The pharmacodynamic and pharmacokinetic interaction of pentobarbital and chlorpromazine in rats

The effect of chlorpromazine on the duration of loss of righting reflex (LRR, sleeping time) of pentobarbital and vice versa in a various dosage ranges were studied in rats. The logarithm of the dose versus sleeping time profile of pentobarbital was shifted to the left and the slope of the profile was decreased as the dose of chlorpromazine was increased. The logarithm of chlorpromazine dose versus duration of LRR during pentobarbital coadministration also showed a distinct dose-dependent profile. However, chlorpromazine itself showed ambiguous duration of LRR because the terminal point of the pharmacologic effect, i.e., the recovery of the righting reflex (RRR, the awakening time), was often difficult to determine clearly. The isobolographic method was introduced to describe the drug interaction of pentobarbital and chlorpromazine quantitatively. Assuming that the sites of action of chlorpromazine and pentobarbital were in the brain, the brain concentrations of pentobarbital at RRR were plotted against the brain concentration of chlorpromazine at RRR. The plots showed a hyperbola-like curve, indicating that there was a supra-additive interaction. In order to clarify the relationship between brain concentrations of the two drugs at RRR, a theoretical consideration was made under the following assumptions: (1) chlorpromazine and pentobarbital have a common central depressant effect, (2) the concentration-effect relationship is described by Hill's equation and (3) the mode of interaction of these drugs is simple additive. The results indicated that the isobolographic plot of pentobarbital and chlorpromazine was reasonably described by the theory and that chlorpromazine enhanced the effect of pentobarbital at least in an additive manner.