Abstract

This study used a steady-state approach to evaluate the relationships between the pharmacodynamic and pharmacokinetic characteristics of nifedipine and verapamil. In anesthetized and instrumented dogs, i.v. bolus/infusion dosing regimens were used for each drug to achieve and maintain stable drug concentrations in four different ranges rapidly. For both compounds, increases in doses were associated with disproportionate higher plasma drug concentrations, greater hemodynamic effects and significant reductions in systemic drug clearance. Progressive increases in the dose of nifedipine produced reductions in arterial pressure and reflex augmentation in cardiac output, together with decreases in calculated hepatic plasma flow which closely paralleled the decline in mean aortic pressure. Increasing doses of verapamil also resulted in decreased hepatic plasma flow, which was associated with both systemic hypotension and drug-induced decreases in cardiac output. These data imply that the hemodynamic effects of both nifedipine and verapamil result in changes in hepatic plasma flow which, in turn, result in significant alterations in systemic drug clearance. In this experimental model, the calculated hepatic plasma flow and observed systemic clearance values for nifedipine and verapamil were closely related to concentrations of the respective drugs in plasma.