Interaction between antidepressants and alpha1‐adrenergic receptor antagonists on the binding to alpha1‐acid glycoprotein

α 1‐Receptor antagonists and antidepressant agents are basic (cationic) drugs that are known to bind to α1‐acid glycoprotein (AAG). Since these drugs are frequently co‐administered and since they bind to the same protein, this investigation was designed to evaluate the “in vitro” ability of antidepressants, α1‐receptor antagonists, and propranolol to displace [3H]imipramine and [3H]prazosin from the AAG binding site(s). Equilibrium dialysis was employed. Of the drugs studied, the following order of potency in displacing [3H]prazosin was found: trazodone > prazosin > doxazosin > propranolol > doxepin = amoxapine = trimazosin = amitriptyline > imipramine > nortriptyline = desipramine = nomifensine > bupropion = maprotiline. [3H]lmipramine binding from AAG was displaced with the following potency order: prazosin > imipramine > propranolol > doxazosin > nortriptyline > desipramine > trimazosin. Tricyclic antidepressants produced similar degrees of displacement of both [3H]imipramine and [3H]prazosin from AAG; whereas, α1‐receptor antagonists were more effective displacers of [3H]prazosin than of [3H]imipramine. Furthermore, the demethylated metabolites of imipramine and amitriptyline were less potent displacers than their parent compounds. These results suggest that more than a single binding site may be available for binding to AAG and that hydrophobic bonding is important in the binding of drugs to AAG.