酚麻氯汀胶囊中氯马斯汀的LC-MS-MS测定方法及在健康人体中的相对生物利用度研究  

Determination by HPLC-MS-MS method and bioequivalence of clemastine in health volunteers

作　　者：宋冬梅[1] 张煊[1] 刘婷立[1] 郭智[2] 易志恒[3] 潘琳 

机构地区：[1]沈阳亿灵医药科技有限公司,沈阳110179 [2]内蒙古医学院附属医院,呼和浩特010050 [3]湖南迪诺制药有限公司,长沙410329

出　　处：《中国新药杂志》2011年第12期1103-1107,共5页Chinese Journal of New Drugs

摘　　要：目的：建立人血浆中氯马斯汀的LC-MS-MS测定法,评价酚麻氯汀胶囊中氯马斯汀在健康人体的相对生物利用度。方法：采用开放、随机、双周期、两制剂、双序列单次给药的交叉试验设计。19例健康志愿者分别口服相当于富马酸氯马斯汀0.67 mg剂量的受试制剂和参比制剂。以硝苯地平为内标,采用甲基叔丁基醚为提取溶剂,用LC-MS-MS法测定血浆中氯马斯汀的质量浓度,经WinNonlin 6.0软件处理血药质量浓度数据后得药动学数据。结果：氯马斯汀的线性范围为5.09~407.20 ng·L-1,定量下限为5.09ng·L-1,绝对回收率为79.7%~80.6%,绝对基质效应为101.0%~103.6%,批内和批间精密度与准确度均符合要求。受试制剂中氯马斯汀的t1/2为（20.67±3.56）h,Cmax为（142.07±65.69）ng·L-1,Tmax为（4.21±1.23）h,AUC0-t为（2 829±1 681）ng·h·L-1;参比制剂中氯马斯汀的的t1/2为（20.83±4.94）h,Cmax为（1 46.55±60.16）ng·L-1,Tmax为（4.13±1.27）h,AUC0-t为（2 839±1 560）ng·h·L-1。以AUC0-t计算,与参比制剂比较,受试制剂中氯马斯汀的平均相对生物利用度为（101.7±23.4）%。结论：本方法灵敏、准确,适于临床药动学研究;两种制剂中的氯马斯汀具有生物等效性。Objective： To develop an HPLC-MS-MS assay for determination of clemastine in human plasma,and estimate the bioequivalence of clemastine in paracetamol,clemastine fumarate and pseudoephedrine hydrochloride capsule in healthy volunteers.Methods： An open,randomized,two-periods,two-treatment,two-sequence,and crossover clinical trial was performed in 19 healthy male volunteers.They were orally administrated with a single dose of clemastine fumarate 0.67 mg.The plasma concentration of clemastine was determined by LC-MS-MS using nifedipine as an internal standard and methyl tert-butyl ether as an extraction solvent.The plasma concentration-time curves as well as pharmacokinetics of both test and reference formulations were analyzed using WinNonlin 6.0 software.Results： Calibration curve of clemastine was linear in the range of 5.09~407.20 ng·L-1 and LLOQ was 5.09 ng·L-1.Absolute recovery and matrix effect were in the range of 79.7%~80.6% and 101.0%~103.6%,respectively.Accuracy and precision（intra-run and inter-run） were conformed to the requirement.The main pharmacokinetic parameters of clemastine in the test and reference formulations were as follows： t1/2 were（20.67±3.56） and（20.83±4.94） h,Cmax were（142.07±65.69） and（146.55±60.16） ng·L-1,Tmax were（4.21±1.23） and（4.13±1.27） h,and AUC0-t were（2 829±1 681） and（2839±1 560） ng·h·L-1.The relative bioavailability of clemastine in the test formulation was（101.7±23.4）% as estimated by AUC0-t.Conclusion： HPLC-MS-MS method is sensitive and accurate for determination of clemastine,and the two formulations of clemastine are bioequivalent.

关 键 词：酚麻氯汀胶囊 氯马斯汀 高效液相色谱-串联质谱 相对生物利用度 

分 类 号：R969.1[医药卫生—药理学]