HPLC-MS/MS法同时测定人血浆中曲美布汀及代谢产物N-去甲基曲美布汀浓度及其药动学研究  

Simultaneous determination of trimebutine and its metabolites N-monodesmethyl trimebutine in human plasma by HPLC-MS/MS and its pharmacokinetics

作　　者：任秀华[1] 雷永芳[1] 陈倩[1] 付伟[1] 张冬林[1] 袁春平[2] 刘东[1] 

机构地区：[1]华中科技大学同济医学院附属同济医院药学部,武汉430030 [2]广东环球制药有限公司,广东佛山528305

出　　处：《中南药学》2015年第12期1251-1255,共5页Central South Pharmacy

基　　金：科技部重大专项"泌尿生殖系统肿瘤的国际化新药临床评价研究技术平台建设(编号:2012ZX09303018);同济医院同济医院引领未来临床新技术;新业务基金项目"治疗药物与毒物监测及临床试验生物样本分析技术平台建设(编号:122901)

摘　　要：目的建立一种快速、灵敏并同时测定人血浆中曲美布汀及其代谢产物N-去甲基曲美布汀浓度的高效液相色谱-质谱联用(HPLC-MS/MS)检测方法。方法以莫沙必利为内标,血浆样品经甲醇沉淀后,经HPLC-MS/MS分离分析。采用Diamonsil C18柱(2.1 mm×150 mm,5μm),流动相为乙腈-5 mmol·L^(-1)乙酸铵(含0.02%甲酸)(60:40,v/v);流速0.3 m L·min^(-1),采用电喷雾离子源(ESI),以多离子反应监测方式(MRM)进行正离子监测,曲美布汀、N-去甲基曲美布汀和内标莫沙必利的定量分析离子对分别为m/z 388.2/343.1、374.4/195.1和422.3/198.2。结果曲美布汀在1.05~658.00 ng·m L-1(r=0.9992)与峰面积线性关系良好,定量限为1.05 ng·m L^(-1),低(2.63 ng·m L^(-1))、中(65.80 ng·m L^(-1))、高(562.40ng·m L^(-1))3个浓度的平均方法回收率RSD均<15%。N-去甲基曲美布汀在7.57~4730.00 ng·m L^(-1)(r=0.9975)内与峰面积线性关系良好,定量限为7.57 ng·m L^(-1),低(18.92 ng·m L^(-1))、中(473.00ng·m L^(-1))、高(3784.00 ng·m L^(-1))3个浓度的平均方法回收率RSD均<15%。结论本方法灵敏、准确、可靠,适用于曲美布汀及其代谢产物N-去甲基曲美布汀的人体药动学研究及其血药浓度监测。Objective To establish a rapid and sensitive high performance liquid chromatography tandem mass spectrometry（HPLC-MS/MS） method to simultaneously and quantitatively determine trimebutine（TM） and its major metabolites N-monodesmethyl trimebutine（NTM） in human plasma. Methods Plasma samples were precipitated with methanol and determined by HPLC-MS/MS with mosapride as the internal standard. The analytes were chromatographed on a Diamonsil C18 column（2.1 mm×150 mm, 5 μm） with the mobile phase of 60% acetonitrile and 30% 5 mmol·L-（-1） ammonium acetate（containing 0.02% formic acid）（v/v） at a flow rate of 0.3 m L·min-（-1）. Detection was carried out on a triple quadrupole tandem mass spectrometer in multiple reactions monitoring（MRM） mode using positive electrospray ionization（ESI） with using target ions at m/z 388.2/343.1（TM）, 374.4/195.1（NTM） and 422.3/198.2（mosapride）, respectively. Results The RSD for TM at low（2.63 ng·m L-（-1））, medium（65.80 ng·m L-（-1）） and high concentration（562.40 ng·m L-（-1）） was less than 15%. The calibration curve of TM was obtained at 1.05- 658.00 ng·m L-（-1）（r = 0.9992） with good linearity. The low limit of quantitation was 1.05 ng·m L-（-1）. Meanwhile, the RSD for NTM at low（18.92 ng·m L-（-1））, medium（473.00 ng·m L-（-1）） and high concentration（3784.00 ng·m L-（-1）） was also less than 15%. The calibration curve for NTM was obtained at 7.57- 4730.0 ng·m L-（-1）（r = 0.9975） with good linearity. The low limit of quantitation was 7.57 ng·m L-（-1）. Conclusion The method is sensitive and precise and is suitable for human pharmacokinetic studies of trimebutine and its metabolites.

关 键 词：高效液相色谱串联质谱法 曲美布汀 N-去甲基曲美布汀 血药浓度监测 

分 类 号：R917[医药卫生—药物分析学]