The enantiomer-specific kinetics and dynamics of verapamil after rapid intravenous administration to sheep: physiological analysis and modeling

Abstract

The lung, myocardial and systemic kinetics of the enantiomers of verapamil, and their myocardial effects, were measured after administration of 10 mg of racemic verapamil during 2 min to chronically instrumented sheep; the data were used to develop a physiological model of the process. Verapamil was characterized by relatively slow transit through the lungs and heart. The lung kinetic values were membrane limited, whereas the tissue/blood equilibrium half-life for the heart was approximately 8 min. There was little difference between the kinetic values of the enantiomers, with the exception of their extent of deep distribution into the lung. The time course of the increase in myocardial blood flow caused by verapamil was best related to the time course of the arterial verapamil concentrations, whereas the time course of increases in the interval between P and R waves of the electrocardiogram and decreases in the maximum rate of rise of left ventricular pressure were best related to the time course of its myocardial concentrations. Thus, the observed hysteresis for these effects compared with arterial blood was largely caused by the time required for the myocardial equilibration. The model predicted that the myocardial concentrations of verapamil were relatively insensitive to the duration of injection of a given bolus dose, but that rapid injection caused transient, high arterial concentrations. It also predicted that the bolus dose of verapamil should be modified over a 2-fold range to account for physiologically plausible variations in base-line cardiac output and myocardial blood flow.