液相色谱-串联质谱法快速测定人血浆中氯马斯汀及其药动学

Rapid determination and pharmacokinetics study of clemastine in human plasma by LC-MS/MS

目的建立人血浆中氯马斯汀的液相色谱-串联质谱(LC-MS/MS)快速测定方法,并研究氯马斯汀注射液在健康中国人体内的单、多剂量药动学特征。方法血浆样品用氢氧化钠碱化并加甲醇沉淀蛋白后,以正己烷提取,采用LC-MS/MS法测定。以0.2%甲酸(含5 mmol·L^(-1)醋酸铵)-甲醇(30:70,V/V)为流动相。采用ESI源在MRM模式下用于定量分析的反应离子对分别为m/z344.2→215.1(氯马斯汀)和m/z275.1→230.1(内标氯苯那敏)。12名健康志愿者单次及多次肌内注射氯马斯汀2mg,评价其药动学特征。结果氯马斯汀在0.02～24μg·L^(-1)内线性良好。氯马斯汀单次给药及多次给药d3后主要药动学参数:ρ_(max)分别为(2.4±1.4),(5.5±0.7)μg·L^(-1);AUC_(0-96)分别为(65±16),(257±33)μg·h·L^(-1);t_(1/2)分别为(40±7),(47±19)h。结论本试验建立的测定方法快速灵敏。氯马斯汀注射液的人体药动学特征无性别差异,多次给药后在人体内存在蓄积现象。

AIM To establish a LC-MS/MS method for the rapid determination of clemastine in human plasma and to study the pharmacokinetics of clemastine injection in healthy Chinese volunteers after single and multiple dose administration. METHODS The protein in the plasma samples was precipitated with sodium hydroxide prior to methanol, then clemastine and the internal standard （IS） were extracted with n-hexane. The mobile phase was methanol-5 mmol·L^-1 ammonium acetate buffer solution containing 0.2% formic acid （70 ： 30,V/V） . The ion transitions recorded in multiple reaction monitoring mode were m/z 344.2→215.1 and m/z 275.1→230.1 for clemastine and the IS, respectively. Twelve health Chinese volunteers were treated with single and multiple dose clemastine injection by intramuscular injection. The clemastine concentrations in plasma were determined by the LC-MS/MS method and the pharmaeokinetic parameters were calculated. RESULTS The calibration curve of clemastine in human plasma was linear over the concentration rang6 of 0.02-24 μg· L^-1. The main pharmacokinetics parameters of clemastine after single and multiple dose administration were as follows： ρmax （2.4 ± 1.4）, （5.5 ± 0.7） μg·L^-1; AUC0_96 （65 ±16）, （257 ± 33） μg·h·L^-1; tin （40 ± 7）, （47 ± 19） h, respectively. CONCLUSION The method is convenient and sensitive. The pharmaeokinetics characteristics of clemastine are no gender difference. Clemastine is eliminated slowly from the body with accumulation after multiple close administration in vivo.