二甲双胍原研制剂格华止?与一种仿制制剂在大鼠模型中药代动力学和药效学比较

doi:10.5246/jcps.2019.02.013

中国药学(英文版) ›› 2019, Vol. 28 ›› Issue (2): 134-142.DOI: 10.5246/jcps.2019.02.013

二甲双胍原研制剂格华止?与一种仿制制剂在大鼠模型中药代动力学和药效学比较

严妍^1,2, 李玲¹, 李蕊¹, 于文君¹, 韩毅³, 马玉奎⁴, 李妍^3*

1. 山东大学药学院临床药学系, 山东济南 250012
2. 天津市环湖医院药剂科, 天津 300060
3. 山东省千佛山医院药学部, 山东济南 250014
4. 山东省药学科学院, 山东济南 250100

收稿日期:2018-11-17 修回日期:2019-01-16 出版日期:2019-02-28 发布日期:2019-01-28
通讯作者: Tel.: +86-13791126823, E-mail: li_xyan@126.com
基金资助:
The National Key Development Plan for Precision Medicine Research (Grant No. 2017YFC0910004) and Jinan Science Project (Grant No. 201602171).

Pharmacokinetic and pharmacodynamic comparison between Glucophage? and a generic metformin in a rat model

Yan Yan^1,2, Ling Li¹, Rui Li¹, Wenjun Yu¹, Yi Han³, Yukui Ma⁴, Yan Li^3*

1. Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong Province, China
2. Department of Pharmacy, Tianjin Huanhu Hospital, Tianjin 300060, China
3. Department of Pharmacy, Shandong Provincial Qianfoshan Hospital, Jinan 250014, Shandong Province, China
4. Shandong Academy of Pharmaceutical Sciences, Jinan 250100, Shandong Province, China

Received:2018-11-17 Revised:2019-01-16 Online:2019-02-28 Published:2019-01-28
Contact: Tel.: +86-13791126823, E-mail: li_xyan@126.com
Supported by:
The National Key Development Plan for Precision Medicine Research (Grant No. 2017YFC0910004) and Jinan Science Project (Grant No. 201602171).

摘要/Abstract

摘要：

此研究旨在比较二甲双胍原研制剂格华止^®与一种仿制制剂在大鼠模型中药代动力学和药效学差异, 从而评价仿制制剂的生物等效性。单次灌胃给予成年雄性Zucker大鼠180 mg/kg的格华止^®和二甲双胍仿制制剂(n = 6), 测定并比较两组间的药代动力学参数(AUC_0–t, AUC_0–∞, C_max)和血糖水平。在药效学试验中, 分别每天给予成年雄性Zucker大鼠180 mg/kg和300 mg/kg的格华止^®和二甲双胍仿制制剂六周(n = 6), 测定大鼠体重、空腹血糖、糖化血红蛋白和血清胰岛素水平并进行比较。数据分析使用SPSS 22.0和Prism 7软件。统计学显著性水平设定为P<0.05。在单剂量实验中, 二甲双胍原研制剂组和仿制制剂组的药代动力学参数(AUC_0–t, AUC_0–∞, C_max)无显著性差异(P>0.05)。然而仿制制剂组给药后2小时(P=0.03)和4小时(P=0.04)大鼠的血糖要显著高于原研制剂组。在多剂量试验中, 六周时高剂量原研制剂组的大鼠的空腹血糖, HOMA-IR, 体重等要显著低于高剂量仿制制剂组(P<0.05)。两组间的糖化血红蛋白和血清胰岛素水平没有显著性差异。在低剂量组中, 六周时原研制剂组的空腹血糖要显著低于仿制制剂组, HOMA-IR和体重水平无明显差异。同时, 组间血脂水平也无明显差异。在此研究中, 二甲双胍仿制制剂和原研制剂格华止^®在大鼠模型中的药代动力学参数没有显著差异。但是, 在多次给药后, 格华止^®在血糖和体重控制、改善胰岛素抵抗等方面优于仿制制剂。

关键词: 二甲双胍, 仿制药, 生物等效性, 临床等效性, 一致性评价

Abstract:

In the present study, we aimed to compare the pharmacokinetics and pharmacodynamics between Glucophage^®and a generic metformin formulation in a diabetic rat model in order to assess the bioequivalence of the generic formulation.Adult male Zucker diabetes fatty rats received Glucophage^® or the generic metformin through gastric gavage at a dose of 180 mg/kg (n = 6 per condition). Both pharmacokinetic parameters (AUC_0–t, AUC_0–∞, C_max) of metformin and plasma glucose levels were compared between the two groups. For pharmacodynamics, rats received Glucophage^® or the generic metformin at doses of 180 and 300 mg·kg^–1·d^–1 for 6 weeks. The measurements included body weight, fasting plasma glucose, glycosylated serum protein (GSP) and serum insulin. Data were analyzed with SPSS 22.0 and Prism 7. The level of statistical significance was set at P<0.05.In single dosing experiments, pharmacokinetic parameters (t_1/2, AUC_0–t and C_max) did not differ between Glucophage^® and the generic metformin (P>0.05). However, plasma glucose was significantly higher in the generic metformin group at 2 h (P = 0.03) and 4 h (P = 0.04) after drug treatment. In repeated dosing experiments, fasting glucose, HOMA-IR and body weight in rats receiving high-dose Glucophage^®were significantly lower at the end of the 6-week treatment period than those in rats receiving high-dose generic metformin (P<0.05 for all). GSP and serum insulin did not differ significantly between the two groups. In rats receiving low-dose metformin, fasting glucose was lower in the Glucophage^® group. HOMA-IR and body weight did not differ between the two groups. Moreover, blood lipids did not differ significantly between the two groups. The generic metformin used in the current study did not differ significantly in pharmacokinetic characteristics with Glucophage^®. However, Glucophage^® was superior in terms of glucose control, body weight loss and insulin sensitivity in repeated administration.

Key words: Metformin, Generic drug, Bioequivalence, Clinical equivalence, Consistency evaluation

中图分类号:

R969.1

Supporting:

严妍, 李玲, 李蕊, 于文君, 韩毅, 马玉奎, 李妍. 二甲双胍原研制剂格华止?与一种仿制制剂在大鼠模型中药代动力学和药效学比较[J]. 中国药学(英文版), 2019, 28(2): 134-142.

Yan Yan, Ling Li, Rui Li, Wenjun Yu, Yi Han, Yukui Ma, Yan Li. Pharmacokinetic and pharmacodynamic comparison between Glucophage? and a generic metformin in a rat model[J]. Journal of Chinese Pharmaceutical Sciences, 2019, 28(2): 134-142.

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二甲双胍原研制剂格华止?与一种仿制制剂在大鼠模型中药代动力学和药效学比较

Pharmacokinetic and pharmacodynamic comparison between Glucophage? and a generic metformin in a rat model

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