THE ENANTIOMER-SPECIFIC KINETICS AND DYNAMICS OF VERAPAMIL AFTER RAPID INTRAVENOUS ADMINISTRATION TO SHEEP - PHYSIOLOGICAL ANALYSIS AND MODELING

The lung, myocardia and systemic kinetics of the enantiomers of verapa mil, 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 pro cess. Verapamil was characterized by relatively slow transit through t he lungs and heart. The lung kinetic values were membrane limited, whe reas the tissue/blood equilibrium half-life for the heart was approxim ately 8 min. There was little difference between the kinetic values of the enantiomers, with the exception of their extent of deep distribut ion 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 a rterial verapamil concentrations, whereas the time course of increases in the interval between P and R waves of the electrocardiogram and de creases 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 blo od was largely caused by the time required for the myocardial equilibr ation. The model predicted that the myocardial concentrations of verap amil were relatively insensitive to the duration of injection of a giv en bolus dose, but that rapid injection caused transient, high arteria l concentrations. It also predicted that the bolus dose of verapamil s hould be modified over a 2-fold range to account for physiologically p lausible variations in base-line cardiac output and myocardial blood f low.