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Global Optimization of the Michaelis-Menten parameters using physiologically-based pharmacokinetic (PBPK) modeling and chloroform vapor uptake data in F344 rats
Citation:
Evans, M., C. Eklund, D. williams, Y. Sey, AND J. Simmons. Global Optimization of the Michaelis-Menten parameters using physiologically-based pharmacokinetic (PBPK) modeling and chloroform vapor uptake data in F344 rats. INHALATION TOXICOLOGY. Taylor & Francis, Inc., Philadelphia, PA, 32(3):97-109, (2020). https://doi.org/10.1080/08958378.2020.1742818
Impact/Purpose:
PBPK models are well-established frameworks used to describe absorption, distribution, metabolism, and excretion of xenobiotics. For volatile organic chemicals, metabolism is considered essential for toxicity development. In addition, , the technique of vapor uptake inhalation can be used in combination with a PBPK model to estimate metabolic constants for volatile compounds. The resulting calibrated PBPK model can then be used for extrapolation across different routes or species extrapolation. The accuracy in the estimation of metabolic parameters for volatile compounds is important for these extrapolations. This research makes use of a global optimization technique specifically designed to search for hard to estimate parameters, like our metabolic estimates. To our knowledge, this is the first time that global optimization has been applied to estimate metabolism for a volatile compound. We chose chloroform as a volatile compound of interest, a disinfection by product of chlorination and a regulated trihalomethane. The results of our research demonstrates that global optimization was helpful in determining a robust estimate for metabolic rate (1.2 mg/h). The affinity constant was harder to estimate, due to multiple minima present in the data cost function. Further research will determine ways in which to improve the estimation of affinity values for different volatile chemicals.
Description:
To quantify metabolism, a physiologically based pharmacokinetic (PBPK) model for a volatile compound can be calibrated with the closed chamber (i.e. vapor uptake) inhalation data. Here, we introduce global optimization as a novel component of the predictive process and use it to illustrate a procedure for metabolic parameter estimation.
URLs/Downloads:
DOI: Global Optimization of the Michaelis-Menten parameters using physiologically-based pharmacokinetic (PBPK) modeling and chloroform vapor uptake data in F344 rats
https://pubmed.ncbi.nlm.nih.gov/32241199/