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CHARACTERISTICS OF DIGOXIN INTERACTION WITH QUINIDINE, VERAPAMIL AND AMIODARONE: IN VIVO AND IN VITRO STUDIES

Recently several drugs which are commonly coadministered with digoxin have been shown to cause toxic accumulation of the cardiac glycoside. The interactions with quinidine and verapamil have been attributed in part to reduced renal clearance of digoxin. Since GFR is not altered it appears that renal tubular secretion of digoxin must be inhibited. We studied the effect of amiodarone on serum digoxin concentrations (SDC) in 10 children aged 0.5-18 yrs. There was a 68-800% increase in SDC (P<.025) when both drugs were used in normally recommended doses. Digoxin renal clearance was reduced by 10-44% without corresponding alteration in creatinine clearance. A similar interaction was demonstrated in rats. The addition of amiodarone 30 mg/kg/day caused SDC to increase from 0.68±0.08 (mean ± SD) to 11.22 ± 2.16 ng/ml (P<0.005). Subsequent studies in vitro have examined the effect of quinidine, verapamil, and amiodarone on the uptake of 125I digoxin in renal cortical slices of rats. Therapeutic concentrations of quinidine (5 ug/ml), verapamil (500 ng/ml), and amiodarone(2 ug/ml) caused significant inhibition of digoxin uptake by renal slices (26%, 15%, and 16% respectively) (P<.01). Quinidine and verapamil were shown to cause further dose-dependent inhibition of digoxin uptake. These studies support the suggestion that elevated SDC is induced by reduction in the tubular secretion of digoxin caused by quinidine, verapamil, and amiodarone. Whenever these drugs are added to digoxin therapy, follow-up assessment of SDC is mandatory.