Extending a pharmacodynamic model for nuclear receptor-induced enzyme production with spatial resolution

Abstrakt

The subject of the talk is efficient modelling of the intracellular action of a drug binding to the nuclear pregnane X receptor. The binded complex enters the cell nucleus and acts on DNA, resulting in enhanced production of an enzyme supposed to metabolize, among others, the substances responsible for the disease. Traditionally, a methodologv called pharmacokinetic/pharmacodynamic (PKPD) modelling is used to perform the corresponding in silico simulations. It is based on a compartmental model, which simplifies the complex processes in the human body through the definition of a small number of compartments representing organs, tissues, cells, cytoplasm or abstract units. Inside a compartment, the concentrations of all substances are assumed to be distributed homogeneously, i.e. there is no spatial dependence. The involved processes are modelled through diffusion laws, mass-action kinetics, Michaelis-Menten kinetics or the Hill equation. They lead to a system of ODEs for the time-dependence of the concentrations of the active substances.