健康志愿者二甲双胍缓释片群体药动学模型的初步研究  

Preliminary study on population pharmacokinetic model of metformin sustainedrelease tablets in healthy subjects

作　　者：徐懿萍[1] 陈冰[1] 荣征星[2] 陈红专[2] 张军东 

机构地区：[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

出　　处：《药学实践杂志》2013年第5期338-342,346,共6页Journal of Pharmaceutical Practice

基　　金：上海市科学技术委员会(10DZ1920803);科技部重大新药创制专项(2012ZX09303006)

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1000mg，收集受试者服药后0～24h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Ka分别为（95．8±7．46）L／h、（553±45．9）L及（0．5964-0．070）／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。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. Con- centration 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 mcfformin pharmacokinetics were assessed. Results One-compartment model with first-order absorption was the best for the PPK of mefformin 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 pharmacokinetie study and body weight had statisti- cally significant effect on the clearance of metformin.

关 键 词：二甲双胍 群体药动学 液相色谱质谱联用 

分 类 号：R944.9[医药卫生—药剂学] R587.1[医药卫生—药学]