Male Hartley guinea pigs were treated with the enkephalinase inhibitor thiorphan by inhaled or intravenous administration routes and potentiation of substance P-induced airway obstruction examined. Inhaled thiorphan was several thousand times more potent than intravenous thiorphan. The biologic half-life was less than 5 min for aerosolized thiorphan and greater than 20 min after intravenous administration. The very high potency of aerosolized thiorphan may be a result of its direct targeting to enkephalinase concentrated within the airway epithelium. The short duration of action of inhaled thiorphan may reflect its rapid diffusion from the airway surface.