Leukotrienes have been proposed as important chemical mediators of allergic inflammation, and there is evidence that azelastine (Astelin) can affect leukotriene-mediated allergic responses. One of the enzymes required for the synthesis of leukotrienes from arachidonic acid is 5-lipoxygenase (5-LO). Azelastine, which is preferentially taken up by the lung and alveolar macrophages, inhibits leukotriene generation in the airways. This property of azelastine may contribute to its therapeutic efficacy in the long-term treatment and management of rhinitis and asthma. Azelastine does not directly inhibit 5-LO in disrupted murine peritoneal cells and rat basophilic leukemia cells (IC50 > 100 microM), but does have moderate 5-LO inhibitory activity in intact murine peritoneal cells (IC50 = 10 microM, 5 min) and in chopped guinea pig liver (IC50 = 14 microM, 2 hr). The generation and release of leukotrienes in human neutrophils and eosinophils is also inhibited by azelastine (IC50 = 0.9-1.1 microM). Furthermore, azelastine is a potent and specific inhibitor of allergen-induced generation of leukotrienes in the nose of the guinea pig (ID50 < 100 micrograms/kg, im, 20 min) as well as in patients with rhinitis (2 mg, po, 4 hr; ID50 < 30 micrograms/kg). Azelastine also inhibits allergen-induced, leukotriene-mediated, pyrilamine-resistant bronchoconstriction (oral ID50 = 60 micrograms/kg, 2 hr and 120 micrograms/kg, 24 hr). This profile suggests that azelastine may be a novel inhibitor of Ca(2+)-dependent translocation of 5-lipoxygenase from cytosol to the nuclear envelope or a FLAP inhibitor rather than a direct 5-LO inhibitor.