Zafirlukast

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Abstract
Zafirlukast is a competitive and selective leukotriene receptor antagonist indicated for the prophylaxis and treatment of chronic asthma. The rationale for the development of leukotriene antagonists was based on in vitro and in vivo data demonstrating the extensive role of the cysteinyl leukotrienes C 4 (LTC4), D4 (LTD4) and E4 (LTE4) in the pathogenesis of asthma. Initial data have demonstrated an improvement in pulmonary function and symptom control and a reduction in the use of short-acting inhaled β2-adrenoceptor agonist therapy in patients with mild to moderate asthma treated with oral zafirlukast at the recommended dosage of 20mg twice daily. Available data also suggest that zafirlukast may significantly reduce the incidence of asthma exacerbations. Data on the comparative efficacy of zafirlukast and existing antiasthma medications are limited. Results from 2 double-blind randomised studies comparing zafirlukast 20mg twice daily with sodium cromoglycate aerosol or dry powder inhalation reported similar efficacy for both drugs. In a comparison with inhaled beclomethasone dipropionate (0.2 to 0.25mg twice daily), improvements in morning peak expiratory flow rate, forced expiratory volume in 1 second and daytime symptom score were significantly less with zafirlukast 20mg twice daily for 6 weeks. However, available data suggest that patient compliance and patient preference may be greater with oral zafirlukast 20mg twice daily than with twice-daily inhaled corticosteroid therapy. Confounding results from 2 studies preclude any clear conclusions regarding the potential steroid-sparing effect of zafirlukast at the recommended dosage of 20mg twice daily. Furthermore, Churg-Strauss syndrome has been reported in 6 patients who were being withdrawn from oral corticosteroid therapy while receiving treatment with oral zafirlukast. It is, therefore, recommended that zafirlukast-treated patients who require a reduction in their oral corticosteroid therapy are closely monitored. Zafirlukast is generally well tolerated. Reports of elevated liver enzymes in patients receiving high dosages of zafirlukast (80mg twice daily) preclude the use of dosages exceeding 40mg twice daily. Careful monitoring is necessary in zafirlukast-treated patients receiving concomitant therapy with drugs such as warfarin, terfenadine and erythromycin because of the potential for drug interactions. Thus, zafirlukast is a potentially useful addition to current antiasthma therapies in patients with mild to moderate asthma. Because zafirlukast is administered orally, it may be particularly beneficial in patients poorly compliant with asthma therapy as a result of poor inhaler technique. Further investigation of the efficacy of zafirlukast is expected to more clearly define its position in the management of asthma. The cysteinyl leukotrienes C4 (LTC4), D4 (LTD4) and E4 (LTE4) are important inflammatory mediators clearly implicated in the pathogenesis of asthma. Zafirlukast is a competitive inhibitor of LTD4 and LTE4. In vitro, zafirlukast antagonised the contractile response of guinea-pig and human airway smooth muscle to LTD4 and LTE4 and competitively inhibited the binding of LTD4 and LTE4 to guinea-pig lung parenchymal membrane. Zafirlukast is selective for cysteinyl leukotriene receptors and demonstrated minimal affinity for a variety of other receptor types, including α- and β-adrenoceptors and muscarinic receptors in isolated tissue. In vivo, zafirlukast antagonised the pulmonary effects of LTC4 and LTD4 and showed potential anti-inflammatory activity in guinea-pig airways with inhibition of the eosinophil chemotactic responses to LTC4, LTD4 and LTE4 and a reduction in LTD4-induced oedema. Bronchial challenge studies in humans have demonstrated the protective efficacy of oral zafirlukast against bronchoconstriction induced by various stimuli, including LTD4, exercise and cold air. Similarly, oral administration of zafirlukast showed protective efficacy relative to placebo against the early and late bronchoconstrictive response to allergen challenge. Zafirlukast has also been reported to reduce cellular infiltration into the airways after allergen challenge. However, further investigations are necessary to clearly determine the extent of the protection conferred by zafirlukast against increased bronchial hyperresponsiveness associated with the late phase response. The pharmacokinetics of zafirlukast are best described by a 2-compartment model. Maximum plasma concentrations (Cmax) were achieved 3 hours after single-dose oral administration of zafirlukast 20 or 40mg to healthy volunteers. The absolute bioavailability of zafirlukast is unknown; however, coadministration with food produced an approximately 40% reduction in the bioavailability of the drug. The drug binds extensively to plasma proteins (>99%), predominantly to albumin and has a mean terminal elimination half-life of approximately 10 hours in both healthy volunteers and patients with asthma. Zafirlukast undergoes extensive hepatic metabolism. Hydroxylation by cytochrome P450 CYP2C9 is the major biotransformation pathway for the drug. The metabolites of zafirlukast appear to contribute little to its overall activity. The faeces are the main route of elimination, with urinary excretion accounting for 100), most of the data from these studies are available in abstract form only. In double-blind randomised studies, oral zafirlukast 20mg twice daily generally produced significantly greater improvements in asthma symptom scores, nocturnal awakenings, forced expiratory volume in 1 second (FEV1) and peak expiratory...