Dronedarone and Vitamin K Antagonists: A Review of Drug-drug Interactions

Shailesh C. Shirolkar, MD; Mona Fiuzat, PharmD; Richard C. Becker, MD


American Heart Journal. 2010;160(4):577-582. 

In This Article

Pharmacokinetics and Metabolism

Warfarin is a racemic mixture of 2 optically active isomers (R and S enantiomers), is highly water soluble, rapidly absorbed, has high bioavailability, and has a half-life of 36 to 42 hours. It reaches maximal blood concentrations in approximately 90 minutes after oral administration and circulates bound mainly to albumin. It accumulates in the liver where the S enantiomer of warfarin is metabolized primarily by the cytochrome P450 (CYP) 2C9 enzyme of the cytochrome P450 system, whereas the R enantiomer is metabolized primarily by CYP1A2 and CYP3A4 enzymes. The S enantiomer of warfarin is 2.7 to 3.8 times more potent than the R enantiomer and has a half life of 29 hours as compared to 45 hours for the R enantiomer.[11,12]

When administered orally, amiodarone has a bioavailability of approximately 50%. Maximum plasma concentrations are seen in 3 to 7 hours after oral ingestion. Onset of action may occur in 2 to 3 days but usually takes 1 to 3 weeks. Amiodarone has a very large volume of distribution, and it extensively accumulates in adipose tissue and organs such as the liver, lung, and spleen. Desethylamiodarone (DEA) is a major metabolite of amiodarone, and it accumulates in almost all tissues. Studies of DEA in animals show that it has electrophysiologic and antiarrhythmic effects similar to amiodarone. Although data on the activity of DEA is lacking in humans, Vaughan-Williams class III effects correlate more closely with DEA accumulation than with amiodarone accumulation. The elimination of amiodarone is primarily by hepatic metabolism and biliary excretion with minimal excretion in urine.[13]

When oral amiodarone therapy is discontinued, biphasic elimination is observed. Initial one-half reduction of plasma levels occurs in 2.5 to 10 days followed by a slower terminal elimination phase that ranges from 26 to 107 days (mean 53 days). The mean plasma elimination half-life of DEA is approximately 61 days. It seems that initial elimination of amiodarone occurs from well-perfused tissue followed by slow elimination from poorly perfused tissue. Amiodarone is metabolized to DEA by CYP3A4 and CYP2C8. CYP1A2, CYP2C19, and CYP2D6 enzymes have minor contributions to amiodarone metabolism.[14] Amiodarone and DEA inhibit the activity of certain cytochrome P450 enzymes. In a study by Ohyama et al,[15] amiodarone inhibited CYP2C9, CYP2D6, and CYP3A4, whereas DEA inhibited CYP1A1, CYP1A2, CYP3A4, CYP2C9, CYP2C19, and CYP2D6. The inhibition of CYP activities by DEA exerts more potent effects when compared to amiodarone. The inhibition of CYP2C9 by DEA and amiodarone is the primary cause of the drug-drug interaction seen with warfarin.[16]

Dronedarone is a synthetic derivative of amiodarone. Its structure lacks the iodine moieties but has a methyl sulfonamide group. After oral intake, dronedarone is well absorbed (70%-94%) with steady state plasma concentrations being reached in approximately 1 week. The elimination half-life is approximately 30 hours, and clearance is predominantly in feces.[17–19] CYP3A4 is responsible for the metabolism of dronedarone. Dronedarone undergoes N-debutylation to form SR35021 (active N-debutyl metabolite), oxidative deamination to form the inactive propanoic acid metabolite (SR90154), and direct oxidation. Thirty uncharacterized metabolites are formed when above metabolites undergo further metabolism. SR35021 is 1/10 to 1/3 as potent as dronedarone. In a study with 14C-labeled orally administered dronedarone, approximately 6% and 84% of the labeled dose was excreted in urine and feces, respectively, primarily as metabolites. Although in vivo data are lacking, dronedarone is a CYP3A4 substrate, and a moderate inhibitor of CYP3A4. Dronedarone does not significantly inhibit CYP1A2, CYP2C9, CYP2C19, and CYP2C8.[20,21]


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