Prediction of diazepam disposition in the rat and man by a physiologically based pharmacokinetic model

A physiologically based pharmacokinetic model for diazepam disposition was developed in the rat, incorporating anatomical, physiological, and biochemical parameters, i.e., tissue volume, blood flow rate, serum free fraction, distribution of diazepam into red blood cells, drug metabolism and tissue-to-blood distribution ratio. The serum free fraction of diazepam was determined by equilibrium dialysis at 37 degrees C and was constant over a wide concentration range. Partition of diazepam between plasma and erythrocytes was determined in vitro at 37 degrees C, and the resultant blood-to-plasma concentration ratio was constant over a wide concentration range. The enzymatic parameters (Km, Vmax) of the eliminating organs, i.e., liver, kidney, and lung, previously determined using microsomes, were used for the prediction. The tissue-to-blood distribution ratios inferred by inspection of the data when pseudoequilibrium is reached after i.v. bolus injection of 1.2 mg/kg diazepam were corrected according to the method of Chen and Gross. Predicted diazepam concentration time-course profiles in plasma and various organs or tissues, using an 11-compartmental model, were compared with those observed. Prediction was successful in all compartments including brain, the target organ of diazepam. Scale-up of the disposition kinetics of diazepam from rat to man was also successful.