The 5-Lipoxygenase Inhibitory Activity of Zileuton in In Vitro and In Vivo Models of Antigen-Induced Airway Anaphylaxis

Summary: Leukotrienes are biologically active lipid mediators capable of producing airway inflammation, hyperresponsiveness and bronchoconstriction. The first enzyme in the metabolic pathway of arachidonic acid leading to the leukotrienes is 5-lipoxygenase (5-LO). A selective and potent 5-LO inhibitor, zileuton (N-1(1-benzob]thien-2-ylethyl)-N-hydroxyurea, A-64077) was evaluated in models of airway anaphylaxis, where leukotrienes are a major component. In vitro, zileuton inhibited antigen-induced contractions of guinea-pig tracheal strips (GPTS) from actively sensitized animals with an IC₅₀ of 6 μM. Similar results were obtained in human bronchial strips passively sensitized to IgE. Zileuton had little or no effect on contractions elicited by acetylcholine, prostaglandin D₂ (PGD₂), or the thromboxane agonist, U-44069. In anesthetized sensitized guinea-pigs pretreated with meclofenamic acid and mepyramine, a single aerosol exposure of antigen produced a substantial decrease in dynamic lung compliance (C_dyn). These profound changes in lung function were dose-dependently inhibited by orally administered zileuton (ED₅₀=12 mg/kg). These results demonstrate that zileuton is a potent, selective inhibitor of in vitro contraction of GPTS and antigen-induced bronchoconstriction in vivo. These data also confirm the participation of 5-LO products in these models of airway anaphylaxis and suggest the usefulness of the guinea-pig for identifying and characterizing the pulmonary effects of 5-LO inhibitors.