The initial (distribution) half-life (t½) of digoxin is about 30 minutes after IV administration in both anephric patients and patients with normal renal function. In patients with normal renal function, digoxin has an elimination t½ of 34-44 hours. The elimination t½ of digoxin is prolonged in patients with renal failure; in anephric patients the elimination t½ is about 4.5 days or longer. The elimination t½ is decreased in patients with acute digoxin overdosage. Elimination t½ of digoxin is prolonged in hypothyroid patients and decreased in hyperthyroid patients. In patients with biliary fistulas, plasma t½ is unchanged. In undigitalized patients, institution of fixed daily digoxin maintenance therapy without an initial loading dose results in steady-state plasma concentrations after 4-5 elimination t½s (about 7 days in patients with normal renal function).
In most patients, only small amounts of digoxin are metabolized, but the extent of metabolism is variable and may be substantial in some patients. Some metabolism presumably occurs in the liver, but digoxin is also apparently metabolized by bacteria within the lumen of the large intestine following oral administration and possibly after biliary elimination following parenteral administration. The extent of metabolism by bacteria in the large intestine following oral administration appears to vary inversely with the bioavailability of the preparation. Digoxin undergoes stepwise cleavage of the sugar moieties to form digoxigenin-bisdigitoxoside, digoxigenin-monodigitoxoside, and digoxigenin; these metabolites have progressively decreasing cardioactivity. Digoxigenin is subsequently epimerized and/or conjugated to form cardioinactive compounds. Digoxin also undergoes reduction of the lactone ring to form dihydrodigoxin, which also undergoes stepwise cleavage of the sugar moieties to form dihydrodigoxigenin-bisdigitoxoside, dihydrodigoxigenin-monodigitoxoside, and dihydrodigoxigenin; the reduced metabolites are essentially cardioinactive. Some patients may form substantial amounts of the reduced metabolites; data suggest that, in about 10% of patients receiving digoxin, about 40% or more of the drug excreted in urine will consist of reduced metabolites. Because of the rapid and enhanced absorption, use of liquid-filled capsules may minimize the formation of reduced metabolites in such patients. In patients who form substantial amounts of reduced metabolites, alteration of enteric bacterial flora by some anti-infective agents (e.g., erythromycin) may result in a substantial change in digitalization.
Digoxin is excreted mainly in urine, principally as unchanged drug, by glomerular filtration and active tubular secretion; tubular reabsorption may also occur. In most patients, small amounts of reduced metabolites are also excreted in urine, but in some patients, about 40% or more of the drug excreted in urine consists of reduced metabolites. In healthy individuals, about 50-70% of an IV dose of digoxin is excreted unchanged in urine. Small amounts of cardioactive metabolites and unchanged digoxin are also excreted in the bile and feces. In patients with renal failure, fecal excretion of digoxin and its metabolites may be increased.
The amount of digoxin eliminated daily is a function of the amount of drug in the body. About 30% of the total amount of digoxin in the body is eliminated daily in patients with normal renal function; anuric patients eliminate approximately 14% of the total daily. The percentage of digoxin eliminated from the body daily can be estimated by the following equation:daily % loss = 14 + (creatinine clearance [in mL/minute] / 5)
This method should be used cautiously, since creatinine clearance does not accurately measure renal or total body clearance of digoxin. Increased urinary output apparently does not increase digoxin excretion. Digoxin metabolism and excretion are apparently not altered in patients with liver disease and normal renal function.