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.

The Influence of Diltiazem Hydrochloride on Trough Serum Digoxin Concentrations

A significant drug interaction between verapamil and digoxin, resulting in elevated serum digoxin concentrations, has been well documented in the medical literature. However, a similar interaction between digoxin and the calcium channel blockers nifedipine and diltiazem has not been conclusively established. This study investigated the influence of diltiazem hydrochloride on trough serum concentrations of concurrently administered digoxin in eight healthy volunteers. During the control phase of the study, volunteers were administered digoxin 0.25 mg/d for 13 days, and subsequently judged to be at steady state by serial determinations of digoxin serum concentrations. Twenty-four hour urine collections were done for creatinine clearance and urinary digoxin clearance determinations. Phase II of the study involved the addition of diltiazem hydrochloride 30 mg qid to the on-going, daily regimen of digoxin. After 14 days of concomitant therapy, steady-state trough digoxin concentrations were again determined, as well as creatinine clearances and urinary digoxin clearances. This investigation demonstrates that concomitant administration of diltiazem hydrochloride with digoxin results in significantly elevated steady-state trough digoxin concentrations (0.32 ± 0.07 ng/ml increasing to 0.48 ± 0.06 ng/ml, p<0.01). Urinary digoxin clearance decreased from 223.5 ± 35.7 ml/min to 153.4 ± 17.5 ml/min (p<0.05). Creatinine clearances were unaltered. A review of the current literature on this topic is included.

Cross reactivity of the EMIT digoxin assay with digoxin metabolites, and validation of the method for measurement of urinary digoxin.

In evaluating the EMIT (Syva Co.) digoxin assay, we found no cross reactivity between dihydrodigoxin, the major digoxin metabolite, and the EMIT digoxin antibody from two different lots. However, the antibody does cross react, essentially completely, with the digoxin hydrolysis metabolites digoxigenin, digoxigenin mono-digitoxide, and digoxigenin bis-digitoxide. The EMIT method can be used to measure digoxin in urine diluted at least 50- to 100-fold with digoxin-free human plasma; the inter-assay coefficient of variation of this assay is 6%. In addition, we validated the manual EMIT serum digoxin assay, using external ("TRI-rac") quality controls.