On the determination of the time delay in reaching the steady state drug concentration in the organ compared to plasma

A problem of substantial delay in reaching the steady state drug concentration in particular organ (compartment) compared to the time of reaching the steady state plasma concentration is considered. It is shown that the ratio of the terminal (V-beta) and the steady state (V-ss) volumes of distribution, V-beta/V-ss, appears to be an indication of possible lag in reaching the steady state in the organ tissue compared to plasma. The estimations of the time of reaching the steady state drug concentration in the organ are suggested. The in-vivo based pharmacokinetic model, which uses the experimentally measured drug plasma concentration time course and the appropriate equation for the kinetics of drug distribution into the tissues, is suggested. It is intended to determine the kinetic mechanism of drug distribution into the tissues. The model was applied to interpret the kinetics of drug distribution into the brain. The importance of precise measurement of drug plasma concentration at terminal phase for obtaining accurate values of V-beta and V-ss is emphasized: this allows predicting a possible slow plasma-tissue drug transfer and substantial difference in time of reaching the steady state by the body and plasma. (c) 2007 Wiley-Liss, Inc.