健康志愿者二甲双胍缓释片群体药动学模型的初步研究

徐懿萍; 陈冰; 荣征星; 陈红专; 张军东

doi:10.3969/j.issn.1006-0111.2013.05.005

健康志愿者二甲双胍缓释片群体药动学模型的初步研究

doi: 10.3969/j.issn.1006-0111.2013.05.005

1.
上海交通大学医学院附属瑞金医院, 上海 200025
2.
上海交通大学基础医学院药理学教研室, 上海 200025
3.
上海信谊药厂有限公司药物研究所, 上海 201206

基金项目: 上海市科学技术委员会(10DZ1920803)、科技部重大新药创制专项(2012ZX09303006).

Preliminary study on population pharmacokinetic model of metformin sustained-release tablets in healthy subjects

1.
School of Medicine, Ruijin Hospital affiliated to Shanghai Jiaotong University, Shanghai 200025, China
2.
School of Medicine, Shanghai Jiaotong University, Shanghai 200025 China
3.
Shanghai sine pharmaceutical R&D center, Shanghai 201206 China

摘要: 目的建立中国健康志愿者服用二甲双胍缓释片的群体药动学(PPK)模型,并研究不同生理因素对二甲双胍药动学参数的影响。方法 20名中国健康受试者(男性11名、女性9名),单剂量给予二甲双胍缓释片 1 000 mg,收集受试者服药后0~24 h血样标本,建立液相色谱-质谱/质谱(LC-MS/MS)方法测定人血浆二甲双胍浓度,采用非线性混合效应模型(NONMEM)建立二甲双胍的群体药动学(PPK)模型,并探讨生理因素对二甲双胍药动学的影响。结果二甲双胍药动学符合一房室模型,清除率(CL/F)、分布容积(Vd/F)和吸收速率常数K_a分别为(95.8±7.46) L/h、(553±45.9) L及(0.596±0.070)/h。引入体重作为CL/F及Vd/F的协变量,使模型显著改善(P<0.05)。结论 NONMEM法可以用于二甲双胍药动学研究,且体重对二甲双胍清除率存在显著影响。
- 二甲双胍 /
- 群体药动学 /
- 液相色谱质谱联用
Abstract: Objective To establish a population pharmacokinetic (PPK) model of metformin in healthy Chinese subjects, and evaluate the effect of different physiological factors on pharmacokinetic parameters of metformin. Methods A single dose, open label PK study was designed to assess the pharmacokinetics of metformin in healthy Chinese subjects (11 male and 9 female subjects). After 1 000 mg single dose of metformin sustained release tablets being taken, 0~24 h blood samples of each subject were collected. Concentration of plasma metformin was measured by the LC-MS/MS method. Non-compartment analysis was carried out through Winonlin 5.01 software. A PPK model in healthy Chinese subjects was established by using NONMEM. The effects of body weight and other physiological factors on metformin pharmacokinetics were assessed. Results One-compartment model with first-order absorption was the best for the PPK of metformin and the CL/F, Vd/F and Ka were (95.8±7.46) L/h, (553±45.9) L, and (0.596±0.070)/h, respectively. It was proved that, the simulation of model improved significantly (P<0.05) when body weight was used as the covariate of CL/F and Vd/F. Conclusion The PPK method could be used in the metformin pharmacokinetic study and body weight had statistically significant effect on the clearance of metformin.
- metformin /
- population pharmacokinetics (PPK) /
- LC-MS/MS

