Amiodarone and its metabolite desethylamiodarone interact directly with calmodulin, altering its active conformation and inhibiting its biological activity, which may explain some of the side effects of amiodarone therapy.
Abstract: Long‐term amiodarone therapy is invariably associated with some side effects. Although its mechanism of action, as an antiarrhythmic drug is well understood, the side effect profile of amiodarone is not yet established. To determine possible mechanisms, the interaction of amiodarone and its major metabolite desethylamiodarone with calmodulin was investigated, since calmodulin is known to regulate Ca 2+ transport, cell proliferation and the enzymes involved in signal transduction and nucleotide metabolism. The interaction between the drugs and calmodulin was studied by monitoring intrinsic tyrosine fluorescence of calmodulin and by using a fluorescent probe, N‐phenyl‐1‐naphthylamine (NPN). 14 C‐Chlorpromazine displacement studies were conducted to differentiate the specific binding sites. The effect on the biological activity of calmodulin was determined with calmodulin dependent phosphodiesterase and Ca 2+ ‐ATPase. The dansyl calmodulin was used as fluorescent probe to study the effect of these drugs on complex formation between calmodulin and phosphodiesterase. Both amiodarone and desethylamiodarone decreased tyrosine fluorescence of calmodulin with IC50 of 4.9 and 4.4 μM respectively and these interactions were Ca 2+ ‐dependent. NPN fluorescence was also affected in a concentration dependent manner. These drugs also displaced bound 14 C‐chlorpromazine from calmodulin and the effect was biphasic. However, desethylamiodarone was more potent than amiodarone. The binding of 3 H‐amiodarone to calmodulin was modified by a variety of compounds, one class of compounds decreased and the other increased 3 H‐amiodarone binding to calmodulin. Only, desethylamiodarone inhibited the phosphodiesterase activation by calmodulin with IC50 of 13.2 μM without changing the basal enzyme. Desethylamiodarone was more potent in altering calmodulin‐dependent synaptic membrane Ca 2+ ‐ATPase activity than amiodarone. Desethylamiodarone also inhibited Ca 2+ ‐dependent complex formation between dansyl calmodulin and phosphodiesterase more effectively than amiodarone. These data suggest that amiodarone and desethylamiodarone interact with calmodulin at specific sites altering its active conformation and some of the side effects associated with amiodarone therapy may be due to this interaction with calmodulin.
Vig et al. (Tue,) studied this question.