PHARMACOKINETIC AND PHARMACODYNAMIC STUDIES OF CENTRALLY ACTING DRUGSIN RAT - EFFECT OF PENTOBARBITAL AND CHLORPROMAZINE ON ELECTROENCEPHALOGRAM IN RAT

Electroencephalogram (EEG) alterations in rat after the i.v. administr ation of pentobarbital (PTB) and chlorpromazine (CPZ) were measured by power spectral analysis. The time courses of PTB concentrations in pl asma, cerebrospinal fluid (CSF) and brain were determined after the i. v. administration of PTB (20, 40 mg/kg) by GC-MS. The PTB concentratio ns in plasma, CSF and brain could be described by a biexponential equa tion, a CSF model and a blood flow limited model, respectively. The re lationship between the alteration of EEG and the PTB concentrations in the CSF or brain or the effect compartment were analyzed using the si gmoid E(max) model. The alteration of EEG after PTB administration cou ld be described by the PTB concentration in these compartments using t he sigmoid E(max) model. These results indicated that the site of acti on for the alteration of EEG after PTB administration is in instantane ous equilibrium with the CSF, the brain and the effect compartment. Th us, alterations in EEG after PTB administration can be predicted by mo nitoring the total PTB concentration in plasma. The alteration of EEG after i.v. administration of CPZ (4 mg/kg) showed a two-phase variatio n. Although the relationship between the alteration of EEG and the CPZ concentrations in CSF or the striatum or the effect compartment (tota l and free drug) were analyzed using the linear model, the E(max) mode l or the sigmoid E(max) model, the two-phase alteration of EEG after C PZ administration could not be described by any of these models. These results indicated that the pharmacokinetic and pharmacodynamic modeli ng of CPZ during the alteration of EEC may be complicated due to sever al pharmacokinetic and pharmacodynamic factors, such as an alteration of the free fraction of CPZ in the striatum, the formation of active m etabolites, and two different intrinsic effects of CPZ on the EEG (one in an increase and the other in a decrease of the brain's electrical activity).