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（英文）
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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(AUC0–t,AUC0–∞,Cmax)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(AUC0–t, AUC0–∞,Cmax)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。
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(AUC0–t, AUC0–∞, Cmax) 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(t1/2, AUC0–t and Cmax) 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.
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(AUC0–t, AUC0–∞, Cmax) 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(t1/2, AUC0–t and Cmax) 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.
引文
[1]Alberti,K.G.;Zimmet,P.Z.Definition,diagnosis and classification of diabetes mellitus and its complications.Part 1:diagnosis and classification of diabetes mellitus provisional report of a WHO consultation.Diabetic Med.1998,15,539-553.
[2]International Diabetes Federation.Global diabetes plan2011-2021.2012,7-7.This article can be found online at https://www.idf.org/our-activities/advocacy-awareness/resources-and-tools/129:global-diabetes-plan-2011-2021.html.
[3]Chinese Diabetes Society.China guideline for type 2diabetes.Chin.J.Diabetes Mellitus.2014,6,447-498.
[4]American Diabetes Association.Standards of medical care in diabetes--2017.Diabetes Care.2017,40,S48-S56.
[5]American Diabetes Association.Standards of medical care in diabetes--2014.Diabetes Care.2014,37,S14-S80.
[6]Group UK Prospective Diabetes Study.Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes(UKPDS 34).Lancet.1998,352,854-865.
[7]Holman,R.R.;Paul,S.K.;Bethel,M.A.;Matthews,D.R.;Neil,H.A.W.;Holman,R.R.;Bethel,M.A.;Matthews,D.R.10-year follow-up of intensive glucose control in type 2diabetes.N.Eng.J.Med.2008,359,1577-1589.
[8]Evans,J.M.M.;Donnelly,L.A.;Emsliesmith,A.M.;Alessi,D.R.;Morris,AD.Metformin and reduced risk of cancer in diabetic patients.BMJ.2005,330,1304-1305.
[9]Cushman,W.C.;Grimm,R.H.;Cutler,J.A.;Evans,G.W.;Capes,S.;Corson,M.A.;Sadler,L.S.;Alderman,M.H.;Peterson,K.;Bertoni,A.;Basile J.N.Rationale and design for the blood pressure intervention of the Action to Control Cardiovascular Risk in Diabetes(ACCORD)trial.J.Am.Coll.Cardiol.2007,99,S44-S55.
[10]Men,P.;Gu,X.C.;Zhai,S.D.A consistency evaluation based on Chinese literatures for generic metformin hydrochloride.Clin.Med.J.2016,4,30-34.
[11]Li,L.L.;Du,L.P.;Zhang,Y.X.;Mei,D.Inter-Changeability between Generic Medicines and Brand-name Medicines.J.Chin.Pharm.Sci.2015,50,178-181.
[12]Sambol,N.C.;Chiang,J.;O'Conner,M.;Liu,C.Y.;Lin,E.T.;Goodman,A.M.;Benet,L.Z.;Karam,J.H.Pharmacokinetics and pharmacodynamics of metformin in healthy subjects and patients with noninsulin-dependent diabetes mellitus.J.Clin.Pharmacol.1996,36,1012-1021.
[13]Duong,J.K.;Kumar,S.S.;Kirkpatrick,C.M.;Greenup,L.C.;Arora,M.;Lee,T.C.;Timmins,P.;Graham,G.G.;Furlong,T.J.;Greenfield,J.R.Population pharmacokinetics of metformin in healthy subjects and patients with type 2diabetes mellitus:simulation of doses according to renal function.Clin.Pharmacokinet.2013,52,373-384.
[14]Meredith,P.Bioequivalence and Other Unresolved Issues in Generic Drug Substitution.Clin.Ther.2003,25,2875-2890.
[15]Hwang,I.K.;Kim,I.Y.;Joo,E.J.;Shin,J.H.;Choi,J.W.;Won,M.H.;Yoon,Y.S.;Seong,J.K.Metformin normalizes type 2 diabetes-induced decrease in cell proliferation and neuroblast differentiation in the rat dentate gyrus.Neurochem.Res.2010,645-650.
[16]Metais,C.;Forcheron,F.;Abdallah,P.;Basset,A.;Carmine,P.D.;Bricca,G.;Beylot,M.Adiponectin receptors:expression in Zucker diabetic rats and effects of fenofibrate and metformin.Metabolism.2008,57,946-953.
