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The Mechanism and Drug Interaction - Amiodarone and Digoxin


  • Digoxin and amiodarone are medications that are commonly used in patients with heart failure and/or atrial/ventricular arrhythmias.
  • The coadministration of amiodarone and digoxin can increase the serum concentrations of digoxin and the risk for digoxin toxicity.
  • Amiodarone increases digoxin concentrations by inhibiting the P-glycoprotein (P-gp) mediated efflux transporter on the apical surface of the intestinal enterocyte, biliary canalicular membrane and the renal tubular cells that facilitates the elimination of digoxin from the body.
  • In addition, amiodarone may also influence serum concentrations by changing the tissue distribution of digoxin.  This effect is dependent on concentrations of amiodarone; the greater the concentration of amiodarone the greater the increase in serum digoxin levels.

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA
Last Reviewed: August 2015


  • The use of the cardiac glycoside, digoxin (Digitek; Lanoxin) is common in the treatment of symptomatic heart failure (HF) as well as in patients with atrial arrhythmias in need ventricular rate control.1,2  While digoxin therapy does offer a number of therapeutic benefits, unfortunately, it has not been proven to reduce mortality in patients with HF.  In addition, it is a narrow therapeutic index medication and thus requires monitoring of serum concentrations to avoid toxicity.   In regard to digoxin use for arrhythmias, some patients will require antiarrhythmic treatment for ventricular arrhythmias in addition to the rate control offered by digoxin; the well known antiarrhythmic medication, amiodarone (Cordarone), is frequently used in these scenarios.2,3  This is an example of a handful of patient populations with multiple cardiovascular problems that are candidates for and often receive treatment with both digoxin and amiodarone.  Unfortunately, there is a clinically relevant drug interaction between the two, wherein amiodarone increases the concentration of digoxin.  If ignored, the patient is at increased risk for digoxin toxicity.4-8   

    What is the mechanism by which amiodarone increases digoxin concentrations?
    First, it is important to recognize the profiles of each of these medications as it relates to their metabolism and elimination.  Digoxin does not undergo any metabolism via the cytochrome P450 (CYP450) enzyme system but rather is a major substrate for the efflux pump known as multidrug resistance-associated protein (MDR) or more commonly called, P-glycoprotein (P-gp).9,10  P-glycoprotein is normally found on the epithelial and endothelial surfaces in the gastrointestinal tract, blood brain barrier, liver and kidney and is involved in moving drug from the inside of the cell to the outside of the cell (i.e., efflux).11  Amiodarone, on the other hand, is metabolized to an active metabolite, desethylamiodarone (DEA), mainly by CP450 2C8 and 3A4.  In addition, amiodarone is also a known inhibitor of both CYP3A4 and P-gp.12  Therefore, since digoxin is a major substrate for P-gp and amiodarone is a known inhibitor of P-gp, the primary mechanism by which amiodarone increases digoxin concentrations is through its ability to inhibit the efflux of digoxin (gastrointestinal elimination and renal tubular secretion) from the body.13   It does appear that DEA (rather than the parent drug, amiodarone) is the primary contributor of inhibition to the P-gp mediated elimination of digoxin.13   A second mechanism that may also be contributing to the changes in serum concentrations is a redistribution of digoxin from tissue to serum.8,14,15  This appears to be based on the concentrations of amiodarone present; as amiodarone concentrations increase so do serum digoxin concentrations.8  This change in tissue distribution can affect the interpretation of serum digoxin levels.

    As a result of amiodarone's inhibition of P-gp, the gastrointestinal (which includes biliary) and renal clearance of digoxin is decreased.   Amiodarone's inhibition of P-gp on the apical side of the enterocyte and on the bile canalicular membrane results in an overall increase in bioavailability of digoxin.3  However, it has been suggested that the formulation of digoxin used may also influence the scale of this drug interaction.  For example, digoxin in the form of a solution may be less of a concern due to the P-gp liability in the gastrointestinal tract.10 Lastly, serum concentrations of digoxin appear to fluctuate based on the concentrations of amiodarone, thus adding another factor that needs to be taken into consideration when interpreting the concentrations of digoxin.  


    1. Jessup M, Abraham WT, Casey DE et al.  2009 focused update: ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation.  Circulation  2009;119:1977-2016.
    2. Fuster V, Ryden LE, Cannom DS et al.  ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients with Atrial Fibrillation):  developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society.  Circulation  2006;114:e257-354.
    3. Zipes DP, Camm AJ, Borggrefe M et al.  ACC/AHA/ESC 2006 Guidelines for Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: a report of the American College of Cardiology/American Heart Association task Force and the European Society of Cardiology Committee for Practice Guidelines (writing committee to develop Guidelines for Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society.  Circulation  2006;114:e385-484.
    4. Moysey JO, Jaggarao NS, Grundy EN et al.  Amiodarone increases plasma digoxin concentrations.  Br Med J  1981;282:272.  
    5. Nademanee K, Kannan R, Hendrickson J et al.  Amiodarone-digoxin interaction: clinical significance, time course of development, potential pharmacokinetic mechanisms and therapeutic implications.  J Am Coll Cardiol  1984;4:111-6.
    6. Fenster PE, White NE Jr, Hanson CD.  Pharmacokinetic evaluation of the digoxin-amiodarone interaction.  J Am Coll Cardiol  1985;5:108-12.
    7. Oetgen WJ, Sobol SM, Tri TB et al.  Amiodarone-digoxin interaction.  Clinical and experimental observations.  Chest  1984;86:75-9.
    8. DeVores KJ, Hobbs RA.  Plasma digoxin concentration fluctuations associated with timing of plasma sampling and amiodarone administration.  Pharmacotherapy  2007;27:472-475.
    9. Cavet ME, West M, Simmons NL.  Transport and epithelial secretion of cardiac glycoside, digoxin, by human intestinal epithelial (Caco-2) cells.  Br J Pharmacol  1996;118:1389-1396.
    10. Fenner KS, Troutman MD, Kempshall S et al.  Drug-drug interactions mediated through P-glycoprotein: clinical relevance and in vitro-in-vivo correlation using digoxin as a probe drug.  Clin Pharm Therap  2009;85:173-181.
    11. Thiebaut F, Tsuruo T, Hamada H et al.  Immunohistochemical localization in normal tissues of different epitopes in the multidrug transport protein P170: evidence for localization in brain capillaries and cross reactivity of one antiobody with a muscle protein.  J Histochem Cytochem  1989;37:159-164.
    12. Amiodarone (Cordarone) product package insert.  Wyeth Pharmaceuticals Inc.  Philadelphia, PA.  November 2008.
    13. Kakumoto M, Takara K, Sakaeda T et al.  MDR1-mediated interaction of digoxin with antiarrhythmic or antianginal drugs.  Biol Pharm Bull  2002;25:1604-7.
    14. Venkatesh N, Al-Sarraf L, Kannan R, Singh BN.  Tissue-serum correlates of digoxin-amiodarone pharmacokinetic interaction in rats: evidence for selective tissue accumulation and reduced tissue binding.  J Pharm Sci 1985;74:1067-70.
    15. Venkatesh N, Singh B, Al-Sarraf L, Kannan R.  Digoxin-desethylamiodarone interaction in the rat: comparison with the effects of amiodarone.  J Cardiovasc Pharmacol  1986;8:309-13.

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MESH Terms & Keywords

  • Digoxin Amiodarone Drug Interaction