A biosimulation model is being developed to provide a quantitative description of the key processes involved in acetaminophen-induced liver injury: acetaminophen metabolism, reactive metabolite formation, glutathione depletion and resynthesis, ROS formation, energy homeostasis, mitochondrial dysfunction, necrosis, apoptosis, and tissue regeneration. The current stage of the platform includes a whole-body physiologically based pharmacokinetic (PBPK) model for acetaminophen and its metabolites in the mouse, rat, and human. The PBPK model is linked to a pharmacodynamic (PD) model describing the reaction of acetaminophen-derived N-acetyl-p-benzoquinone imine (NAPQI) with glutathione and the resulting depletion and resynthesis of glutathione. The formation of NAPQI-adducts with cellular proteins and increased oxidative stress resulting from glutathione depletion are linked to cellular damage and response. This PBPK/PD model of acetaminophen metabolism and glutathione depletion has been used to investigate the extent to which differences in metabolism and glutathione homeostasis explain interspecies differences in susceptibility to acetaminophen toxicity.

Biosimulation of acetaminophen-induced liver injury using the Entelos Physiolab platform

240th National Meeting (2010)

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