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Vol. 302, Issue 2, 577-583, August 2002

Digoxin Uptake, Receptor Heterogeneity, and Inotropic Response in the Isolated Rat Heart: A Comprehensive Kinetic Model

Wonku Kang and Michael Weiss

Section of Pharmacokinetics, Department of Pharmacology, Martin Luther University, Halle, Germany

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 alpha 2- and then the alpha 1-isoform of Na+/K+-ATPase mediates the positive inotropic effect of digoxin with increasing dosage.

0022-3565/02/3022-0577$07.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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