Pharmacokinetics of digoxin in the rat

Previous studies on the pharmacokinetics of 3H-digoxin in the rat have been based on total radioactivity in the plasma, even though the drug is extensively metabolized in this species. A comparison of total radioactivity vs. unchanged drug in rat plasma after administration of 3H-digoxin clearly showed the need to separate digoxin from its metabolites. The pharmacokinetics of digoxin were therefore examined using solvent extraction and thin-layer chromatography to isolate unchanged drug. Digoxin levels after a 1 mg/kg iv dose were measured in the plasma and urine of adult male rats in which the bile duct or the ureters had been ligated, as well as in sham-operated controls. In all cases, digoxin concentrations were best described by a two-compartment open model. Digoxin was rapidly eliminated from the plasma of controls, with a half-life of 2.5 hr, a volume of distribution of 3.6 liter/kg, and a renal clearance somewhat lower than the glomerular filtration rate. No significant change in these parameters was observed in rats with bile duct ligation. The total body clearance of 5.77 ml/min in the controls was reduced by only 10% in the bile duct-ligated rats. In animals with bilateral ureter ligation, the body clearance was reduced by 30% and the plasma half-life of digoxin was increased to 4 hr, although no significant change in the apparent volume of distribution was noted. Approximately 60% of the total body clearance was unaffected by bile duct and ureter ligations, and was assumed to be due to biotransformation. Biliary excretion was found to be important for digoxigenin bisdigitoxoside, inasmuch as rats with bile duct ligation showed elevated metabolite levels in the plasma as well as a 3-fold increase in renal excretion of the bisglycoside.