DETERMINING KINETIC CONSTANTS OF CHLORINATED ETHANE METABOLISM IN THE RAT FROM RATES OF EXHALATION
DETERMINING KINETIC CONSTANTS OF CHLORINATED ETHANE METABOLISM IN THE RAT FROM RATES OF EXHALATION
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DOI：
10.1016/0041-008x(89)90016-1
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发表时间：
1989-06-15
影响因子：
3.8
通讯作者：
ANDERSEN, ME
中科院分区：
文献类型：
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作者：
GARGAS, ML;ANDERSEN, ME
化学代谢的动力学常数被用来开发基于生理的药代动力学（PB-PK）模型，预测挥发性化学物质在甘露醇系统中的时程分布。气体吸收技术已被证明可用于确定各种挥发性化合物的动力学常数，包括以下氯乙烷：氯乙烷，1，1-二氯乙烷，1，2-二氯乙烷和1，1，1-三氯乙烷。不幸的是，低蒸汽压材料和那些表现出增加血液和组织溶解度不能通过气体吸收方法检查。开发了一种替代气相方法，其中大鼠首先通过恒定浓度吸入暴露6小时，然后置于具有新鲜空气流的2.5升呼出气室中，并对室流出物进行连续分析以获得试验化学品。所产生的消除行为是非常敏感的代谢，和化学代谢的动力学常数估计通过模拟与PB-PK模型包含的方程，准确地描述了实验条件。测定了1，1，2-三氯乙烷、1，1，1，2-四氯乙烷、1，1，2，2-四氯乙烷、五氯乙烷和六氯乙烷的优化最大代谢率（Vmax），所得值分别为7.69、6.39、12.9、9.71和1.97 mg/kg/hr。使用这些测试化学品中的几种，PB-PK建模将化学品的被毛吸附确定为全身暴露后对呼气室浓度时间过程的显著贡献。
The kinetic constants of chemical metabolism are used to develop physiological based pharmacokinetic (PB-PK) models which predict the time course distribution of volatile chemicals in mannalian systems. Gas uptake techniques have proved useful in determining kinetic constants for a variety of volatile compounds including the following chloroethanes: ethyl chloride, 1,1-dichloroethane, 1,2-dichloroethane, and 1,1,1-trichloroethane. Unfortunately, low vapor pressure materials and those exhibiting increasing blood and tissue solubilities could not be examined by gas uptake methods. An alternative gas phase method was developed in which rats were first exposed by constant concentration inhalation for 6 hr and then placed in 2.5-liter exhaled breath chambers with fresh air flow and chamber effluent was serially analyzed for test chemical. The resulting elimination behavior was extremely sensitive to metabolism, and kinetic constants for chemical metabolism were estimated by simulation with a PB-PK model containing equations that accurately described the experimental conditions. Optimized maximum metabolic rates (Vmax) were determined for 1,1,2-trichloroethane, 1,1,1,2-tetrachloroethane, 1,1,2,2-tetrachloroethane, pentachloroethane, and hexachloroethane with resulting values of 7.69, 6.39, 12.9, 9.71, and 1.97 mg/kg/hr, respectively. With several of these test chemicals the PB-PK modeling identified fur adsorption of chemical as significantly contributing to the exhalation chamber concentration time course after whole body exposure.