A physiologically based pharmacokinetic (PBPK) model incorporating mixed enzyme inhibition was used to determine the mechanism of metabolic interactions occurring during simultaneous exposures to the organic solvents chloroform and trichloroethylene (TCE). Visualization-based sensitivity and identifiability analyses of the model were performed to determine the conditions under which four inhibitory parameters describing inhibitor binding could be estimated. The sensitivity methods were used to reduce the 4-parameter estimation problem into two distinct 2-parameter problems. The inhibitory parameters were then estimated from multiple closed-chamber gas-uptake experiments using graphical methods. The estimated values of the four inhibitory parameters predicted that chloroform and TCE interact in a competitive manner. Based on the model analysis, we present recommendations for the design of experiments for determination of inhibition mechanism in binary chemical mixtures. We assert that a thorough analysis of the parameter-dependent sensitivity and identifiability characteristics can be used to plan efficient experimental protocols for the quantitative analysis of inhalation pharmacokinetics.

中文翻译：

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基于可视化的混合抑制二元PBPK模型分析：抑制机理的确定。

基于生理学的药代动力学（PBPK）模型结合了混合酶抑制作用，用于确定在同时暴露于有机溶剂氯仿和三氯乙烯（TCE）期间发生的代谢相互作用的机制。对模型进行了基于可视化的敏感性和可识别性分析，以确定可以估计描述抑制剂结合的四个抑制参数的条件。灵敏度方法用于将4参数估计问题简化为两个不同的2参数问题。然后使用图形方法从多个封闭室气体吸收实验中估算抑制参数。四个抑制参数的估计值预测氯仿和TCE以竞争方式相互作用。根据模型分析，我们提出了用于确定二元化学混合物中抑制机理的实验设计的建议。我们断言，对依赖于参数的敏感性和可识别性特征的透彻分析可用于计划有效的实验方案，以进行吸入药代动力学的定量分析。