The impact of metabolic disorders on the therapeutic efficacy and toxicity of amiodarone: mechanisms and management strategies

Amiodarone is one of the most effective and commonly prescribed class III antiarrhythmic agents. However, its pharmacokinetics may be impaired and toxicity may be aggravated by metabolic disorders. The review presents data showing that dyslipidemia, obesity, and type 2 diabetes mellitus significantly affect pharmacokinetics, pharmacodynamics and toxic profile of amiodarone. These conditions alter the drug’s binding to lipoproteins, the activity of cytochrome P450- dependent monooxygenases and tissue distribution, thereby increasing the risk of accumulation and toxic effects. Chronic heart failure further impairs drug metabolism and contributes to multisystem toxicity. The current clinical guidelines do not adequately address these critical aspects. Therefore, more rigorous monitoring of these patients and their plasma drug concentration (on individual basis) is suggested, along with a generally more cautious approach to amiodarone use. Future perspectives include prospective clinical trials on amiodarone, physiologically based pharmacokinetic modeling for personalized dosing, based on body mass index, lipid profile, and comorbidities, pharmacogenomic studies (cytochrome P450 polymorphisms), as well as biomarker discovery for drug toxicity prediction.

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