We have shown that there is a pharmacokinetic interaction between amiodarone and digoxin that results in an increase in steady-state serum and tissue concentrations of digoxin in rats. There is a linear correlation between serum levels of amiodarone, as well as desethylamiodarone, and steady-state serum digoxin levels in rats treated with amiodarone. Since desethylamiodarone is formed in amounts equal to that of the parent compound during chronic amiodarone therapy, we investigated the possibility of desethylamiodarone directly interacting with digoxin in rats. Rats that received digoxin alone showed a serum level of 0.32 +/- 0.08 ng/ml, whereas those that received combination therapies showed a serum level of 3.25 +/- 1.06 ng/ml (p less than 0.001) with desethylamiodarone administration, and 3.00 +/- 0.87 ng/ml with amiodarone administration. Concomitant administration of desethylamiodarone and digoxin increased digoxin concentration in the myocardium by 110% (p less than 0.001), in the skeletal muscle by 208% (p less than 0.001) and in the brain by 110% (p less than 0.001). The corresponding figures for amiodarone-digoxin administration were 94% (p less than 0.001), 172% (p less than 0.001) and 80% (p less than 0.001). The tissue/serum ratios of digoxin concentrations in the myocardium, skeletal muscle, and brain were decreased in the rats that received combination therapies, indicating reduced tissue binding of digoxin. The data indicate that desethylamiodarone interacts with digoxin in a manner similar to that of the parent compound.