[1]	Krentz AJ,Bailey CJ.Oral antidiabetic agents:current role in type 2 diabetes mellitus[J].Drugs,2005,65(3):385.
[2]	Johansen K.Efficacy of metformin in the treatment of NIDDM,mea-analysis[J].Diabetes care,1999;22(1):33.
[3]	Wildasin EM,Skaar DJ,Kirchain WR,et al.Metformin, apromising oral antihyperglycemic for the treatment of noninsulin-dependent diabetes mellitus[J].J Pharmacother,1997,17(1):62.
[4]	Graham GG,Punt J,Arora M,et al.Clinical pharmacokinetics of metformin[J].Clin Pharmacokinet,2011,50(2):81.
[5]	Jabbour S,Ziring B.Advantages of extended-release metformin in patients with type 2 diabetes mellitus[J].Postgrad Med,2011,123(1):15.
[6]	Schwartz SL,Gordi T,Hou E,et al.Clinical development of metformin extendedrelease tablets for type 2 diabetes:an overview. Expert Opin Drug Metab Toxicol[J].2008,4(9):1235.
[7]	Cullen E, Liao J,Lukacsko P,et al.Pharmacokinetics and dose proportionality of extended-release metformin following administration of 1 000,1 500,2 000 and 2 500 mg in healthy volunteers[J].Biopharm Drug Dispos,2004,25(6):261.
[8]	Sheiner LB,Rosenberg B,Marathe VV.Estimation of population characteristics of pharmacokinetic parameters from routine clinical data[J].J Pharmacokinet Biopharm,1977,5(5):445.[JP+1]
[9]	Vozeh S,Steimer JL,Rowland M,et al.The use of population pharmacokinetics in drug development[J].Clin Pharmacokinet,1996,30(2):81.[JP+1]
[10]	Aarons L,Balant LP,Mentré F,et al.Population approaches in drug development.Report on an expert meeting to discuss population pharmacokinetic/pharmacodynamic software[J].Eur J Clin Pharmacol,1994;46(5):389.
[11]	Hong Y,Rohatagi S,Habtemariam B,et al.Population exposureresponse modeling of metformin in patients with type 2 diabetes mellitus[J].J Clin Pharmacol,2008,48(6):696.[JP3]
[12]	Charles B,Norris R,Xiao X,et al.Population pharmacokinetics of metformin in late pregnancy[J].Ther Drug Monit,2006,28(1):67.
[13]	厉伟兰,刘晓东,谢林,等.二甲双胍缓释片人体药代动力学及其相对生物利用度[J].江苏药学与临床研究,2006,14(2):72.
[14]	汤净,钟国平,刘伟东,等.国产盐酸二甲双胍缓释片的人体药动学及相对生物利用度[J].中国新药杂志,2005,14(2):197.
[15]	廉江平,张鹏,李小川,等.盐酸二甲双胍缓释片的药代动力学及相对生物利用度研究[J].西北药学杂志,2007,22(5):227.
[16]	陈勇川,何菊英,唐敏,等.盐酸二甲双胍缓释片人体相对生物利用度及其药代动力学研究[J].第三军医大学学报,2005,27(21):2148.
[17]	杨洁,张银娣,胡刚,等.盐酸二甲双胍缓释片人体药代动力学和相对生物利用度研究[J].南京医科大学学报:自然科学版,2007,27(9):920.
[18]	郑恒,陈雅丽,王莉,等.盐酸二甲双胍缓释片药物动力学及生物等效性研究[J].华中科技大学学报:医学版,2007,36(4):517.
[19]	温新国,张霖泽,黄民,等.盐酸二甲双胍缓释片与国外上市品的药动学比较及体内外相关性研究[J].广东药学院学报,2005,21(3):284.
[20]	Proctor WR,Bourdet DL,Thakker DR.Mechanisms underlying saturable intestinal absorption of metformin[J].Drug Metab Dispos,2008,36(8):1650.
[21]	Robert F,Fendri S,Hary L,et al.Kinetics of plasma and erythrocyte metformin after acute administration in healthy subjects[J].Diabetes Metab,2003,29(3):279.
[22]	Briggs GG,Ambrose PJ,Nageotte MP,et al.Excretion of metformin into breast milk and the effect on nursing infants[J].Obstet Gynecol,2005,105(6):1437.
[23]	Pillans PI,Landsberg PG,Fleming AM,et al.Evaluation of dosage adjustment in patients with renal impairment[J].Intern Med J,2003,33(1-2): 10.
[24]	Stepensky D,Friedman M,Raz I,et al.Pharmacokinetic-pharmacodynamic analysis of the glucose-lowering effect of metformin in diabetic rats reveals first-pass pharmacodynamic effect[J].Drug Metab Dispos,2002,30(8):861.
[25]	Lee SH,Kwon KI.Pharmacokinetic-pharmacodynamic modeling for the relationship between glucose-lowering effect and plasma concentration of metformin in volunteers[J].Arch Pharm Res,2004,27(7):806.
[26]	Sun L,Kwok E,Gopaluni B,et al.Pharmacokinetic-pharmacodynamic modeling of metformin for the treatment of type II diabetes mellitus[J].Open Biomed Eng J,2011,5,1.