[17]Atkinson,L.L.;McDonald-Dyck,C.;Benkoczi,C.;Finegood,D.T.Effect of chronic rosiglitazone,metformin and glyburide treatment on beta-cell mass,function and insulin sensitivity in mZDF rats.Diabetes Obes.Metab.2008,10,780-790.
[18]Reaganshaw,S.;Nihal,M.;Ahmad,N.Dose translation from animal to human studies revisited.Faseb.J.2008,22,659-661.
[19]Wallace,T.M.;Levy,J.C.;Matthews,D.R.Use and abuse of HOMA modeling.Diabetes Care.2004,27,1487-1495.
[20]Zhou,X.;Rougée,L.R.;Bedwell,D.W.;Cramer,J.W.;Mohutsky,M.A.;Calvert,N.A.;Moulton,R.D.;Cassidy,K.C.;Yumibe,N.P.;Adams,L.A.Difference in the Pharmacokinetics and Hepatic Metabolism of Antidiabetic Drugs in Zucker Diabetic Fatty and Sprague-Dawley Rats.Drug Metab.Dispos.2016,44,1184-1192.
[21]Xing,J.F.;Hai,S.;Dong,Y.L.;Chen,S.Y.;Hui,F.;Qian,D.Metabolic and pharmacokinetic studies of scutellarin in rat plasma,urine,and feces.Acta Pharmaco.Sin.2011,32,655-663.
[22]Wang,Y.;Yang,G.;Guo,C.X.;Pei,Q.;Zhang,R.R.;Huang,L.Plasma Double-peak Phenomenon Following Oral Administration.Chin.J.Clin.Pharmacol.Ther.2014,19,341-345
[23]Lal,J.;Jain,G.K.Effect of centchroman coadministration on the pharmacokinetics of metformin in rats.Indian J.Pharmaco.2010,42,146-149.
[24]Choi,Y.H.;Kim,S.G.;Lee,M.G.Dose-independent pharmacokinetics of metformin in rats:Hepatic and gastrointestinal first-pass effects.J.Pharm.Sci-us.2006,95,2543-2552.
[25]Freisleben,H.J.;Fürstenberger,H.J.;Deisinger,S.;Freisleben,K.B.;Wiernsperger,N.;Zimmer,G.Interaction of glucose and metformin with isolated red cell membrane.Arzneimittel forsch.1996,46,773-778.
[26]Kyung,K.M.;Sook,J.H.;Shin,Y.C.;Hae,K.J.;Jung,J.H.;Kyun,K.T.;Jeong,K.M.;Hee,L.S.;Soo,K.K.;Doo,R.B.The Effect of Glucose Fluctuation on Apoptosis and Function of INS-1 Pancreatic Beta Cells.Korean Diabetes J.2010,34,47-54.
[27]Brownlee,M.;Hirsch,I.B.Glycemic variability:a hemoglobin A1c-independent risk factor for diabetic complications.JAMA.2006,295,1707-1708.
[28]Cao,Y.;Dai,W.;Liao,F.;Jun,Y.E.;Zhang,R.;Liu,Y.;Wang,Y.The relationship between blood glucose fluctuation and early diabetic nephropathy in type 2diabetes.Chin.J.Clin.Healthc.2013,6,612-614.
[29]Zhang,X.G.;Zhang,Y.Q.;Zhao,D.K.;Wu,J.X.;Zhao,J.;Jiao,X.M.;Chen,B.;Lv,X.F.Relationship between blood glucose fluctuation and macrovascular endothelial dysfunction in type 2 diabetic patients with coronary heart disease.Eur.Rev.Med.Pharmaco.2014,18,3593-3600
[30]Lawes,C.V.;Bennett,D.A.;Suh,I.;Lam,T.H.;Whitlock,G.;Barzi,F.;Woodward,M.Blood glucose and risk of cardiovascular disease in the Asia Pacific region.Diabetes Care.2004,27,2836-2842.
[31]Wilner,A.N.Therapeutic equivalency of generic antiepileptic drugs:results of a survey.Epilepsy Behav.2004,5,995-998.
[32]Tacca,M.D.Lack of pharmacokinetic bioequivalence between generic and branded amoxicillin formulations.A post-marketing clinical study on healthy volunteers.Br.J.Clin.Pharmacol.2009,68,34-42.
