Pharmacokinetic and pharmacodynamic studies of centrally acting drugs in rat: effect of pentobarbital and chlorpromazine on electroencephalogram in rat.

Electroencephalogram (EEG) alterations in rat after the i.v. administration of pentobarbital (PTB) and chlorpromazine (CPZ) were measured by power spectral analysis. The time courses of PTB concentrations in plasma, cerebrospinal fluid (CSF) and brain were determined after the i.v. administration of PTB (20, 40 mg/kg) by GC-MS. The PTB concentrations in plasma, CSF and brain could be described by a biexponential equation, a CSF model and a blood flow limited model, respectively. The relationship between the alteration of EEG and the PTB concentrations in the CSF or brain or the effect compartment were analyzed using the sigmoid Emax model. The alteration of EEG after PTB administration could be described by the PTB concentration in these compartments using the sigmoid Emax model. These results indicated that the site of action for the alteration of EEG after PTB administration is in instantaneous equilibrium with the CSF, the brain and the effect compartment. Thus, alterations in EEG after PTB administration can be predicted by monitoring the total PTB concentration in plasma. The alteration of EEG after i.v. administration of CPZ (4 mg/kg) showed a two-phase variation. Although the relationship between the alteration of EEG and the CPZ concentrations in CSF or the striatum or the effect compartment (total and free drug) were analyzed using the linear model, the Emax model or the sigmoid Emax model, the two-phase alteration of EEG after CPZ administration could not be described by any of these models. These results indicated that the pharmacokinetic and pharmacodynamic modeling of CPZ during the alteration of EEG may be complicated due to several pharmacokinetic and pharmacodynamic factors, such as an alteration of the free fraction of CPZ in the striatum, the formation of active metabolites, 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.