盐酸曲美他嗪片在健康人体内的药代动力学研究及生物等效性评价

目的:建立人血浆中盐酸曲美他嗪浓度的LC-MS/MS法,并用于盐酸曲美他嗪片的药代动力学和生物等效性研究。方法:采用自身双交叉试验设计,20名男性受试者随机分成2组,分别单剂量口服20 mg受试制剂或参比制剂,0~24 h间隔采集血样。以LC-MS/MS内标法(盐酸丁咯地尔)测定盐酸曲美他嗪血药浓度,采用Inertsil ODS-2色谱柱(250 mm×4.6 mm,5 μm),流动相为甲醇-含0.1%甲酸、0.2%醋酸铵的水溶液(55:45, v/v);多反应监测 ⁺离子通道分别为 m/z 267→181(曲美他嗪)和 m/z 308→237(丁咯地尔)。DAS 2.1计算药代动力学参数。结果:建立的LC-MS/MS法在0.5~200 μg·L^-1范围内线性关系良好,最低检测限为0.05 μg·L^-1,批内及批间精密度RSD均小于15%。受试制剂与参比制剂的 T_max分别为(1.8±0.7)h和(1.8±0.8)h, C_max分别为(60.1±10.7)μg·L^-1和(59.6±10.5)μg·L^-1, t_1/2分别为(6.1±1.1)h和(6.1±1.0)h,AUC_{0-24 h}分别为(518±126)h·μg·L^-1和(518±120)h·μg·L^-1。结论:建立的LC-MS/MS法准确可靠,可用于盐酸曲美他嗪片的药代动力学和生物等效性评价。

Objective:To establish an LC-MS/MS method for the determination of trimetazidine dihydrochloride in human plasma,and adopt the method to study the pharmocokinetics and bioequivalence of trimetazidine dihydrochloride tablets. Methods:In a randomized two-way crossover study,20 healthy male volunteers were divided into two groups,and were administered respectively with a single oral dose of test or reference preparations containing 20 mg trimetazidine dihydrochloride.The blood samples were collected at predetermined time intervals up to 24 hours.The plasma concentration of trimetazidine dihydrochloride was determined by LC-MS/MS.The chromatographic separation was performed on an Inertsil ODS-2(250 mm×4.6 mm,5 (] 45, v/v).The analytes were detected by multiple reaction monitoring of the ⁺ ions with transitions of m/z 267→ 181 and m/z 308→237 for trimetazidine and buflomedil,respectively.The pharmacokinetic parameters were estimated by DAS 2.1 software. Results:The established LC-MS/MS method showed linear calibration in the range over 0.5-200 μg·L^-1 with a LOD of 0.05 μg·L^-1 for quantification of trimetazidine dihydrochloride in human plasma.The intra-and inter-batch standard deviation was less than 15%.The pharmacokinetic parameters for the test and reference tablets were as follows: T_max(1.8±0.7)and(1.8±0.8)h, C_max(60.1±10.7)and(59.6±10.5)μg·L^-1, t_1/2(6.1±1.1)and(6.1±1.0)h,AUC_{0-24 h}(518±126)and(518±120)h·μg·L^-1,respectively. Conclusions:The LC-MS/MS method is sensitive and suitable for the pharmacokinetic and bioequivalence evaluation of trimetazidine dihydrochloride tablets.