Visualization-based analysis for a mixed-inhibition binary PBPK model: Determination of inhibition mechanism

Abstract

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.