TY - JOUR T1 - Digoxin Uptake, Receptor Heterogeneity, and Inotropic Response in the Isolated Rat Heart: A Comprehensive Kinetic Model JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 577 LP - 583 DO - 10.1124/jpet.302.2.577 VL - 302 IS - 2 AU - Wonku Kang AU - Michael Weiss Y1 - 2002/08/01 UR - http://jpet.aspetjournals.org/content/302/2/577.abstract N2 - 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 μmol) 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 (KD,1 = 20.9 nmol, 89% of total receptors) and a high-affinity/low-capacity binding site (KD,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 α2- and then the α1-isoform of Na+/K+-ATPase mediates the positive inotropic effect of digoxin with increasing dosage. The American Society for Pharmacology and Experimental Therapeutics ER -