Amiodarone Interaction Time Differences with Warfarin and Digoxin

Background: Amiodarone has pharmacokinetic and pharmacodynamic interactions with various therapeutic agents. The mechanism of interaction between warfarin and amiodarone is the inhibition of warfarin metabolism by amiodarone, and that between digoxin and amiodarone is the inhibition of digoxin transport by amiodarone. Objective: To investigate the pharmacokinetic magnitude of the time differences between amiodarone–warfarin and amiodarone–digoxin interactions. Methods: Amiodarone was administered concomitantly to 79 inpatients who had been receiving fixed-maintenance doses of warfarin or digoxin. Seventy-seven inpatients were prescribed warfarin therapy, and 54 inpatients were prescribed digoxin therapy. To determine serum concentrations of the warfarin enantiomers digoxin, amiodarone, and desethylamiodarone blood samples were obtained with coadministration of amiodarone. Serum S- and R-warfarin, amiodarone, and desethylamiodarone concentrations were measured by HPLC methods, and serum digoxin concentrations were measured by a fluorescence polarization immunoassay. Results: A remarkable decrease of S-warfarin clearance was observed within approximately the first 2 weeks after coadministration of amiodarone. Only a small decrease in R-warfarin clearance was observed. Digoxin clearance was gradually decreased with time, and a good reverse correlation was obtained between amiodarone or desethylamiodarone concentrations and digoxin clearance. Conclusions: Relatively short-term monitoring of warfarin clearance is required when amiodarone is coadministered. Long-term monitoring of digoxin serum amiodarone and desethylamiodarone concentrations is necessary to detect the amiodarone–digoxin interaction.

Digoxin–Itraconazole Interaction: Possible Mechanisms

Objective To document a case in which the administration of itraconazole was associated with an apparent decrease in digoxin clearance, resulting in an increase in the serum digoxin concentration. Case Summary A man receiving digoxin for atrial fibrillation was concurrently treated with itraconazole 200 mg/d for esophageal candidiasis. The estimated urinary digoxin clearance was decreased during this combination therapy. Discussion Digoxin is primarily cleared by the kidneys, and the mechanism of renal clearance involves both glomerular filtration and tubular secretion. We postulate that itraconazole or a metabolite of this compound may have resulted in decreased tubular secretion of digoxin, accounting for decreased urinary digoxin clearance. Conclusions Monitoring of serum digoxin concentrations should be performed if patients taking digoxin are treated with itraconazole. Further investigation is necessary to elucidate the nature of the interaction between digoxin and itraconazole.