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刊物信息
期刊名称:药物分析杂志
主管单位:中国科学技术协会
主办单位:中国药学会
承办:中国食品药品检定研究院
主编:金少鸿
编辑部主任:粟晓黎
地址:北京天坛西里2号
邮政编码:100050
电话:010-67012819,67058427
电子邮箱:ywfx@nicpbp.org.cn
国际标准刊号:ISSN 0254-1793
国内统一刊号:CN 11-2224/R
邮发代号:2-237

 

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在线固相萃取LC-MS/MS法测定健康人体全血中依维莫司浓度及在药代动力学研究中的应用

Determination of everolimus in whole blood by online SPE LC-MS/MS system and its application in pharmacokinetic study

分类号:
出版年·卷·期(页码):2016,36 (10):0-0
DOI: 10.16155/j.0254-1793.2017.01.01
-----摘要:-------------------------------------------------------------------------------------------

目的:为临床研究依维莫司人体药动学建立一种特异、灵敏、快速、重现性好的在线固相萃取(onlineSPE)-液相色谱-串联质谱(LC-MS/MS)方法,并将其应用于依维莫司在中国健康人群药动学研究。方法:200 μL含依维莫司全血样本与20 μL内标混合后经0.4 mol·L-1硫酸锌80%甲醇水溶液处理,取上清液经在线固相萃取,以含0.1%甲酸5 mmol·L-1甲酸铵水溶液-含0.1%甲酸甲醇溶液(10:90)为流动相,Waters SunFireTM C18色谱柱(4.6 mm×150 mm,3.5 μm)为分析柱,进样量50 μL,室温下测定;采用正离子模式,MRM扫描,依维莫司m/z 975.8→908.6,内标m/z 809.6→756.7,分析时间为5 min。12例健康受试者口服1.5 mg依维莫司片,于不同时间点分别采集静脉血进行药代动力学分析。结果:依维莫司质量浓度在0.201~100.7 ng·mL-1的范围内线性良好(r=0.999 8±0.000 2),最低定量限为0.201 ng·mL-1,回收率在99.2%~105.4%之间,以RSD表示的日内与日间精密度均小于8%,过程效率良好,所有稳定性考察项目结果均符合要求。药动学结果显示,健康受试者口服依维莫司片1.5 mg后,依维莫司在人体内平均达峰时间tmax为0.69 h,平均药峰浓度Cmax为10.56 ng·mL-1,0~96 h时间段药时曲线下面积AUC为AUC0-96 h 65.70 ng·mL-1·h,平均半衰期t1/2 36.50 h。结论:本法经方法学验证,可用于依维莫司的药动学研究和血药浓度监测。

-----英文摘要:---------------------------------------------------------------------------------------

Objective: To offer a specific,sensitive,efficient and robust method for the quantitative determination of everolimus in the whole blood using the online solid phase extraction (SPE)-high performance liquid chromatography coupled with tandem mass spectrometry(LC-MS/MS)system, and to investigate the pharmacokinetics profile in Chinese healthy volunteers. Methods: After mixed with internal standard(IS), 200 μL of the whole blood samples were precipitated by 0.4 mol·L-1 zinc sulphate solution(containing 80% methanol), and the supernatant was analyzed by the online SPE LC-MS/MS system. The analyte was separated on a Waters SunFireTM C18(4.6 mm×150 mm, 3.5 μm)column with mobile phase consisted of 0.1% formic acid, 5 mmol·L-1 ammonium formatemethanol and 0.1% formic acid(10:90). 50 μL of analyte was injected into the column. Positive electrospray ionization and multiple reaction monitoring(MRM)mode was employed. The transition of m/z 975.8→908.6 for everolimus and m/z 809.6→756.7 for the IS were monitored. Each run was 5 min. Venous blood samples for pharmacokinetic measurements were taken at different time points from 12 healthy volunteers after receiving 1.5 mg single dose of everolimus. Results: The linear range of the calibration curve(0.201-100.7 ng·mL-1) was obtained with a good correlation coefficient(r=0.999 8±0.000 2). The lower limit of quantification was 0.201 ng·mL-1, the average recovery was 99.2%-105.4% and the intra- and inter-day precision represented by RSD were <8%. Results for process efficiency test and all stability tests met the acceptance criteria. After oral medication,the mean peak time(tmax) of everolimus in healthy volunteers was 0.69 h, and the mean maximum concentration(Cmax) was 10.56 ng·mL-1. The area under the curve(AUC0-96 h) was 65.70 ng·mL-1·h. This drug's mean half-life was 36.50 h, Conclusion: The method is proved by methodology validation that it can be applied to analyze clinical samples and determine the pharmacokinetics of everolimus.

-----参考文献:---------------------------------------------------------------------------------------
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