LC-MS/MS法同时测定人血浆中吉非替尼及其代谢产物O-去甲基吉非替尼浓度  

Simultaneous determination of gefitinib and its metabolite O-desmethyl gefitinib concentrations in human plasma by LC-MS/MS

作　　者：张元元[1,2] 刘维 周从亚[1,2] 杨平 熊歆 ZHANG Yuan-yuan;LIU Wei;ZHOU Cong-ya;YANG Ping;XIONG Xin(Department of Pharmacy,Peking University Third Hospital,Beijing 100191,China;Therapeutic Drug Monitoring and Clinical Toxicology Center of Peking University,Beijing 100191,China)

机构地区：[1]北京大学第三医院药剂科,北京100191 [2]北京大学治疗药物监测和临床毒理中心,北京100191

出　　处：《中国临床药理学杂志》2021年第22期3157-3160,3172,共5页The Chinese Journal of Clinical Pharmacology

基　　金：国家自然科学基金面上基金资助项目(81672107);国家自然科学基金青年基金资助项目(21405007);国家科技重大专项基金资助项目(2017ZX09304012-007)。

摘　　要：目的建立液相色谱质谱联用法(LC-MS/MS)同时测定人血浆中吉非替尼及其代谢产物O-去甲基吉非替尼浓度的方法,并应用于临床非小细胞肺癌患者的治疗药物监测。方法以硫酸羟氯喹-d4为内标,叔丁基甲醚为提取溶剂,通过高效液相-三重四级杆质谱检测,色谱柱Waters Atlantis Hilic Silica(2.1 mm×150 mm,5.0μm),流动相乙腈-5 mmol·L^(-1)甲酸铵水溶液(含0.1%甲酸,5%乙腈),等度洗脱,流速:0.35 mL·min^(-1),柱温40℃,进样量:2μL,电喷雾电离源(Electrospray ionization source,ESI),采用多反应监测(MRM)及正离子采集模式,定量分析离子对分别为m/z 447.3→m/z 128.1(吉非替尼),m/z 340.2→m/z 247.1(硫酸羟氯喹-d4),m/z 433.2→m/z 128.1(O-去甲基吉非替尼)。结果吉非替尼线性范围在0.5~500 ng·mL^(-1),O-去甲基吉非替尼线性范围在0.25~250 ng·mL^(-1)。吉非替尼批内和批间精密度RSD均小于12.6%,准确度为95.1%~113.1%;O-去甲基吉非替尼批内和批间精密度RSD均小于14.1%,准确度为88.2%~113.4%。临床收集肿瘤科非小细胞肺癌患者使用吉非替尼的血浆样本12例,吉非替尼的血药浓度130~912 ng·mL^(-1),其代谢产物O-去甲基吉非替尼的血药浓度20.7~652 ng·mL^(-1),个体差异较大。结论该方法灵敏度高,样本处理简单,检测时间快速,适于吉非替尼及其代谢产物的血药浓度监测。Objective To develop a method for the simultaneous determination of gefitinib and its metabolite O-desmethyl gefitinib,and the application for therapeutic drug monitoring in non-small cell lung cancer patient plasma.Methods Using hydroxy chloroquine-d4 as internal standard(IS),after extracted by methyl tert-butyl ether,the concentrations of gefitinib and O-desmethyl gefitinib in human plasma were detected by high performance liquid liquid-triple quadrupole mass spectrometry.The analytical column was Waters Atlantis Hilic Silica(2.1 mm×150 mm,5.0μm)and the mobile phase was acetonitrile-5 mmol·L^(-1) ammonium formate(containing 0.1%formic acid and 5.0%acetonitrile)under isocratic elution at the flow rate of 0.35 mL·min^(-1).The column temperature was set at 40℃,and the injection volume was 2μL.The multiple reaction monitoring was used to quantitatively analyze the ionization pairs as m/z 447.3→m/z 128.1(gefitinib),m/z 340.2→m/z 247.1(hydroxychloroquine-d4),m/z 433.2→m/z 128.1(O-desmethyl gefitinib).Results The linear range of gefitinib was 0.5-500 ng·mL^(-1),meanwhile the linear range of O-desmethyl gefitinib was 0.25-250 ng·mL^(-1).For gefitinib,RSDs of intra-and inter-day were lower than 12.6%,the accuracy was 95.1%-113.1%;For O-desmethyl gefitinib,RSDs of intra-and inter-day were lower than 14.1%,the accuracy was 88.2%-113.4%.Plasma samples from twelve non-small cell lung cancer patients received gefitinib therapy were collected.Plasma concentration of gefitinib ranged from 130 to 912 ng·mL^(-1).Meanwhile,the concentration of O-desmethyl gefitinib was 20.7 to 652 ng·mL^(-1),significant variances were found among patients.Conclusion This developed method is sensitive,simple sample processing and rapid detection.It is suitable for the determination of gefitinib and its metabolites in blood drug concentration monitoring.

关 键 词：液相色谱质谱联用法 吉非替尼 非小细胞肺癌 

分 类 号：R979.1[医药卫生—药品]