Sasso Alan F, Georgopoulos Panos G, Isukapalli Sastry S, Krishnan Kannan
Environmental and Occupational Health Sciences Institute, UMDNJ-RW Johnson Medical School, Rutgers University, 170 Frelinghuysen Road, Piscataway, NJ 08854, USA.
J Toxicol. 2012;2012:895391. doi: 10.1155/2012/895391. Epub 2012 Jan 19.
A lipid-based physiologically based toxicokinetic (PBTK) model has been developed for a mixture of six polychlorinated biphenyls (PCBs) in rats. The aim of this study was to apply population Bayesian analysis to a lipid PBTK model, while incorporating an internal exposure-response model linking enzyme induction and metabolic rate. Lipid-based physiologically based toxicokinetic models are a subset of PBTK models that can simulate concentrations of highly lipophilic compounds in tissue lipids, without the need for partition coefficients. A hierarchical treatment of population metabolic parameters and a CYP450 induction model were incorporated into the lipid-based PBTK framework, and Markov-Chain Monte Carlo was applied to in vivo data. A mass balance of CYP1A and CYP2B in the liver was necessary to model PCB metabolism at high doses. The linked PBTK/induction model remained on a lipid basis and was capable of modeling PCB concentrations in multiple tissues for all dose levels and dose profiles.
已针对大鼠体内六种多氯联苯（PCB）的混合物建立了基于脂质的生理药代动力学（PBTK）模型。本研究的目的是将群体贝叶斯分析应用于脂质PBTK模型，同时纳入一个将酶诱导与代谢率联系起来的内部暴露-反应模型。基于脂质的生理药代动力学模型是PBTK模型的一个子集，它可以模拟组织脂质中高度亲脂性化合物的浓度，而无需分配系数。将群体代谢参数的分层处理和CYP450诱导模型纳入基于脂质的PBTK框架，并将马尔可夫链蒙特卡罗方法应用于体内数据。为了对高剂量下的PCB代谢进行建模，肝脏中CYP1A和CYP2B的质量平衡是必要的。链接的PBTK/诱导模型仍然基于脂质，并且能够对所有剂量水平和剂量曲线下多种组织中的PCB浓度进行建模。
