Abstract

The interaction amiodarone-digoxin results in a marked increase in the digoxin serum concentrations. The mechanism of this interaction is still unexplained. The influence of amiodarone on digoxin hepatic extraction in rats was investigated. The digoxin hepatic extraction coefficients were determined using the isolated-perfused livers of control and amiodarone-treated (25, 50, and 100 mg/kg/day for 5 days) rats. When plotted as a function of time, an inverse relationship between the extraction coefficients and the dose of amiodarone was evident. Significant dose-related reductions were observed in hepatic clearances calculated after 16 and 20 min of digoxin infusion when steady state was achieved. Analysis of the hepatic effluent by HPLC revealed only digoxin in the effluent of both control and amiodarone-treated rats; no metabolites were detected. Using liver homogenates, no differences were found in the ability of control or amiodarone-treated (50 mg/kg/day for 5 days) rats to metabolize digoxin. These changes occur without significant lesion of the hepatocytes, inasmuch as the serum concentrations of glutamic-pyruvic and glutamic-oxaloacetic transaminases were not affected by the administration of amiodarone (50 or 100 mg/kg/day for 5 days). Furthermore, a microscopic study of the hepatocytes revealed light cytoplasmic vacuolization, normal Kupffer cells, and no evidence of macrophage proliferation. It was concluded that amiodarone increases digoxin serum concentrations by inhibiting its uptake into the hepatocytes.