Loi C M, Alvey C W, Randinitis E J, Abel R, Young M A, Koup J R
Department of Pharmacokinetics/Drug Metabolism, Parke-Davis Pharmaceutical Research Division, Ann Arbor, Michigan 48105, USA.
J Clin Pharmacol. 1997 Nov;37(11):1038-47. doi: 10.1002/j.1552-4604.1997.tb04285.x.
The object of this study is to evaluate the effects of age, gender, age-by-gender interaction, Type II diabetes, body weight, race, smoking, and formulation on steady-state pharmacokinetics of troglitazone, Metabolite 1 (sulfate conjugate), and Metabolite 3 (quinone metabolite) following multiple-dose oral administration of troglitazone. Pharmacokinetic parameter estimates [Cl/F (apparent oral clearance), AUC0-24 (area under plasma concentration-time curve), and ratio of AUC for troglitazone to Metabolite 1 and to Metabolite 3] obtained from 84 healthy volunteers and 171 patients with Type II diabetes in 8 studies were analyzed using a graphical method (for race and smoking) or a weighted ANCOVA model incorporating gender, health status (healthy vs Type II diabetes), and formulation as main effects; age, age-by-gender interaction, and body weight as continuous covariates. Ratio of AUC for troglitazone to metabolites was also examined by inspection of log-probit plots. Age, gender, age-by-gender, Type II diabetes, and formulation had negligible effects on troglitazone Cl/F, AUC0-24 (all analytes), and AUC ratio of troglitazone to metabolites. Race and smoking did not appear to influence steady-state pharmacokinetics of troglitazone and its metabolites. Although body weight was a significant covariate for AUC0-24 and Cl/F, the explanatory power of the overall model was weak (R2 < 0.2). Log-probit plots did not reveal a polymorphic distribution in AUC ratio of troglitazone to Metabolite 1 or Metabolite 3. Based on pharmacokinetics, dose adjustment for troglitazone in relation to the demographic factors examined is not required due to their poor predictive ability on steady-state pharmacokinetics of troglitazone and its metabolites.
本研究的目的是评估年龄、性别、年龄与性别的交互作用、2型糖尿病、体重、种族、吸烟和制剂对曲格列酮多剂量口服给药后曲格列酮、代谢物1（硫酸结合物）和代谢物3（醌代谢物）稳态药代动力学的影响。使用图形法（针对种族和吸烟）或纳入性别、健康状况（健康与2型糖尿病）和制剂作为主要效应；年龄、年龄与性别的交互作用和体重作为连续协变量的加权协方差分析模型，对8项研究中84名健康志愿者和171名2型糖尿病患者获得的药代动力学参数估计值[Cl/F（表观口服清除率）、AUC0-24（血浆浓度-时间曲线下面积）以及曲格列酮与代谢物1和代谢物3的AUC比值]进行分析。还通过检查对数概率图来检验曲格列酮与代谢物的AUC比值。年龄、性别、年龄与性别的交互作用、2型糖尿病和制剂对曲格列酮Cl/F、AUC0-24（所有分析物）以及曲格列酮与代谢物的AUC比值影响可忽略不计。种族和吸烟似乎不影响曲格列酮及其代谢物的稳态药代动力学。尽管体重是AUC0-24和Cl/F的显著协变量，但总体模型的解释力较弱（R2 < 0.2）。对数概率图未显示曲格列酮与代谢物1或代谢物3的AUC比值存在多态分布。基于药代动力学，由于所研究的人口统计学因素对曲格列酮及其代谢物稳态药代动力学的预测能力较差，因此无需针对这些因素对曲格列酮进行剂量调整。
