Evaluating Life-Stage and Population Toxicokinetic Variability Using In Vitro CYP450 and UGT Metabolism Systems

Absorption, Distribution, Metabolism and Excretion (ADME) are all subject to variation in different human populations as well as lifestages. While physiologic differences will affect all four of these toxicokinetic properties to a moderate degree, differences in metabolism due to either differing enzyme abundances over a lifespan or genetic polymorphisms may have a more significant effect, which could potentially be predicted with an understanding of the physicochemical properties and toxicokinetic differences for each chemical. As experimental data to inform the contribution of either cytochrome P450 enzymes and/or uridine diphosphoglucuronosyl transferases (UGTs) to xenobiotic metabolism is very limited, particularly for non-drug chemicals subject to TSCA, FIFRA, and other legislative mandates, this effort set out to generate in vitro toxicokinetic clearance data for a subset of isozymes known to affect toxicokinetic variability more readily than others based on earlier studies by this lab. The data were used as inputs in a PBTK modeling platform designed to adjust for ontogenetic differences across different lifestages, to evaluate the contribution of each toward toxicokinetic variability. This dataset provides chemical-specific information, toxicokinetic assay and analytical data used as inputs in the model; along with model outputs for evaluation.

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