LC-MS/MS同时测定曲美布汀和活性代谢物在Beagle犬体内的血药浓度及其药代动力学研究  

LC-MS/MS simultaneous determination and pharmacokinetics of trimebutine and it's metabolite in Beagle plasma

作　　者：杨振东[1] 张琪[1,2] 马博[1] 胡莹莹[1] 郑雅雅[1] 王永禄[1] 

机构地区：[1]南京工业大学药学院,南京210009 [2]南京工业大学江苏省药物研究所,南京210009

出　　处：《药物分析杂志》2012年第8期1351-1356,共6页Chinese Journal of Pharmaceutical Analysis

摘　　要：目的:建立灵敏稳定的HPLC-MS/MS方法,用于测定Beagle犬血浆中的曲美布汀(TM)及N-去甲基曲美布汀(N-TM)含量,并研究曲美布汀片剂在健康Beagle犬体内的药代动力学。方法:样品处理采用液液萃取方法,选择西布曲明(IS)为内标。进行HPLC-MS/MS分析,采用ESI源,MRM离子检测模式,TM、N-TM和IS的检测离子对分别为m/z 388.2→343.2,m/z 374.2→195.2,m/z 280.3→125.1。单剂量给药300 mg后,测定犬血浆中TM及N-TM的浓度,并计算药代动力学参数。结果:血浆中TM及N-TM检测的线性范围分别为1～500 ng.mL-1(r=0.9959),0.2～100 ng.mL-1(r=0.9951),萃取回收率均高于85%,日内、日间RSD均小于10%。犬血浆中TM及N-TM Cmax分别为(192±32.1)ng.mL-1和(47.1±22.6)ng.mL-1,Tmax均为(0.667±0.258)h和(1.08±0.492)h,T1/2分别为为(10.8±4.27)h和(7.06±2.53)h。结论:该方法可简便、高效地测定犬血浆中TM及N-TM浓度,并应用于药代动力学研究。Objective：To develop an LC-MS/MS method for the simultaneous determination of trimebutine（TM） and N-monodemethyltrimebutine（N-TM） concentration in dog plasma to study the pharmacokinetics of TM maleate in healthy Beagles.Method：The analytes were extracted from plasma samples by liquid-liquid extraction and sibutramine was selected to be the internal standard.Detection was carried out on a triple quadrupole tandem mass spectrometer in multiple reactions monitoring（MRM） mode using positive electrospray ionization（ESI）.The ion combination of m/z 388.2→m/z 343.2,m/z 374.2→m/z 195.2,m/z 280.3→m/z 125.1 was used to qualify TM,N-TM and the internal standard,respectively.After a single oral dose of 300 mg TM,the concentrations of TM and N-TM were detected and the pharmacokinetic parameters were calculated by DAS 2.0.Result：The calibration curve was in good linearity over the range of 1-500 ng·mL-1（r=0.9959） for TM and 0.2-100 ng·mL-1（r=0.9951） for N-TM.The intra-day and inter-day precisions（RSD） were lower than 10% and the extraction recovery was higher than 85% for both determined compounds.The main pharmacokinetic parameters of Cmax,Tmax and T1/2 were（192±32.1）ng·mL-1,（0.667±0.258）h,（10.8±4.27）h for trimebutine（47.1±22.6）ng·mL-1,（1.08±0.492）h,7.06±2.53 h for N-TM,respectively.Conclusion：The method is shown to be simple,accurate,sensitive and specific for the simultaneous determination of TM and N-TM in Beagles plasma and can be used for the pharmacokinetic study.

关 键 词：曲美布汀(TM) N-去甲基曲美布汀(N-TM) LC-MS/MS 药代动力学 比格犬血浆样品检测 

分 类 号：R917[医药卫生—药物分析学]