P-glycoprotein as the Mediator of Itraconazole–Digoxin Interaction

To the Editor:

The drug interactions involving azole antifungal agents can be divided into the following categories: 1) additive dangerous interactions, 2) modifications of antifungal kinetics by other drugs, and 3) modifications of the kinetics of other drugs by antifungal agents. Of particular interest in the third category is the interaction between itraconazole and digoxin.[1,2] Only within the past 2 years has the mechanism of this drug interaction been clarified.

Drug Characteristics

Itraconazole is usually well tolerated and is associated with a low incidence of mild and transient adverse reactions.[1-3] Itraconazole has been shown to increase the bioavailability of many drugs, including digoxin. Induction and inhibition of cytochrome P-450 is the mechanism associated with the most serious pharmacokinetic drug interactions of itraconazole; however, in the case of digoxin a mechanism that is not mediated by cytochrome P-450 is of utmost importance.[2,3]

Digoxin is a cardiac glycoside that is fairly well absorbed after oral administration but has an extremely low toxic-to-therapeutic ratio.[3] Digoxin is not extensively metabolized; cytochrome P-450 is not utilized, and liver metabolism is negligible.[3-5] In some individuals, up to 90% of digoxin is excreted by the kidneys as unchanged drug. Current pharmacologic literature recognizes that digoxin is transported by an adenosine triphosphate–dependent efflux pump, P-glycoprotein.[5-7] P-glycoprotein regulates active secretion and passive reabsorption of digoxin by renal tubules.[8,9] Importantly, itraconazole is a known inhibitor of P-glycoprotein, and this leads to potentially serious digoxin serum toxicity.[3,10]

Pharmacologic Interaction

P-glycoprotein is found in the kidneys, liver, small intestine, colon, and adrenal glands.[4,10] There is clear differential expression of P-glycoprotein in normal tissue, and this may suggest that the protein has distinct physiologic roles associated with specialized cell functions, such as those found at the renal tubular level.[10] The reason for this differential expression is unknown. P-glycoprotein is responsible for adenosine triphosphate–dependent efflux of drugs because of plasma membrane channels formed by transmembrane domains.[4,10] Adenosine triphosphate hydrolysis using nucleotide-bound adenosine triphosphate is presumably the energy source. Levels of P-glycoprotein are correlated with the amount of drug transported out of the cell.[10]

Several studies have reported elevated digoxin plasma concentrations after concomitant therapy with itraconazole.[8,9] One study noted a twofold increase in digoxin serum concentration if itraconazole (200 mg/day) was used concomitantly for 10 days. Additionally, case reports have been published citing development of digoxin intoxication with the addition of itraconazole.[9,10] A controlled prospective study by Jalava et al[9] found that mean serum concentrations of digoxin were higher during the itraconazole phase than during the placebo phase. Combination therapy with itraconazole and digoxin increased the area under the concentration-time curve for digoxin up to 68%.[9] In comparing itraconazole with placebo therapy in combination with digoxin, peak concentrations of digoxin increased to 4.7 ± 0.4 nmol/liter from 3.5 ± 0.5 nmol/liter and the half-life of digoxin increased to 29 ± 4 hours from 21 ± 1 hours. Mean renal clearance of digoxin decreased from 2.19 ± 0.11 mL/min/kg to 1.75 ± 0.06 mL/min/kg with itraconazole.[9] Numerous other studies have also found that therapeutic doses of itraconazole increased the area under the concentration-time curve and decreased the renal clearance of digoxin. The bioavailability of digoxin was increased by 30%.[8,9] In addition, it was found that peak concentrations of digoxin were about 30% higher during the itraconazole phase than during the placebo phase.[9]

Conclusion

The recent discovery of P-glycoprotein has been a major advancement in the recognition and understanding of several drug interactions, including the interaction between itraconazole and digoxin. Digoxin is not metabolized; thus renal tubular clearance is the main elimination mechanism. Renal tubular clearance, normally mediated by P-glycoprotein, is effectively inhibited by co-administration of itraconazole, resulting in increased serum digoxin levels and serum digoxin toxicity. Digoxin toxicity may manifest itself as visual changes and disturbances, gastrointestinal distress, bradycardia, and life-threatening arrhythmias. This understanding has been achieved only in the last 2 years. Caution is necessary when digoxin and itraconazole are used concurrently, and the serum digoxin concentration should be monitored closely to avoid potentially serious and harmful consequences.