复方盐酸二甲双胍片在健康志愿者体内的药物动力学和生物等效性

Pharmacokinetics and Bioequivalence of Compound Mefformin Hydrochloride Tablets in Healthy Volunteers

目的:研究复方盐酸二甲双胍片在健康志愿者体内的药物动力学和生物等效性。方法:18名男性健康志愿者随机交叉单次口服复方盐酸二甲双胍片(含盐酸二甲双胍1000 mg,格列本脲5 mg,受试制剂)或联合服用盐酸二甲双胍片1 000 mg和格列本脲片5 mg(参比制剂)后,采用HPLC法分别测定盐酸二甲双胍和格列本脲的经时血药浓度,用3P97软件计算其药物动力学参数和相对生物利用度,评价两种制剂的生物等效性。结果:单次口服受试制剂和参比制剂后,盐酸二甲双胍主要药物动力学参数C_(max)分别为(1.60±0.55)μg·ml^(-1)和(1.46±0.46)μg·ml^(-1),t_(max)分别为(2.1±0.7)h和(2.5±0.8)h,t_(1/2)分别为(4.9±1.7)h和(4.3±1.6)h,AUC_(0→24)分别为(10.47±2.89)μg·ml^(-1)·h和(9.22±2.56)μg·ml^(-1)·h,AUC_(0→∞)分别为(10.95±3.13)μ·ml^(-1)·h和(9.53±2.73)μg·ml^(-1)·h,受试制剂的相对生物利用度F_(0→24)为114.8%±17.6%。格列本脲主要药物动力学参数C_(max)分别为(117.70±28.38)μg·L^(-1)和(106.92±33.76)μg·L^(-1),t_(max)分别为(4.1±2.7)h和(3.8±1.8) h,t_(1/2)分别为(7.6±4.1)h和(8.8±3.9)h,AUC_(0→30)分别为(899.97±296.76)μg·L^(-1)·h和(902.64±353.82)μg·L^(-1)·h,AUC_(0→∞)分别为(943.00±290.09)μg·L^(-1)·h和(989.82±399.90)μg·L^(-1)·h,受试制剂的相对生物利用度F_(0→30)为104.91%±28.31%。结论:两制剂两组分的AUC、C_(max)对数值,经F分析、双单侧t检验和(1-2α)%置信区间法统计分析。表明两种制剂具有生物等效性。

Objective： To study the pharmacokinetics and bioequivalence of two different formulations of mefformin hydrochloride combined with glibenclamide in healthy volunteers. The formulations were a combination mefformin hydrochloride/glibenclamide tablet versus mefformin hydrochloride and glibenclamide coadministered separately. Method： A single oral dose of mefformin hydrochloride / glibenclamide 1 000/5 nag tablets or mefformin hydrochloride 1 000 nag with glibenclamide 5 nag were given to 18 healthy male volunteers in an open randomized crossover design. The concentrations of mefformin hydrochloride and glibenclamide in plasma were determined by HPLC method. The pharmacokinetic parameters and relative bioavailability were calculated by 3P97 program. Result： The main pharmacokinetic parameters of metformin hydrochlofide of two formulations were as follows： Cmax were （ 1.60 ± 0.55 ） μg·ml^-1 and （ 1.46 ±0.46） μg·ml^-1, tmax were（2.1 ±0.7）h and（2.5 ±0.8）h,t1/2 were（4.9 ± 1.7）h and（4.3 ± 1.6）h, AUC0→24 were（ 10.47 ± 2.89） μg·ml^-1·h and（9.22 ±2.56） μg·ml^-1·h,AUC0→∞ were （ 10.95 ± 3.13 ） μg·ml^-1·h and（9.53 ± 2.73 ）μg·ml^-1·h,respectively. The relative bioavailability of mefformin hydrochloride was 114.8% ± 17.6%. The main pharmacokinetic parameters of glibenclamide of two formulations were as follows ： Cmax were （ 117.70 ± 28.38 ） μg·L^-1 and （ 106.92 ± 33.76） μg·L^-1 , tmax were （4.1 ± 2.7）h and（3.8 ±1.8）h,t1/2 were（7.6 ±4.1）h and（8.8 ±3.9）h, AUC0→30 were（899.97 ±296.76） μg·L^-1·h and（902.64 ± 353.82 ） μg·L^-1·h ,AUC0→∞ were （ 943.00 ± 290.09 ） μg·L^-1· h and （ 989.82 ± 399.90 ） μg·L^-1·h, respectively. The relative bioavailability of glibenclamide was 104.91% ± 28.31%. Conclusion： The result demonstrated that the two formulations were bioequivalent by analysis of variance, two-one sided test and 90 % confidential interval.