Verapamil pharmacodynamics after intravenous and oral dosing: theoretic consideration

Differences in the potency of intravenous (IV) and oral verapamil have recently been reported with the concentration-response curve for PR-interval prolongation being shifted further to the right following oral administration relative to IV administration. Using well-established pharmacokinetic models, a theoretic basis for these observations is presented. Simultaneous curve fitting of the IV and oral verapamil plasma concentration and PR-interval data to a single pharmacokinetic-pharmacodynamic model allowed prediction of differences in the pharmacodynamic potency of verapamil as a function of the rate of drug administration. These data indicate that the rate of input of drug into the systemic circulation can influence the rate and extent of entry of drug into an effect compartment, which in turn can result in different plasma concentration-response relationships.