SUBCELLULAR PHARMACOKINETICS AND DRUG PROPERTIES - NUMERICAL SIMULATIONS IN MULTICOMPARTMENT SYSTEMS

The methodology and results of numerical simulations of drug distribut ion in multicompartment systems, represented by a catenary set of alte rnating aqueous and lipid compartments, are reviewed. Transport, membr ane accumulation, protein binding, first order elimination (biotransfo rmation or excretion), but not ionisation have been considered as the processes determining the drug distribution. The simulations provide t he time courses of the drug concentrations in individual compartments as dependent on hydrophobicity and elimination rate parameters of drug s because the model parameters are substituted by their relationships to the drug properties. The simulation results are fitted with empiric al functions, mostly in the form of the hydrophobicity-concentration p rofiles for a pre-defined time of exposure. The shape of the profiles is different for open and closed biological systems (with and without elimination, respectively) as well as for individual periods of the dr ug distribution in closed systems (non-equilibrium, mixed, equilibrium ). Fitting the empirical functions to experimental data enables one to verify quantitatively the simulation results. The use of the approach for formulation of mechanistic conclusions is exemplified.