Multiscale zonation-resolved modeling of dose-dependent determinants of acetaminophen-induced liver injury

Introduction: modeling as a solution to reduce DILI impact. Methods: patient cohort, encompassing both lower and higher APAP overdoses, and analyzed how zonal variations in metabolism factors impacted the generation of liver damage. Results: The results showed a significant difference in the sensitivity of the metabolic parameters at different overdose levels. Some, such as drug uptake rate, led to increased damage; others, such as CYP450 enzymatic activity, showed overdose-dependent effects, and others, such as the sulfation rate, showed only limited effects. Discussion: Overall, this study highlights the importance of collecting proper metabolic expression (specifically drug uptake rate, CYP450 enzymatic activity, and glutathione quantity) to ensure an accurate estimation of patient damage.