[33]Tacca,M.D.;Pasqualetti,G.;Gori,G.;Pepe,P.;Paolo,A.D.;Lastella,M.;Negri,F.D.;Blandizzi,C.Comparative pharmacokinetic and pharmacodynamic evaluation of branded and generic formulations of meloxicam in healthy male volunteers.Ther.Clin.Risk Manag.2013,303-311.
[34]Meredith,P.A.Generic drugs.Therapeutic equivalence.Drug Safety.1996,15,233-242.
[2]International Diabetes Federation.Global diabetes plan2011-2021.2012,7-7.This article can be found online at https://www.idf.org/our-activities/advocacy-awareness/resources-and-tools/129:global-diabetes-plan-2011-2021.html.
[3]Chinese Diabetes Society.China guideline for type 2diabetes.Chin.J.Diabetes Mellitus.2014,6,447-498.
[4]American Diabetes Association.Standards of medical care in diabetes--2017.Diabetes Care.2017,40,S48-S56.
[5]American Diabetes Association.Standards of medical care in diabetes--2014.Diabetes Care.2014,37,S14-S80.
[6]Group UK Prospective Diabetes Study.Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes(UKPDS 34).Lancet.1998,352,854-865.
[7]Holman,R.R.;Paul,S.K.;Bethel,M.A.;Matthews,D.R.;Neil,H.A.W.;Holman,R.R.;Bethel,M.A.;Matthews,D.R.10-year follow-up of intensive glucose control in type 2diabetes.N.Eng.J.Med.2008,359,1577-1589.
[8]Evans,J.M.M.;Donnelly,L.A.;Emsliesmith,A.M.;Alessi,D.R.;Morris,AD.Metformin and reduced risk of cancer in diabetic patients.BMJ.2005,330,1304-1305.
[9]Cushman,W.C.;Grimm,R.H.;Cutler,J.A.;Evans,G.W.;Capes,S.;Corson,M.A.;Sadler,L.S.;Alderman,M.H.;Peterson,K.;Bertoni,A.;Basile J.N.Rationale and design for the blood pressure intervention of the Action to Control Cardiovascular Risk in Diabetes(ACCORD)trial.J.Am.Coll.Cardiol.2007,99,S44-S55.
[10]Men,P.;Gu,X.C.;Zhai,S.D.A consistency evaluation based on Chinese literatures for generic metformin hydrochloride.Clin.Med.J.2016,4,30-34.
[11]Li,L.L.;Du,L.P.;Zhang,Y.X.;Mei,D.Inter-Changeability between Generic Medicines and Brand-name Medicines.J.Chin.Pharm.Sci.2015,50,178-181.
[12]Sambol,N.C.;Chiang,J.;O'Conner,M.;Liu,C.Y.;Lin,E.T.;Goodman,A.M.;Benet,L.Z.;Karam,J.H.Pharmacokinetics and pharmacodynamics of metformin in healthy subjects and patients with noninsulin-dependent diabetes mellitus.J.Clin.Pharmacol.1996,36,1012-1021.
[13]Duong,J.K.;Kumar,S.S.;Kirkpatrick,C.M.;Greenup,L.C.;Arora,M.;Lee,T.C.;Timmins,P.;Graham,G.G.;Furlong,T.J.;Greenfield,J.R.Population pharmacokinetics of metformin in healthy subjects and patients with type 2diabetes mellitus:simulation of doses according to renal function.Clin.Pharmacokinet.2013,52,373-384.
[14]Meredith,P.Bioequivalence and Other Unresolved Issues in Generic Drug Substitution.Clin.Ther.2003,25,2875-2890.
[15]Hwang,I.K.;Kim,I.Y.;Joo,E.J.;Shin,J.H.;Choi,J.W.;Won,M.H.;Yoon,Y.S.;Seong,J.K.Metformin normalizes type 2 diabetes-induced decrease in cell proliferation and neuroblast differentiation in the rat dentate gyrus.Neurochem.Res.2010,645-650.
[16]Metais,C.;Forcheron,F.;Abdallah,P.;Basset,A.;Carmine,P.D.;Bricca,G.;Beylot,M.Adiponectin receptors:expression in Zucker diabetic rats and effects of fenofibrate and metformin.Metabolism.2008,57,946-953.
[17]Atkinson,L.L.;McDonald-Dyck,C.;Benkoczi,C.;Finegood,D.T.Effect of chronic rosiglitazone,metformin and glyburide treatment on beta-cell mass,function and insulin sensitivity in mZDF rats.Diabetes Obes.Metab.2008,10,780-790.