[1]	续畅, 周心娜, 漆璐, 王瑜, 王兴河. 基于文献计量学对我国临床试验用药品管理研究现状的数据挖掘 . 药学实践与服务, 2025, 43(): 1-6. doi: 10.12206/j.issn.2097-2024.202404050
[2]	冯一帆, 严啸东, 张文彬, 李炳锋, 郭美丽. 菸花苷长期给药对脑缺血再灌注损伤大鼠神经功能的影响 . 药学实践与服务, 2025, 43(): 1-7. doi: 10.12206/j.issn.2097-2024.202407038
[3]	迟文雅, 袁艳, 李伟林, 吴茼妤, 俞媛. 负载骨髓间充质干细胞/白藜芦醇脂质体的水凝胶支架治疗创伤性脑损伤的研究 . 药学实践与服务, 2025, 43(2): 67-74. doi: 10.12206/j.issn.2097-2024.202406034
[4]	何静, 安晔, 张朝绅. 复方黑参滴丸与复方黑参丸药效学实验比较研究 . 药学实践与服务, 2025, 43(1): 17-21. doi: 10.12206/j.issn.2097-2024.202404009
[5]	魏雨辰, 田家盛, 王道鑫, 凌期盛, 王治, 缪朝玉. 烟酰胺单核苷酸口服给药对高血压大鼠的影响 . 药学实践与服务, 2025, 43(5): 1-9. doi: 10.12206/j.issn.2097-2024.202412006
[6]	江冼芮, 段雅倩, 刘畅, 张成中. 淫羊藿中黄酮苷类化合物的群体感应抑制作用研究 . 药学实践与服务, 2025, 43(4): 1-5. doi: 10.12206/j.issn.2097-2024.202409060
[7]	晁亮, 王辉, 沈淑琦, 游飘雪, 冀凯宏, 洪战英. 基于UHPLC-Q/TOF-MS代谢组学策略的葛根-知母药对防治阿尔茨海默病的药效与作用机制研究 . 药学实践与服务, 2025, 43(1): 30-40. doi: 10.12206/j.issn.2097-2024.202409035
[8]	曹奇, 张嘉宝, 王培. 基于无监督自动降维分析与手动圈门联用的骨骼肌髓系细胞多色流式分析方法 . 药学实践与服务, 2025, 43(3): 118-122. doi: 10.12206/j.issn.2097-2024.202404077
[9]	舒飞, 孙蕊, 宋凯, 张元林, 闫家铭, 舒丽芯. 粉-液双室袋产品的综合评价 . 药学实践与服务, 2025, 43(2): 92-96. doi: 10.12206/j.issn.2097-2024.202312009
[10]	崔亚玲, 吴琼, 马良煜, 胡北, 姚东, 许子华. 肝素钠肌醇烟酸酯乳膏中肌醇烟酸酯皮肤药动学研究 . 药学实践与服务, 2025, 43(1): 6-9, 21. doi: 10.12206/j.issn.2097-2024.202404006
[11]	吴海韵, 杨甜, 张弛, 梁文仪, 苏娟. 气相色谱-离子迁移谱技术在中药研究中的应用进展 . 药学实践与服务, 2025, 43(): 1-6. doi: 10.12206/j.issn.2097-2024.202409007
[12]	杨嘉宁, 赵一颖, 肖伟. 七味脂肝方对非酒精性脂肪性肝炎动物模型的药效学评价 . 药学实践与服务, 2024, 42(9): 389-398. doi: 10.12206/j.issn.2097-2024.202404096
[13]	宋雨桐, 夏德润, 顾珩, 唐少文, 易洪刚, 沃红梅. 帕博利珠单抗与铂类化疗方案在晚期非小细胞肺癌一线治疗中的药物经济学评价 . 药学实践与服务, 2024, 42(8): 334-340. doi: 10.12206/j.issn.2097-2024.202303023
[14]	戴菲菲, 傅翔, 陈琼年, 俞苏纯. 上海某二级医院革兰阴性菌流行特征的回顾性分析 . 药学实践与服务, 2024, 42(12): 528-532. doi: 10.12206/j.issn.2097-2024.202305005
[15]	夏哲炜, 曾垣烨, 朱海菲, 李育, 陈啸飞. 核磁共振磷谱法测定磷酸氢钙咀嚼片中药物含量 . 药学实践与服务, 2024, 42(9): 399-401, 406. doi: 10.12206/j.issn.2097-2024.202404063
[16]	景凯, 杨慈荣, 张圳, 臧艺蓓, 刘霞. 黄芪甲苷衍生物治疗慢性心力衰竭小鼠的药效评价及作用机制研究 . 药学实践与服务, 2024, 42(5): 190-197. doi: 10.12206/j.issn.2097-2024.202310004
[17]	陈炳辰, 佟达丰, 万苗, 闫飞虎, 姚建忠. UPLC-MS/MS法测定小鼠血浆中紫杉醇脂肪酸酯前药及其药代动力学研究 . 药学实践与服务, 2024, 42(8): 341-345. doi: 10.12206/j.issn.2097-2024.202404082
[18]	赖立勇, 夏天爽, 徐圣焱, 蒋益萍, 岳小强, 辛海量. 中药青蒿抗氧化活性的谱效关系研究 . 药学实践与服务, 2024, 42(5): 203-210, 216. doi: 10.12206/j.issn.2097-2024.202211012
[19]	张艺昕, 关欣怡, 王博宁, 闻俊, 洪战英. 二氢吡啶类钙离子拮抗药物手性分析及其立体选择性药动学研究进展 . 药学实践与服务, 2024, 42(8): 319-324. doi: 10.12206/j.issn.2097-2024.202308062
[20]	毛智毅, 王筱燕, 陈晓颖, 汤逸斐. 度拉糖肽联合二甲双胍对肥胖型2型糖尿病患者机体代谢、体脂成分及血清脂肪因子的影响 . 药学实践与服务, 2024, 42(7): 305-309. doi: 10.12206/j.issn.2097-2024.202305032

