PREDICTION OF CHANGES IN THE CLINICAL PHARMACOKINETICS OF BASIC DRUGSON THE BASIS OF OCTANOL-WATER PARTITION-COEFFICIENTS

A physiologically based pharmacokinetic model for basic drugs has been established on the basis of acl octanol- partition coefficients of th e non-ionized, unbound drugs (P-oct). The parameters for the-physiolog ical model in man were estimated from a regression equation obtained f or the relationships between the P-oct and the tissue-plasma partition coefficient, the hepatic Intrinsic clearance (CLint,h) and the blood- to-plasma concentration ratio in rabbits, The plasma concentrations ob served after intravenous administration oi ten basic drugs (3.2 mg kg( -1)) to rabbits agreed with the levels predicted using the physiologic al model (r = 0.710-0.980). In man, the predicted plasma concentration s of basic drugs were in good agreement with reported values (r = 0.72 9-0.973), except for diazepam and pentazocine. Variations in plasma an d brain-concentration profiles of clomipramine and nitrazepam in vario us disease states were simulated using the model. We assumed that the changes in unbound fraction of drug in serum (f(p)), CLint,h and the h epatic blood flow rate were from 0.25- to 4-fold that of the control a nd that fat volume changed by 0.2- to 5-fold. With regard to changes i n f(p), we predicted that the brain-plasma concentration ratio of clom ipramine was 1.5- to 25-fold that of the control. 24 h after intraveno us administration, although the variations in the plasma concentration -time profiles were less marked. Plasma concentrations predicted for s everal basic drugs were in good agreement with reported values and thi s physiological model could be useful for predicting drug-disposition kinetics in man.