PHARMACOKINETIC ANALYSIS OF CHLORPROMAZINE IN RAT SERUM, CEREBROSPINAL-FLUID AND STRIATUM

The time courses of the total concentration of chlorpromazine (CPZ) an d its S-oxide (CPZSO) in serum after i.v. administration of CPZ are de scribed by a two compartment model and a simple metabolism model, resp ectively. The time course of the free CPZ concentration in serum is pr edicted by the correlation between the ratio of CPZSO/CPZ and the free fraction of CPZ in serum which was established in the previous study. The time course of CPZ concentration in cerebrospinal fluid (CSF) is described by a basic physiological model in which the CSF compartment is connected with the serum compartment (free drug) by the apparent di ffusion clearance. Equilibrium dialysis of the striatum homogenate was carried out to clarify the CPZ disposition in the striatum. Since the binding curves of CPZ in the striatum on the Langmuir plot and the Sc atchard plot were a sigmoidal and an upward curve, the time course of the drug's concentration was analyzed on a simple kinetic model design ed in conformity with a blood-flow limited model. The time course was described by a simple kinetic model for up to 8 h after CPZ administra tion. These pharmacokinetic models for CSF and the striatum will be us ed to analyze the relationship between the pharmacokinetics and pharma codynamics of CPZ.