Issues in the pharmacokinetics of trichloroethylene and its metabolites
Issues in the pharmacokinetics of trichloroethylene and its metabolites
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DOI：
10.1289/ehp.8691
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发表时间：
2006-09-01
影响因子：
10.4
通讯作者：
Evans, Marina V.
中科院分区：
文献类型：
--
作者：
Chiu, Weihsueh A.;Okino, Miles S.;Evans, Marina V.
在了解三氯乙烯（TCE）的复杂药效学方面取得了很大进展。定性而言，TCE在局部或体循环中代谢为多种代谢物是明确的。其中许多代谢物被认为具有毒理学重要性。此外，努力开发生理药代动力学（PBPK）模型，导致更好的定量评估TCE及其代谢产物的剂量。作为TCE健康风险评估中关键问题的小型专著的一部分，本文回顾了TCE药代动力学和最近PBPK建模工作中的一些当前科学问题，重点关注自2000年以来发表的文献。特别注意的是影响PBPK建模应用于风险评估的因素。最近的TCE PBPK建模工作，再加上方法学的进步，在表征不确定性和变异性，表明严格的PBPK建模TCE风险评估的应用似乎是可行的，至少对于TCE及其主要氧化代谢产物三氯乙酸和三氯乙醇。然而，一些基本的结构假设，如肠肝再循环，血浆结合，和组织分布的流动或扩散限制治疗需要额外的评价和分析。此外，还有许多具有潜在毒理学意义的代谢物，如三氯乙醛、二氯乙酸和谷胱甘肽结合衍生物，由于分析困难或体循环中浓度低，可靠的药代动力学数据很少。这将是一个挑战，为这种情况下开发可靠的剂量测定。
Much progress has been made in understanding the complex pharmacoldnetics of trichlornethylene (TCE). Qualitatively, it is dear that TCE is metabolized to multiple metabolites either locally or into systemic circulation. Many of these metabolites are thought to have toxicologic importance. In addition, efforts to develop physiologically based pharmacokinetic (PBPK) models have led to a better quantitative assessment of the dosimetry of TCE and several of its metabolites. As part of a mini-monograph on key issues in the health risk assessment of TCE, this article is a review of a number of the current scientific issues in TCE pharmacokinetics and recent PBPK modeling efforts with a focus on literature published since 2000. Particular attention is paid to factors affecting PBPK modeling for application to risk assessment. Recent TCE PBPK modeling efforts, coupled with methodologic advances in characterizing uncertainty and variability, suggest that rigorous application of PBPK modeling to TCE risk assessment appears feasible at least for TCE and its major oxidative metabolites trichloroacetic acid and trichloroethanol. However, a number of basic structural hypotheses such as enterohepatic recirculation, plasma binding, and flow- or diffusion-limited treatment of tissue distribution require additional evaluation and analysis. Moreover, there are a number of metabolites of potential toxicologic interest, such as chloral, dichloroacetic acid, and those derived from glutathione conjugation, for which reliable pharmacokinetic data is sparse because of analytical difficulties or low concentrations in systemic circulation. It will be a challenge to develop reliable dosimetry for such cases.