Elucidating mechanisms of amiodarone-induced hepatotoxicity

Amiodarone is widely used to treat irregular heartbeat. As the population ages, both this heart problem and the use of amiodarone are becoming more common. Some patients being treated with amiodarone experience unwanted, and sometimes toxic, effects to their liver. Concern about this potential problem makes using amiodarone more difficult for physicians and denies many patients the benefit of amiodarone. We have observed that amiodarone interferes with the normal processing of fats by the liver and believe this causes its liver effects. We propose using a commonly prescribed drug, fenofibrate, which reduces fat levels, to protect the liver from these potential adverse effects of amiodarone. Our study will explore the effects of amiodarone on the regulation of fat in the liver. Changes in activation of genes that control fat processing will be studied both in mice and in cultures of liver tissue. Fenofibrate will be given to half the mice to determine if adverse effects of amiodarone on the processing of fats and on liver function can be prevented or corrected. To determine if there is benefit to humans, patients who have been taking amiodarone for long enough to demonstrate changes in their liver function will be asked to take fenofibrate for 8 weeks. If their liver function improves, then patients who are about to start amiodarone will be given fenofibrate to determine if unwanted changes in liver function can be prevented. The results of this research may improve the lives of millions of patients taking amiodarone. Avoiding the liver effects of amiodarone would reduce its cost of use and improve the balance of benefit to risk so that physicians would be more comfortable prescribing this valuable drug.