Itraconazole Increases Serum Digoxin Concentration

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Abstract
Itraconazole can interact with several drugs by inhibiting their metabolism. Many drugs known to increase serum digoxin concentration are inhibitors of CYP enzymes (e.g. verapamil, diltiazem, amiodarone, cyclosporine). Case reports suggest that itraconazole, added to digoxin therapy, may induce digoxin intoxications; hence we wanted to study their possible interaction. In this two‐phase study ten healthy young volunteers ingested 0.25 mg of digoxin daily for 20 days. Concomitantly, they received either 200 mg itraconazole or placebo orally once daily for 10 days in a double‐blind, randomized, cross‐over study design. Serum concentrations of digoxin and itraconazole were measured (12 hr after administration) on days 1, 2, 4, 6, 8, 10, 11, 12, 14, 16, 18 and 20. Digoxin concentrations were measured by fluorescence polarization immunoassay and confirmed (days 10 and 20) by affinity column‐mediated immunoassay. Itraconazole increased serum digoxin concentration in each of the subjects. On the 10th day of the placebo phase serum digoxin concentration was 1.0±0.1 nmol/1, and on the 10th day of the itraconazole phase 1.8±0.1 nmol/1 (P<0.001). Care should be taken if itraconazole is prescribed to patients using digoxin. The mechanism of the itraconazole‐digoxin interaction is unclear but may be related to CYP3A4‐mediated changes in the pharmacokinetics of digoxin.

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