Digoxin uptake, receptor heterogeneity, and inotropic response in the isolated rat heart: a comprehensive kinetic...

The cardiac pharmacokinetics of digitalis glycosides is not well understood. In the present study, a mechanism-based pharmacokinetic/pharmacodynamic model was developed to describe the uptake kinetics, receptor interaction, and positive inotropic effect of digoxin in the single-pass isolated perfused rat heart. Three doses of digoxin (0.1, 0.2, and 0.3 micromol) were administered to the heart (n = 12) as consecutive 1-min infusions followed by 15-min washout periods. Outflow concentration and left ventricular developed pressure were measured and analyzed by the model. The uptake of digoxin by the heart was limited by capillary permeability with a permeation clearance of 2.35 ml/min/g (about one-third of perfusate flow). Binding kinetics was determined by a mixture of two receptor subtypes, a low-affinity/high-capacity binding site (K(D,1) = 20.9 nmol, 89% of total receptors) and a high-affinity/low-capacity binding site (K(D,2) = 1.5 nmol, 11%). The time course of inotropic response was linked to receptor occupation, with higher efficiency of the high-affinity receptor population. The results suggest that, in the rat heart, consecutive inhibition of first the alpha(2)- and then the alpha(1)-isoform of Na(+)/K(+)-ATPase mediates the positive inotropic effect of digoxin with increasing dosage.