Abstract 12150: Dronedarone is a Potent Cardiac and Hepatic CPT-1 Inhibitor

Purpose: Dronedarone was developed on the basis that it would represent a class III anti-arrhythmic devoid of “amiodarone-like” adverse effects. Indeed, photosensitization and iodine-related thyroid toxicity do not occur with dronedarone. However, a number of other adverse effects have emerged. We tested the hypothesis that, like amiodarone, dronedarone modifies cellular metabolism by inhibiting mitochondrial fatty acid uptake via the carnitine shuttle. Methods: We compared the efficacy of dronedarone as an inhibitor of cardiac and hepatic carnitine palmitoyl transferase-1 (CPT-1) with that of the known CPT-1 inhibitors perhexiline and amiodarone. Male 6-week old Sprague-Dawley rats were euthanized under 2% isoflurane. Hearts and livers were rapidly removed, homogenised and placed on ice. CPT-1 activity was measured by the formation of palmitoyl-carnitine, as previously described1. Samples were ultracentrifuged and supernatants were injected for detection by liquid-chromatography/mass-spectometry. Dronedarone (5, 10, 50, 100 and 500μM) was compared to amiodarone (100, 200 and 500μM), perhexiline (20, 50, 100, 150 and 200μM), and the physiological inhibitor of CPT-1, malonyl-CoA (1μM). Concentration-response curves were expressed via log(inhibitor) vs normalized responses. Results: (1) Malonyl-CoA inhibited CPT-1 by >90% in both heart and liver, while perhexiline was more potent than amiodarone as CPT-1 inhibitor (Table). (2) Dronedarone was equipotent (IC50 approximately 40μM) in both heart and liver, and approximately 3-fold more potent than amiodarone. Conclusion: Dronedarone, like amiodarone and perhexiline, inhibits cardiac and hepatic CPT-1. This has potential advantages regarding haemodynamic stability in atrial fibrillation, but may predispose to eventual hepato- and cardiotoxic effects. Ref: 1. Kennedy JA, Unger S, Horowitz JD. Biochem Pharmacology 1996, 52, p273-280.