Development and evaluation of a harmonized physiologically based pharmacokinetic (PBPK) model for perchloroethylene toxicokinetics in mice, rats, and humans
Development and evaluation of a harmonized physiologically based pharmacokinetic (PBPK) model for perchloroethylene toxicokinetics in mice, rats, and humans
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DOI：
10.1016/j.taap.2011.03.020
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发表时间：
2011-06-15
影响因子：
3.8
通讯作者：
Ginsberg, Gary L.
中科院分区：
文献类型：
--
作者：
Chiu, Weihsueh A.;Ginsberg, Gary L.
本文报道了一种“协调”PBPK模型的发展，该模型用于小鼠、大鼠和人体内的过氯乙烯（四氯乙烯或百分之一）的毒性动力学，包括百分之一的氧化和谷胱甘肽（GSH）偶联，氧化代谢物三氯乙酸（TCA）的内部动力学，以及GSH偶联代谢物n -乙酰化三氯酰半胱氨酸和二氯乙酸的尿排泄动力学。该模型利用了比以往任何单独分析更广泛的体外和体内数据，体外数据用于初始或“基线”参数估计，体内数据集分为用于“校准”和用于“评估”的数据集。参数校准利用有限的贝叶斯分析，包括平坦的先验，并仅使用通过马尔可夫链蒙特卡罗（MCMC）获得的后验模式进行推断。正如预期的那样，被吸收的百分之一的主要消除途径预计是作为母体化合物的呼出，代谢占摄入的不到20%，除了口服暴露的小鼠，在较低暴露的情况下，代谢预计略高于50%。在这三个物种中，血液中perc的浓度、perc氧化的程度和TCA的产生量都是很好的估计，剩余不确定度类似于2倍。然而，由此得出的谷胱甘肽结合量的估计范围在人类（类似于3000倍）和小鼠（类似于60倍）中相当广泛。虽然在小鼠中，谷胱甘肽结合的高端估计值低于氧化的估计值，但在人类中，其估计值从远低于氧化率到远高于氧化率不等。目前尚不清楚该范围在多大程度上反映了不确定性、可变性或两者的结合。重要的是，通过将总代谢分解为单独的氧化和共轭途径，这一方法在最近的国家研究委员会评论中也被推荐，该分析调和了先前发表的PBPK模型之间的差异，这些模型得出了人类低代谢和预测人类高代谢。本质上，如果增加一些附加条件，这两个结论都与数据一致：在人类中，氧化代谢低，而谷胱甘肽结合代谢可能高或低，具有不确定性和/或跨越三个数量级的个体间变异性。为了更好地表征人体内谷胱甘肽结合的不确定性和可变性，需要更多关于百分之五谷胱甘肽结合的内部动力学的直接数据，如血液和/或组织中的三氯酰谷胱甘肽或三氯乙烯基半胱氨酸。Elsevier Inc.出版。
This article reports on the development of a "harmonized" PBPK model for the toxicokinetics of perchloroethylene (tetrachloroethylene or perc) in mice, rats, and humans that includes both oxidation and glutathione (GSH) conjugation of perc, the internal kinetics of the oxidative metabolite trichloroacetic acid (TCA), and the urinary excretion kinetics of the GSH conjugation metabolites N-Acetylated trichlorovinyl cysteine and dichloroacetic acid. The model utilizes a wider range of in vitro and in vivo data than any previous analysis alone, with in vitro data used for initial, or "baseline," parameter estimates, and in vivo datasets separated into those used for "calibration" and those used for "evaluation." Parameter calibration utilizes a limited Bayesian analysis involving flat priors and making inferences only using posterior modes obtained via Markov chain Monte Carlo (MCMC). As expected, the major route of elimination of absorbed perc is predicted to be exhalation as parent compound, with metabolism accounting for less than 20% of intake except in the case of mice exposed orally, in which metabolism is predicted to be slightly over 50% at lower exposures. In all three species, the concentration of perc in blood, the extent of perc oxidation, and the amount of TCA production is well-estimated, with residual uncertainties of similar to 2-fold. However, the resulting range of estimates for the amount of GSH conjugation is quite wide in humans (similar to 3000-fold) and mice (similar to 60-fold). While even high-end estimates of GSH conjugation in mice are lower than estimates of oxidation, in humans the estimated rates range from much lower to much higher than rates for perc oxidation. It is unclear to what extent this range reflects uncertainty, variability, or a combination. Importantly, by separating total perc metabolism into separate oxidative and conjugative pathways, an approach also recommended in a recent National Research Council review, this analysis reconciles the disparity between those previously published PBPK models that concluded low perc metabolism in humans and those that predicted high perc metabolism in humans. In essence, both conclusions are consistent with the data if augmented with some additional qualifications: in humans, oxidative metabolism is low, while GSH conjugation metabolism may be high or low, with uncertainty and/or interindividual variability spanning three orders of magnitude. More direct data on the internal kinetics of perc GSH conjugation, such as trichlorovinyl glutathione or tricholorvinyl cysteine in blood and/or tissues, would be needed to better characterize the uncertainty and variability in GSH conjugation in humans. Published by Elsevier Inc.