Pharmacokinetics of Digoxin and Main Metabolites/Derivatives in Healthy Humans

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Abstract
Three healthy, young male volunteers received doses of 0.6 and 1.2 mg of specifically labelled [3H]digoxin each by intravenous (i.v.) bolus injection and oral (p.o.) administration in accordance with a randomized four-way crossover design. Plasma, urine, and feces samples were taken over an interval of 144 h after drug administration. Total radioactivity and individual radioactivity assignable to digoxin and its metabolites were measured. After i.v. administration, the mean ± SD recovery of total radioactivity, as percent of dose, was complete, urine 81.3 ± 2.0% and feces 17.1 ± 2.8%. The mean recovery of digoxin and that of its metabolites in urine was digoxin 75.6 ± 3.0%, dihy-drodigoxin 2.8 ± 1.6%, digoxigenin bisdigitoxoside 1.6 ± 0.1%, and additional metabolites 1.5 ± 0.3%. Judging from the metabolite data in urine and considering the 5% impurity of the administered dose, metabolism of digoxin appeared to be insignificant after i.v. administration. The total and renal clearances of digoxin were, on average, 193 ± 25 ml min-1 and 152 ± 24 ml min-1. The mean steady state volume of distribution was 489 ± 73 L and the mean residence time 41 ± 5 h. For the metabolites dihydrodigoxin and digoxigenin bisdigitoxoside the mean residence times were on average 35 ± 9 h and 53 ± 11 h; the renal clearances were 79 ± 13 ml min-1 and 100 ± 26 ml min-1. After p.o. administration, the mean recovery of total radioactivity, as percent of the dose, was also complete, urine 65.7 ± 1.98% and feces 31.6 ± 7.6%. The mean recovery of digoxin and that of its metabolites, as percent of dose, in urine was digoxin 51.5 ± 11.4%, dihydrodigoxin 4.5 ± 3.9%, digoxigenin bisdigitoxoside 1.9 ± 0.1%, polar metabolites 5.5 ± 3.8%, and additional metabolites 1.3 ± 0.6%. After p.o., as compared to i.v. administration, larger amounts of all the metabolites were formed in accordance with first pass metabolism/degradation. Maximum mean plasma concentrations of 4.3 ± 2.5 ng ml-1 and 9.5 ± 1.1 ng ml-1 for digoxin were observed at 40 ± 10 min after p.o. administration of 0.6 and 1.2 mg of the drug. The mean absolute bioavailability of digoxin from an aqueous solution was 0.67 ± 0.14. Renal clearance and mean oral residence time for digoxin were on average 176 ± 28 ml min-1 and 37 ± 4 h after p.o. administration. For the metabolites, dihydrodigoxin and digoxigenin bisdigitoxoside, renal clearance was on average 86 ± 28 ml min-1 and 105 ± 26 ml min-1 after p.o. administration, confirming the values obtained after i.v. dosing.

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