METABOLISM AND EXCRETION OF ZAFIRLUKAST IN DOGS, RATS, AND MICE

The in vivo metabolism and excretion of zafirlukast [Accolate; lfonyla minocarbonyl)phenylmethyl]-1-methylindole], a selective peptide leukot riene receptor agonist, were investigated in mice, rats, and dogs. Leu kotrienes are a class of compounds that have been identified as being responsible for the contraction of human airway and lung vascular smoo th muscle. A chemical agent that is effective in blocking the induced constricting actions of leukotrienes could be used to treat inflammato ry processes in the pulmonary system. Zafirlukast has been shown to be clinically efficacious and has been approved for the treatment of ast hma in humans. To determine the metabolic fate of zafirlukast, the rad io-labeled compound was administered orally to mice, rats, and dogs an d iv to rats and dogs. Plasma, urine, and feces samples were collected , assayed for radioactivity, and profiled for metabolites. Nearly all of the [C-14]zafirlukast-derived radioactivity was excreted in the fec es of the test species, indicating biliary clearance as the major rout e of elimination from the systemic circulation. The primary routes of metabolism in all species studied involved hydrolysis of the amide lin kage at the 5-aminoindole position and hydroxylation at one or more si tes. Additional metabolites were formed by N-acetylation (not in dogs) , demethylation of the indole nitrogen, and N-desmethylation. Accolate is a registered trademark, property of Zeneca Ltd.