期刊类型引用(0)
其他类型引用(10)

点击查看大图

计量

文章访问数: 3332
HTML全文浏览量: 393
PDF下载量: 287
被引次数: 10

姓名
邮箱
手机号码
标题
留言内容
验证码

留言板

健康志愿者二甲双胍缓释片群体药动学模型的初步研究

doi: 10.3969/j.issn.1006-0111.2013.05.005

Preliminary study on population pharmacokinetic model of metformin sustained-release tablets in healthy subjects

期刊类型引用(0)

其他类型引用(10)

计量

健康志愿者二甲双胍缓释片群体药动学模型的初步研究

doi: 10.3969/j.issn.1006-0111.2013.05.005

1. 上海交通大学医学院附属瑞金医院, 上海 200025

2. 上海交通大学基础医学院药理学教研室, 上海 200025

3. 上海信谊药厂有限公司药物研究所, 上海 201206

English Abstract

Preliminary study on population pharmacokinetic model of metformin sustained-release tablets in healthy subjects

1. School of Medicine, Ruijin Hospital affiliated to Shanghai Jiaotong University, Shanghai 200025, China

2. School of Medicine, Shanghai Jiaotong University, Shanghai 200025 China

3. Shanghai sine pharmaceutical R&D center, Shanghai 201206 China

全文HTML

目录

全文HTML

留言板

健康志愿者二甲双胍缓释片群体药动学模型的初步研究

doi: 10.3969/j.issn.1006-0111.2013.05.005

Preliminary study on population pharmacokinetic model of metformin sustained-release tablets in healthy subjects

期刊类型引用(0)

其他类型引用(10)

计量

出版历程

健康志愿者二甲双胍缓释片群体药动学模型的初步研究

doi: 10.3969/j.issn.1006-0111.2013.05.005

1. 上海交通大学医学院附属瑞金医院, 上海 200025 2. 上海交通大学基础医学院药理学教研室, 上海 200025 3. 上海信谊药厂有限公司药物研究所, 上海 201206

English Abstract

Preliminary study on population pharmacokinetic model of metformin sustained-release tablets in healthy subjects

1. School of Medicine, Ruijin Hospital affiliated to Shanghai Jiaotong University, Shanghai 200025, China 2. School of Medicine, Shanghai Jiaotong University, Shanghai 200025 China 3. Shanghai sine pharmaceutical R&D center, Shanghai 201206 China

全文HTML

目录

全文HTML

1. 上海交通大学医学院附属瑞金医院, 上海 200025

2. 上海交通大学基础医学院药理学教研室, 上海 200025

3. 上海信谊药厂有限公司药物研究所, 上海 201206

1. School of Medicine, Ruijin Hospital affiliated to Shanghai Jiaotong University, Shanghai 200025, China

2. School of Medicine, Shanghai Jiaotong University, Shanghai 200025 China

3. Shanghai sine pharmaceutical R&D center, Shanghai 201206 China