Prediction of Drug Disposition in Diabetic Patients by Means of a Physiologically Based Pharmacokinetic Model
Prediction of Drug Disposition in Diabetic Patients by Means of a Physiologically Based Pharmacokinetic Model
复制标题
通过基于生理学的药代动力学模型预测糖尿病患者的药物分布
DOI：
10.1007/s40262-014-0192-8
复制
发表时间：
2015-02-01
影响因子：
4.5
通讯作者：
Liu, Xiao-dong
中科院分区：
文献类型：
--
作者：
Li, Jia;Guo, Hai-fang;Liu, Xiao-dong
背景与目的越来越多的证据表明，糖尿病可影响某些药物的药代动力学，导致药效学和/或毒副作用的改变。本研究旨在建立一种新的基于生理学的药物动力学(PBPK)模型，用于定量预测2型糖尿病患者的药物药代动力学。方法考虑糖尿病引起的胃排空、肠道转运时间、肝肾功能药物代谢等生理参数的改变。用建立的模型预测了7种药物(安替比林、尼索地平、瑞格列奈、格列本脲、格列美脲、氯唑沙宗和二甲双胍)在非糖尿病患者和糖尿病患者中的血药浓度-时间曲线和药代动力学参数。结果预测的血药浓度-时间曲线下面积(AUC)和最大(峰)浓度(Cmax)与文献报道值有较好的一致性(2倍误差)。敏感性分析表明，肠道通过时间、肝酶活性和肾功能影响这些药物的药代动力学特征。肠道转运时间的缩短只会降低控释药物和低吸收药物的AUC。肾功能损害明显改变主要通过肾脏消除的药物的药代动力学。结论建立的PBPK模型可以定量预测糖尿病引起的药代动力学改变。
Background and ObjectiveAccumulating evidence has shown that diabetes mellitus may affect the pharmacokinetics of some drugs, leading to alteration of pharmacodynamics and/or toxic effects. The aim of this study was to develop a novel physiologically based pharmacokinetic (PBPK) model for predicting drug pharmacokinetics in patients with type 2 diabetes mellitus quantitatively.MethodsContributions of diabetes-induced alteration of physiological parameters including gastric emptying rates, intestinal transit time, drug metabolism in liver and kidney functions were incorporated into the model. Plasma concentration–time profiles and pharmacokinetic parameters of seven drugs (antipyrine, nisoldipine, repaglinide, glibenclamide, glimepiride, chlorzoxazone, and metformin) in non-diabetic and diabetic patients were predicted using the developed model. The PBPK model coupled with a Monte-Carlo simulation was also used to predict the means and variability of pharmacokinetic parameters.ResultsThe predicted area under the plasma concentration–time curve (AUC) and maximum (peak) concentration (Cmax) were reasonably consistent (<2-fold errors) with the reported values. Sensitivity analysis showed that gut transit time, hepatic enzyme activity, and renal function affected the pharmacokinetic characteristics of these drugs. Shortened gut transit time only decreased the AUC of controlled-released drugs and drugs with low absorption rates. Impairment of renal function markedly altered pharmacokinetics of drugs mainly eliminated via the kidneys.ConclusionAll of these results indicate that the developed PBPK model can quantitatively predict pharmacokinetic alterations induced by diabetes.