Kinetics of the pharmacologic effect of chlorpromazine was investigated in intact fed rats. After i.v. bolus administration of chlorpromazine (0.5, 2, 4 mg/kg), the time courses of plasma glucose, insulin, adrenaline and noradrenaline levels as well as serum and brain concentrations of the drug were determined. Since the hyperglycemic effect of chlorpromazine is known to be attributable to the endogenously released catecholamines, the effects of adrenaline and noradrenaline on the plasma glucose and insulin regulation system were also determined. The plasma glucose regulation system in rats was investigated by an i.v. glucose tolerance test. From the data obtained, a pharmacokinetic (PK)-pharmacodynamic (PD) model as well as the plasma glucose regulation model was constructed. The hyperglycemic effects of catecholamines during and after i.v. infusion were reasonably well correlated with the plasma concentrations of catecholamines using the PK-PD model. Since a quantitative relationship between plasma concentrations of catecholamines and the brain concentration of chlorpromazine was established in the previous report, the time course of hyperglycemic effect of chlorpromazine was analyzed. The result indicated that the hyperglycemic effect can be described quantitatively by a simple PK-PD model with plasma glucose regulation system, using brain concentrations of chlorpromazine in rats.
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Sato et al. (1988) studied this question.