for R-warfarin and S-warfarin both were obtained in the concentration range of 5 - 1 000 ng.mL-1. Intra- and inter-day relative standard deviation （RSD） for R-warfarin and S-warfarin over the entire concentration range across three validation runs was both less than 10%, and relative error （RE） ranged from -4.9% to 0.7%, separately. The method herein described is effective and convenient, and suitable for the study of metabolic interaction between morinidazole and warfarin. The results showed that coadministration of warfarin with morinidazole did not affect the pharmacokinetics of either R-warfarin or S-warfarin.
出处
《药学学报》
CAS
CSCD
北大核心
2012年第1期105-109,共5页
Acta Pharmaceutica Sinica
基金
国家科技重大专项资助项目(2009ZX09301-001)