[18]Reaganshaw,S.;Nihal,M.;Ahmad,N.Dose translation from animal to human studies revisited.Faseb.J.2008,22,659-661.
[19]Wallace,T.M.;Levy,J.C.;Matthews,D.R.Use and abuse of HOMA modeling.Diabetes Care.2004,27,1487-1495.
[20]Zhou,X.;Rougée,L.R.;Bedwell,D.W.;Cramer,J.W.;Mohutsky,M.A.;Calvert,N.A.;Moulton,R.D.;Cassidy,K.C.;Yumibe,N.P.;Adams,L.A.Difference in the Pharmacokinetics and Hepatic Metabolism of Antidiabetic Drugs in Zucker Diabetic Fatty and Sprague-Dawley Rats.Drug Metab.Dispos.2016,44,1184-1192.
[21]Xing,J.F.;Hai,S.;Dong,Y.L.;Chen,S.Y.;Hui,F.;Qian,D.Metabolic and pharmacokinetic studies of scutellarin in rat plasma,urine,and feces.Acta Pharmaco.Sin.2011,32,655-663.
[22]Wang,Y.;Yang,G.;Guo,C.X.;Pei,Q.;Zhang,R.R.;Huang,L.Plasma Double-peak Phenomenon Following Oral Administration.Chin.J.Clin.Pharmacol.Ther.2014,19,341-345
[23]Lal,J.;Jain,G.K.Effect of centchroman coadministration on the pharmacokinetics of metformin in rats.Indian J.Pharmaco.2010,42,146-149.
[24]Choi,Y.H.;Kim,S.G.;Lee,M.G.Dose-independent pharmacokinetics of metformin in rats:Hepatic and gastrointestinal first-pass effects.J.Pharm.Sci-us.2006,95,2543-2552.
[25]Freisleben,H.J.;Fürstenberger,H.J.;Deisinger,S.;Freisleben,K.B.;Wiernsperger,N.;Zimmer,G.Interaction of glucose and metformin with isolated red cell membrane.Arzneimittel forsch.1996,46,773-778.
[26]Kyung,K.M.;Sook,J.H.;Shin,Y.C.;Hae,K.J.;Jung,J.H.;Kyun,K.T.;Jeong,K.M.;Hee,L.S.;Soo,K.K.;Doo,R.B.The Effect of Glucose Fluctuation on Apoptosis and Function of INS-1 Pancreatic Beta Cells.Korean Diabetes J.2010,34,47-54.
[27]Brownlee,M.;Hirsch,I.B.Glycemic variability:a hemoglobin A1c-independent risk factor for diabetic complications.JAMA.2006,295,1707-1708.
[28]Cao,Y.;Dai,W.;Liao,F.;Jun,Y.E.;Zhang,R.;Liu,Y.;Wang,Y.The relationship between blood glucose fluctuation and early diabetic nephropathy in type 2diabetes.Chin.J.Clin.Healthc.2013,6,612-614.
[29]Zhang,X.G.;Zhang,Y.Q.;Zhao,D.K.;Wu,J.X.;Zhao,J.;Jiao,X.M.;Chen,B.;Lv,X.F.Relationship between blood glucose fluctuation and macrovascular endothelial dysfunction in type 2 diabetic patients with coronary heart disease.Eur.Rev.Med.Pharmaco.2014,18,3593-3600
[30]Lawes,C.V.;Bennett,D.A.;Suh,I.;Lam,T.H.;Whitlock,G.;Barzi,F.;Woodward,M.Blood glucose and risk of cardiovascular disease in the Asia Pacific region.Diabetes Care.2004,27,2836-2842.
[31]Wilner,A.N.Therapeutic equivalency of generic antiepileptic drugs:results of a survey.Epilepsy Behav.2004,5,995-998.
[32]Tacca,M.D.Lack of pharmacokinetic bioequivalence between generic and branded amoxicillin formulations.A post-marketing clinical study on healthy volunteers.Br.J.Clin.Pharmacol.2009,68,34-42.
[33]Tacca,M.D.;Pasqualetti,G.;Gori,G.;Pepe,P.;Paolo,A.D.;Lastella,M.;Negri,F.D.;Blandizzi,C.Comparative pharmacokinetic and pharmacodynamic evaluation of branded and generic formulations of meloxicam in healthy male volunteers.Ther.Clin.Risk Manag.2013,303-311.
[34]Meredith,P.A.Generic drugs.Therapeutic equivalence.Drug Safety.1996,15,233-242.