RT Journal Article SR Electronic T1 Metabolism and Excretion of Zafirlukast in Dogs, Rats, and Mice JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 1069 OP 1076 VO 26 IS 11 A1 R. D. Savidge A1 K. H. Bui A1 B. K. Birmingham A1 J. L. Morse A1 R. C. Spreen YR 1998 UL http://dmd.aspetjournals.org/content/26/11/1069.abstract AB The in vivo metabolism and excretion of zafirlukast [Accolate; 4,5-cyclopentoxycarbonylamino-3-[(2-methoxy-4,2- methylphenylsulfonylaminocarbonyl)phenylmethyl]-1-methylindole], a selective peptide leukotriene receptor agonist, were investigated in mice, rats, and dogs. Leukotrienes are a class of compounds that have been identified as being responsible for the contraction of human airway and lung vascular smooth muscle. A chemical agent that is effective in blocking the induced constricting actions of leukotrienes could be used to treat inflammatory processes in the pulmonary system. Zafirlukast has been shown to be clinically efficacious and has been approved for the treatment of asthma in humans. To determine the metabolic fate of zafirlukast, the radiolabeled compound was administered orally to mice, rats, and dogs and iv to rats and dogs. Plasma, urine, and feces samples were collected, assayed for radioactivity, and profiled for metabolites. Nearly all of the [14C]zafirlukast-derived radioactivity was excreted in the feces of the test species, indicating biliary clearance as the major route of elimination from the systemic circulation. The primary routes of metabolism in all species studied involved hydrolysis of the amide linkage at the 5-aminoindole position and hydroxylation at one or more sites. Additional metabolites were formed byN-acetylation (not in dogs), demethylation of the indole nitrogen, and N-desmethylation. Accolate is a registered trademark, property of Zeneca Ltd. The American Society for Pharmacology and Experimental Therapeutics