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Amiodarone-digoxin interaction in rats. A reduction in hepatic uptake.
C Lambert1, D Lamontagne, H Hottlet
1Research Center, Hôpital du Sacré-Coeur de Montréal, Québec, Canada.
Drug Metabolism and Disposition: the Biological Fate of Chemicals
|November 1, 1989
Summary
Amiodarone significantly increases digoxin levels by inhibiting its uptake into liver cells, not by affecting metabolism or causing liver damage. This finding explains a critical drug interaction mechanism.
Area of Science:
- Pharmacology
- Hepatology
- Drug Interactions
Background:
- The amiodarone-digoxin interaction leads to elevated digoxin serum concentrations.
- The underlying mechanism for this drug interaction remains unclear.
Purpose of the Study:
- To investigate the influence of amiodarone on the hepatic extraction of digoxin in rats.
- To elucidate the mechanism behind the amiodarone-digoxin drug interaction.
Main Methods:
- Isolated-perfused rat livers were used to determine digoxin hepatic extraction coefficients.
- Rats were treated with varying doses of amiodarone (25, 50, 100 mg/kg/day for 5 days).
- High-performance liquid chromatography (HPLC) analyzed hepatic effluent for digoxin and metabolites.
Main Results:
- A dose-dependent reduction in digoxin hepatic extraction coefficients and clearances was observed with amiodarone treatment.
- No digoxin metabolites were detected in the hepatic effluent, indicating metabolism was not affected.
- Amiodarone administration did not cause significant hepatocyte damage, as indicated by normal liver enzyme levels and microscopic examination.
Conclusions:
- Amiodarone increases digoxin serum concentrations primarily by inhibiting the uptake of digoxin into hepatocytes.
- The mechanism does not involve altered digoxin metabolism or direct hepatotoxicity.