Myocardial disposition and cardiac pharmacodynamics of verapamil in the dog.

The disposition of verapamil was studied in anesthetized open-chested dogs following administration of intravenous doses of 0.5 mg/kg. The plasma and myocardial verapamil concentration-time data were fit to a three-compartment model to describe the disposition kinetics. The distribution equilibrium between myocardium and plasma was achieved rapidly and the concentration of verapamil decayed in parallel in these two tissues. The partition coefficient which describes the time averaged myocardial/plasma concentration ratio was 6.21 +/- 2.38. Examination of the relationship between the plasma and myocardial concentrations and the time course of the effect of verapamil, as defined as PR interval prolongation, revealed a hysteresis effect in some dogs. Despite this hysteresis, there was a linear relationship between plasma and myocardial concentrations of verapamil and the degree of prolongation of the PR interval. The results of this study indicate that the concentration in the plasma is in equilibrium with the myocardium and changes in plasma concentration are indicative of parallel changes in myocardial levels. The effect of verapamil on the atrioventricular node is related to the concentration in the myocardium and plasma, but there is substantial interanimal variability in the sensitivity to verapamil.