二维液相色谱法同时测定人血浆中伊马替尼及其代谢产物浓度的方法学研究  

Simultaneous Determination of Imatinib Mesylate and Its Metabolites in Human Plasma by Two-Dimensional Liquid Chromatography:A Methodological Study

作　　者：董馨蔚 蒋刚 马松涛[1] 陈燕 Dong Xinwei;Jiang Gang;Ma Songtao;Chen Yan(Department of Pharmacy,Chengdu Medical College,Chengdu 610500,Sichuan,China;Department of Pharmacy,Sichuan Cancer Hospital&Institute,Sichuan Cancer Center,School of Medicine,University of Electronic Science and Technology of China,Chengdu 610041,Sichuan,China)

机构地区：[1]成都医学院药学院,成都610500 [2]四川省肿瘤医院·研究所四川省癌症防治中心,电子科技大学医学院临床药学部,成都610041

出　　处：《肿瘤预防与治疗》2021年第10期918-925,共8页Journal of Cancer Control And Treatment

基　　金：四川省卫生健康委员会科研课题(编号:20PJ110);四川省医学会青年创新科研课题(编号:Q20058);四川省中医药管理局(编号:2020JC014);希思科-齐鲁肿瘤研究基金项目(编号:Y-QL202101-0125)

摘　　要：目的:建立一种同时、快速检测人血浆中甲磺酸伊马替尼(imatinib mesylate,IM)及其代谢产物浓度的二维液相色谱法,并应用于临床。方法:血浆样品经过蛋白沉淀、离心后直接进样,通过使用二维液相色谱仪进行检测。一维萃取柱:型号为Aston SX1(3.5 mm×25 mm,5μm),流动相为V(甲醇)∶V(乙腈)∶V(磷酸铵水溶液)=25∶20∶55,流速=0.8 mL/min;中间柱:型号为Aston SCB(4.6 mm×10 mm,3.5μm);二维分析柱:型号为Aston SCB(4.6 mm×125 mm,5μm),流动相为V(乙腈)∶V(磷酸铵盐溶液)=38∶62,pH=6.9,流速=1.2 mL/min;柱温:40℃,检测波长:264 nm,进样量:500μL。结果:色谱图显示IM及其代谢产物与杂质分离良好;IM与N-去甲基伊马替尼(N-Desmethyl imatinib,NDI)血药浓度线性范围分别是13.44~1400.00 ng/mL(R^(2)=0.9999)与13.17~1372.00 ng/mL(R^(2)=0.9999),线性关系均良好,定量下限变异系数分别为5.79%和2.77%,灵敏度良好;二者均可在12.80 min内完全出峰,方法回收率均高于90%,日内、日间精密度均小于6%,稳定性试验相对标准偏差均小于5%。所建立方法对10位口服IM的胃肠间质瘤患者进行了IM及NDI血药浓度检测,结果IM血药浓度结果为300.34~1392.07 ng/mL不等;NDI血药浓度在122.44~446.34 ng/mL之间。结论:该方法简便、快捷、灵敏度高、重现性好,结果准确且成本低廉,且适用于临床IM血药浓度检测。Objective:To establish a system of two-dimensional liquid chromatography with ultraviolet detection for simultaneously and rapidly detecting the concentration of imatinib mesylate(IM)and its metabolites in human plasma,and apply it in clinical practice.Methods:Plasma samples were injected directly onto the system after protein precipitation and centrifugation,and were detected by two-dimensional liquid chromatography.The first-dimension column was in version Aston SX1(3.5 mm×25 mm,5μm),with the mobile phase of a solution of methanol,acetonitrile and ammonium phosphate aqueous solution[V(methanol)∶V(acetonitrile)∶V(ammonium phosphate aqueous solution)=25∶20∶55],and the flow rate of(0.8 mL/min);the middle column was in version Aston SCB(4.6 mm×10 mm,3.5μm);the second-dimension column was in version Aston SCB(4.6 mm×125 mm,5μm),with the mobile phase of a solution of acetonitrile and ammonium phosphate salt solution[V(acetonitrile)∶V(ammonium phosphate salt solution)=38∶62,PH=6.9],and the flow rate of 1.2 mL/min;the column temperature was 40℃;the detection wavelength was 264 nm;and the injection volume was 500μL.Results:The chromatogram showed that IM and its metabolites were well separated from impurities.The linear ranges of plasma IM and N-Desmethyl imatinib(NDI)concentrations were 13.44~1,400.00 ng/mL(R^(2)=0.9999)and 13.17~1,372.00 ng/mL(R^(2)=0.9999),respectively,indicating a good linear relationship;the variation coefficients of the lower limit of quantification were 5.79%and 2.77%,respectively,suggesting a good sensitivity;both IM and NDI could completely peak within 12.80 min,with the recovery rates of over 90%,with intra-day and inter-day precision of less than 6%,with stability of less than 6%(relative standard deviation).The established method was performed on 10 gastrointestinal stromal tumor patients who received IM orally.The concentration of plasma IM ranged from 300.34 to 1,392.07 ng/mL,and that of plasma NDI was between 122.44 and 446.34 ng/mL.Conclusion:The method is simple,fas

关 键 词：二维液相 伊马替尼 N-去甲伊马替尼 血药浓度 临床应用 

分 类 号：R969[医药卫生—药理学]