液相色谱-串联质谱法测定美托洛尔缓释片的人体药动学及生物等效性

目的建立测定人血浆中美托洛尔浓度的液相色谱-串联质谱(LC—MS/MS)法,研究健康受试者单剂量和多剂量口服美托洛尔受试制剂和参比制剂后的药动学和生物等效性。方法40名男性健康志愿者进行随机双交叉试验,分别单剂量和多剂量口服美托洛尔受试制剂和参比制剂100 mg,采用LC—MS/ MS法测定血药浓度,用DAS软件计算主要药动学参数。结果单剂量时受试制剂和参比制剂的主要药动学参数如下:c_(max)分别为(144±s 43)和(164±40)μg·L~(-1),t_(max)分别为(3.7±1.2)和(3.5±0.8)h,t_(1/2)分别为(6.0±2.5)和(4.9±2.0)h,AUC_(0～24)分别为(1 639±787)和(1 658±636)μg·h·L~(-1),相对生物利用度为(97±21)%。多剂量达稳态时受试制剂和参比制剂的主要药动学参数如下:c_(max)分别为(241±170)和(232±75)μg·L~(-1),c_(min)分别为(115±66)和(121±64)μg·L~(-1),t_(max)分别为(3.7±1.0)和(3.5±1.6)h,AUC_(ss)分别为(1 905±882)和(1 992±834)μg·h·L~(-1),c_(av)分别为(159±73)和(166±69)μg·L~(-1),DF分别为(77±30)%和(75±31)%。受试制剂与参比制剂的AUC_(0～t),AUC_(0～∞)或AUC_(ss),c_(max)和t_(max)均符合生物等效性要求。结论建立的LC—MS/MS法专属、准确、灵敏度适宜。测定的美托洛尔受试制剂和参比制剂生物等效。

Pharmaeokinetics and bioequivalence of metoprolol sustained release tablets in Chinese healthy volunteers by LC-MS/MS

AIM To establish a LC-MS/MS method for the study of the pharmacokinetics and bioequivalence of metoprolol sustained release tablets in healthy male Chinese volunteers.METHODS A single or multiple oral dose of 100 mg metoprolol sustained released tablets or reference was given to each volunteer according to an open randomized crossover study in 20 health males.The concentrations of metoprolol and reference preparations in plasma were determined by LC-MS/MS method and the pharmacokinetics parameters together with relative bioavailability were calculated with DAS program to evaluate each of the two preparations. RESULTS The main parameters of the tested and reference metoprolol after a single dose were as follows:c_(max) (144±s43) and (164±40)μg·L~(-1),t_(max)(3.7±1.2) and (3.5±0.8)h,t_(1/2)(6.0±2.5) and (4.9±2.0) h, AUC_(0-24)(1 639±787) and (1 658±636)μg·h·L~(-1),respectively.The relative bioavailability was (97±21) %.The main parameters of the tested and reference metoprolol after multiple doses were as follows:c_(max) (241±170) and (232±75)μg·L~(-1),c_(min)(115±66) and (121±64)μg·L~(-1),t_(max)(3.7±1.0) and (3.5±1.6) h,AUC_(ss)(1 905±882) and (1 992±834)μg·h·L~(-1),c_(av)(159±73) and (166±69)μg·L~(-1),DF (77±30)% and (75±31)%,respectively.The AUC_(0-t),AUC_(0-∞)or AUC_(ss),c_(max) and t_(max) of the two preparations were bioequivalent.CONCLUSION The LC-MS/MS method is specific and sensitive.The tested and reference metoprolol sustained released tablet are bioequivalent.