Integration of genome-scale metabolic networks into whole-body PBPK models shows phenotype-specific cases of drug-induced metabolic perturbation

PBPK-GSMN Multiscale modeling workflow. Preparations and input: On the organism level, a comprehensive drug-specific whole-body physiologically based pharmacokinetic (PBPK) model is developed and validated with human pharmacokinetic (PK) data. On the cellular scale, a human genome-scale metabolic network (GSMN) reconstruction is used together with omics data to establish an organ-specific GSMN model and a reference flux distribution. PBPK-GSMN combination: The developed whole-body PBPK model is used to estimate the in vivo organ-specific drug metabolism as time-resolved reaction rates including the absorption, distribution, metabolism, excretion (ADME) processes. The organ-specific GSMN model is extended with the drug-specific xenobiotic metabolism (Table (Table1).1). PBPK-derived xenobiotic reaction rates are iteratively used to constrain the xenobiotic reaction rates in the organ-specific GSMN model. A dynamic version of the minimization of metabolic adjustment algorithm (dMOMA) is used to calculate altered flux distributions in the drug perturbated organ-specific GSMN. Prediction of cellular responses: The combined multi-scale PBPK-GSMN model can be used to predict organ-specific drug-induced metabolic perturbations, resulting in altered intracellular and extracellular reactions rates. The combined model allows the explicit consideration of specific dosing schemes, patient physiology, and genetic characteristic