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.