A new approach: Animal and clinical pharmacology of zafirlukast (Accolate®, ICI-204,219)

Zafirlukast (Accolate®, ICI-204,219) is a potent and selective antagonist of cysteinyl leukotriene receptors in several animal species, as well as in pulmonary tissues from humans. In animals, it inhibits leukotriene- and antigen-induced bronchoconstriction, plasma extravasation in pulmonary tissue, and eosinophil accumulation in lungs, and attenuates late phase bronchoconstriction and airway hyperresponsiveness following antigen inhalation. In humans, zafirlukast is well absorbed following oral administration, with peak plasma concentrations achieved approximately 3 h postdose. The half-life of zafirlukast is 10 h, with steady-state concentrations achieved within 3 days of twice daily dosing. Orally administered zafirlukast decreases the bronchoconstrictor effect of inhaled leukotriene D₄ (LTD₄) in a dose-dependent manner, and reduces the bronchoconstriction induced by cold air, sulphur dioxide, platelet-activating factor or exercise in asthmatic patients. Compared with placebo, zafirlukast reduced allergen-induced bronchoconstriction and the associated bronchial hyperresponsiveness. The action of zafirlukast on the airways has characteristic suggesting it is an antiinflammatory drug. In an initial placebo-controlled study, zafirlukast significantly reduced the cellular infiltrate 48 h after segmental allergen challenge, and reduced superoxide production from purified alveolar macrophages and tumour necrosis factor (TNF)-α concentrations in bronchoalveolar lavage fluid. The pharmacological profile of zafirlukast indicates that it prevents the airflow restriction resulting from bron-choconstriction and other inflammatory changes in the airways and, thus, could be useful as a preventative drug in the management of asthma.