盐酸二甲双胍格列吡嗪胶囊的健康人体药动学研究

Pharmacokinetics of metformin hydrochloride and glipizide in fixed-dose combination in healthy Chinese volunteers

目的:评价健康受试者口服复方制剂盐酸二甲双胍格列吡嗪胶囊(每粒含盐酸二甲双胍250 mg,格列吡嗪2.5 mg)的人体血浆药代动力学特征,为临床用药提供参考依据。方法:20名健康受试者随机分为2组,每组10人(男女各半)。Ⅰ组不同周期先后单剂量口服低剂量(1粒)和高剂量(3粒)试验制剂;Ⅱ组不同周期先后三交叉单剂量口服中剂量(2粒)试验制剂、格列吡嗪片(2.5 mg.片-1)参比制剂2片、盐酸二甲双胍胶囊(250 mg.粒-1)参比制剂2粒,并进行了中剂量试验制剂的多剂量试验。采集受试者的血浆样本,分别采用HPLC-UV法测定血浆中盐酸二甲双胍的浓度,HPLC-MS/MS法测定血浆中格列吡嗪的浓度。DAS 2.0软件计算主要药代动力学参数,并进行统计分析,确定复方用药时盐酸二甲双胍与格列吡嗪是否存在药代动力学相互作用。结果:受试者单剂量服用低、中、高剂量,及多剂量服用中剂量试验制剂达稳态后,血浆中盐酸二甲双胍的Cmax分别为(718±122),(1179±308),(1494±174),(979±268)ng.mL-1;Tmax分别为(1.7±0.63),(3.4±0.94),(2.4±0.70),(3.9±1.4)h;AUC0-t分别(4519±606),(8646±2757),(10040±1501),(8965±2200)ng.h.mL-1;t1/2分别为(3.46±0.34),(4.74±0.80),(4.90±1.42),(4.99±0.58)h;格列吡嗪的Cmax分别为(294±63.4),(432±98.7),(641±76.5),(273±51.5)ng.mL-1;Tmax分别为(1.8±0.54),(1.9±0.78),(1.9±0.47),(4.0±2.0)h;AUC0-t分别为(1642±340),(2788±994),(3508±758),(2841±1003)ng.h.mL-1;t1/2分别为(4.04±0.53),(4.70±0.75),(3.88±0.77),(6.46±5.83)h。单剂量口服盐酸二甲双胍胶囊(500 mg)的Cmax、Tmax、AUC0-t、t1/2分别为:(1179±308)ng.mL-1,(3.35±0.94)h,(8646±2757)ng.h.mL-1,(4.74±0.80)h;单剂量口服格列吡嗪片(5 mg)的Cmax、Tmax、AUC0-t、t1/2分别为:(485±88.9)ng.mL-1,(1.28±0.38)h,(2860±462)ng.h.mL-1,(4.38±0.89)h。单剂量与多剂量口服中剂量试验制剂时,测得盐酸二甲双胍和格列吡嗪的主要药代动力学参数分别均无显著性差异。与单剂量口服相应剂量的格列吡嗪片或盐酸二甲双胍胶囊后的主要药代动力学参数比较,也分别无显著性差异。单剂量服用低、中、高剂量试验制剂后,盐酸二甲双胍和格列吡嗪的Cmax与AUC0-t均随剂量正比例增大。结论:盐酸二甲双胍和格列吡嗪复方给药具有线性药动学特征,均没有积蓄效应,盐酸二甲双胍和格列吡嗪复方给药没有明显的药物相互作用。

Objective：To investigate the clinical plasma pharmacokinetics of mefformin hydrochloride （MET） and glipizide（GLP） in healthy Chinese volunteers post oral administration of fixed -dose combination capsules, each contains 250 mg metformin hydrochloride and 2. 5 mg glipizide. Methods ：20 healthy Chinese volunteers were randomly divided into two groups. Group Ⅰ was administrated with two incremental oral fixed -dose combination capsules（250 mg MET/2. 5 mg GLP, 750 mg MET/7.5 mg GLP）, respectively. Glipizide tablets（5 mg）, mefformin hydrochloride capsules （500 mg）, and fixed -doses combination capsules （500 mg MET/5 mg GLP）, were given to Group Ⅱ with three- period, crossover study design, and multiple oral fix -doses combination capsules were also given to thisgroup. HPLC - UV was used for the determination of metformin and LC - MS/MS for glipizide. The main pharmacokinetic parameters and the statistic analysis results were evaluated by DAS 2. 0 software. Results： After single oral dose of three incremental fixed -dose combination capsules （250 nag MET/2. 5 mg GLP, 500 mg MET/5 mg GLP, 750 mg MET/7. 5 mg GLP） and multiply oral doses of the fixed - dose combination capsules （ 500 mg MET/5 mg GLP）, the main pharmacokinetic parameters of metformin hydrochloride were as follows： Cmax were （718 ± 122）, （1179 ±308）, （1494 ±174） and （979 ±268） ng · mL^-1; Tmax were （1.7 ±0.63）, （3.4 ±0.94）, （2.4 ±0.70） and （3.9±1.4） h; AUC0-t, were （4519±606）, （8646 ±2757）, （10040 ±1501） and （8965 ±2200） ng · mL^-1 ; tl/2 were （3.46 ±0. 34）, （4. 74 ±0. 80）, （4. 90 ± 1.42） and （4. 99 ±0. 58） h, respectively. The main pharmacokinetic parameters of glipizide were as follows： Cmax were （294 ±63.4）, （432 ±98.7）, （641 ±76. 5） and （273 ± 51.5 ）ng · mL^-1 ; Tmax were （ 1.8 ± 0. 54）, （ 1.9 ± 0. 78 ）, （ 1.9 ± 0. 47） and （4. 0 ± 2. 0） h ; AUC0-t, were （ 1642 ±340）, （2788 ±994）, （3508 ±758） and （2841 ± 1003） ng · mL^-1 ; t1/2 were （4. 04 ±0. 53）, （4. 70 ±0. 75）, （ 3.88 ± 0. 77） and （6. 46± 5.83 ） h, respectively. After a single oral does of 500 mg mefformin hydrochloride capsules, C Tmax, AUC0-t, and t1/2were （1179 ±308） ng · mL^-1, （3.35±0.94） h, （8646 ±2757）ng · mL^-1, （4. 74 ±0. 80） h, respectively; and after a single oral does of 5 mg glipizide tablets, they were （485 ± 88. 9）ng · mL^-1, （ 1.28 ± 0. 38） h, （2860 ± 462） ng · mL^-1and （4. 38 ± 0. 89） h, respectively. The statistic analysis resuits showed that there was no remarkable difference between the main pharmaeokinetic parameters of metformin hydrochloride or glipizide in compound and single preparations, respectively, neither remarkable differences between single - and multi -dose administration. The results showed that the AUC and C of metformin hydrochloride and glipizide correlated linearly with doses, respectively. Conclusion：There is no obvious interaction between metformin hydrochloride and glipizide in the fixed -doses combination capsules in vivo, and no significant accumulation effects are observed after multiple oral doses administration of the fix - dose combination capsules. Linear pharmacokinetics are found both in the case of metformin hydrochloride and glipizide.