The pharmacology of verapamil. I. Elimination kinetics in dogs and correlation of plasma levels with effect on the eletrocardiogram.

The elimination kinetics of verapamil, an experimental antiarrhythmic agent which inhibits slow-channel activity, have been studied in mongrel dogs after i.v. drug administration. The disposition of verapamil follows first-order kinetics and may be adequately described by a one-compartment model. After single i.v. doses of the drug, the overall elimination rate constant (mean +/-S.E.M.) was 0.0146 +/- 0.0021 min-1; the apparent volume of distribution was 4.47 +/- 0.40 liters/kg; and the total body drug clearance was 1244 +/- 113.4 ml/min. After longer i.v. infusions, the disposition kinetics were similar to those found with bolus dosing. A linear relationship was found between verapamil plasma concentrations and changes in atrioventricular conduction time, as estimated from the P-R interval of the surface electrocardiogram (r = 0.95, P less than .001). No changes were seen in the QRS duration of Q-T interval. These data show that the effect of verapamil of verapamil on slow-channel-dependent conduction in the heart is directly related to the concentration of the drug in plasma.