A PROPOSED MECHANISM FOR P-AMINOCLONIDINE ALLERGENICITY BASED ON ITS RELATIVE OXIDATIVE LABILITY

p-Aminoclonidine (apraclonidine) is a selective alpha(2) adrenergic ag onist used to reduce intraocular pressure in the treatment of glaucoma . Use of apraclonidine is frequently associated with severe local alle rgic effects which warrant discontinuation of the drug in affected pat ients. We have assessed the oxidative lability of apraclonidine relati ve to a panel of adrenergic agonists and/or known allergens: amodiaqui ne, epinephrine, clonidine, and brimonidine. These compounds were comp ared by their electrochemical potentials as well as their oxidative la bility in the presence of several oxidative enzyme systems (i.e., hors eradish peroxidase, lactoperoxidase, myeloperoxidase, and diamine oxid ase). The half-lives for enzymatic oxidation of these compounds were f ound to parallel the electrochemical oxidation potentials in the order : amodiaquine similar to epinephrine < apraclonidine much less than cl onidine similar to brimonidine. The production of a reactive electroph ilic intermediate of apraclonidine was demonstrated through the format ion of two glutathione apraclonidine adducts from the horseradish pero xidase/H2O2-mediated oxidation of apraclonidine in the presence of glu tathione. A mechanism for apraclonidine allergenicity in vivo is propo sed wherein apraclonidine is bioactivated through oxidation to the bis -iminoquinone followed by protein conjugation to form an apraclonidine -protein hapten that elicits the immune response.