Desethylamiodarone is a noncompetitive inhibitor of the binding of thyroid hormone to the thyroid hormone beta 1-receptor protein.

It has been hypothesized that amiodarone (A), a potent antiarrythmic and antianginal drug, induces a local hypothyroid-like condition in extrathyroidal tissues. This might be related to competitive antagonism of A for the thyroid hormone receptor reported in some studies but denied in others. These conflicting results are presumably due to the poor solubility of A in a hydrophilic environment. We, therefore, studied the effect of the drug and its major metabolite, desethylamiodarone (DEA), on the in vitro binding of thyroid hormone (T3) to its receptor protein using the rat beta 1-thyroid hormone receptor expressed in Escherichia coli. A and DEA stayed in solution up to 10(-4) M when 0.05% Triton X-100 was added to the incubation buffer, as evidenced by a recovery of 80-90% for both chemicals, as measured by HPLC. DEA, but not A, had a clear inhibitory effect on the binding of T3 to its receptor (IC50, 1-3 x 10(-5) M). Scatchard analysis in the presence of DEA demonstrated a dose-dependent decrease in the Ka as well as the maximum binding capacity. Lineweaver-Burke analysis indicated noncompetitive inhibition. Plots of the intercepts of Lineweaver-Burke plots vs. DEA concentration were linear (y = 0.334 + 0.098x), giving a Ki of 30 microM for the binding of DEA to the occupied receptor. Plots of the slopes vs. inhibitor concentration were parabolic (y = 3.01 + 0.06x + 0.16x2), indicating a progressively stronger effect of DEA on the unoccupied receptor as concentrations rise. This preference for the unoccupied receptor is reflected in experiments that show a progressive loss of T3 binding when the receptor was incubated for increasing periods with DEA before adding T3. We conclude that DEA is a noncompetitive inhibitor of the binding of T3 to the beta 1-thyroid hormone receptor protein, interacting preferably with the unoccupied T3 receptor.