A General Mechanism for Drug Promiscuity: Studies with Amiodarone and Other Antiarrhythmics

Abstract

Amiodarone is a widely prescribed antiarrhythmic drug used to treat the most prevalent type of arrhythmia - atrial fibrillation (AF). At therapeutic concentrations, amiodarone alters the function of many diverse membrane proteins, which results in complex therapeutic and toxicity profiles. Other antiarrhythmics, such as dronedarone, similarly alter the function of multiple membrane proteins, suggesting that a polypharmacological mechanism may be beneficial for treating AF, but how do these antiarrhythmics regulate diverse membrane proteins at similar concentrations? One possible mechanism is that these molecules regulate membrane protein function by altering the common environment provided by the host lipid bilayer. We took advantage of the gramicidin channels’ sensitivity to changes in bilayer properties to determine whether commonly used antiarrhythmics - amiodarone, dronedarone, propranolol and pindolol, whose pharmacological modes of action range from multi-target to specific - perturb lipid bilayer properties at therapeutic concentrations. Using an ensemble fluorescence assay, we found that amiodarone and dronedarone are potent bilayer modifiers at therapeutic concentrations; propranolol alters bilayer properties only at supratherapeutic concentration, and pindolol has little effect. Using single-channel electrophysiology, we found that amiodarone and dronedarone, but not propranolol or pindolol, increase bilayer elasticity - and that antiarrhythmics change the physical properties of bilayers formed from plasma membrane-like lipid mixtures. The overlap between therapeutic and bilayer-altering concentrations underscores the need to explore bilayer role in therapeutic and toxic effects of antiarrhythmics and other drugs with multi-target effects. The role of polypharmacy in shaping the therapeutic and toxic effects of drugs and the mechanisms involved remain obscure. Direct interactions at similar concentrations imply that functionally and structurally different targets bind a given drug with similar affinity. Our results suggest an alternative, general mechanism for polypharmacy without invoking structural constraints needed for direct drug-protein interactions.