Abstract
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.
Footnotes
-
This work was partially supported by Deutsche Forschungsgemeinschaft (GRK 134/1-96).
- Abbreviations:
- PK, pharmacokinetic(s)
- PD
- pharmacodynamic(s)
- LV
- left ventricular
- LVDP, LV developed pressure
- DMSO, dimethyl sulfoxide
- Received December 28, 2001.
- Accepted April 19, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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