The relationship between pharmacokinetics and pharmacodynamics of enoximone in healthy man

Abstract

The relationship between the pharmacokinetics and pharmacodynamics of enoximone, a new positive inotropic agent, was investigated in 6 healthy men. The volunteers received single oral and i.v. doses of 3 and 1 mg/kg, respectively, and placebo in a double-blind cross-over trial. Plasma concentrations of enoximone and its sulphoxide metabolite, effects on the corrected electromechanical systole (QS2c), the impedance cardiogram (dZ/dt)/RZ index, blood pressure and heart rate were determined over an 8-h period. Peak effects on QS2c and the (dZ/dt)/RZ index were obtained after approximately 1 h. During the first hour, the cardiac effects lagged behind the high plasma concentrations. Thereafter, the effects on QS2c were closely correlated with the plasma concentrations both of enoximone and its sulphoxide derivative (r greater than or equal to 0.90). The concentration-effect curves of both substances were parallel and were independent of the route of administration. The inotropic activity was not related to the drug level in hypothetical peripheral compartments. The results suggest that determination of plasma enoximone 1 h after administration and thereafter may be useful in assessing the haemodynamic activity of the drug. Should this observation also be present in a clinical situation, plasma enoximone measurement might be a valuable tool in management of patients suffering from heart failure.