Ionization state of amiodarone mediates its mode of interaction with lipid bilayers

Amiodarone is a potent antianginal and antiarrhythmic drug which affects the lipid dynamics. The influence of amiodarone ionization on the lipid transition temperature and enthalpy associated to the liquid crystalline to gel state transition was studied in multilamellar vesicles (MLV) of dipalmitoylphosphatidylcholine (DPPC) by differential scanning measurements (DSC) at different pH. These data were correlated with the calculated number of charged amiodarone molecules inserted into the lipid vesicles. The procedure of calculation requires the knowledge of the intrinsic ionization constant of amiodarone and the area occupied per amiodarone molecule in the close packed state; it can be applied successfully to water insoluble amphiphilic molecules. Only the ionized form of amiodarone molecule destabilizes the lipid matrix organisation whereas no effect was observed with the uncharged form. This destabilizing effect could be explained in terms of a modification of the drug structure induced by its ionization state or in terms of its distribution in the lipid matrix, as an isolated molecule or assembled in clusters depending on its ionization state.