Disposition and metabolism of cetrorelix, a potent luteinizing hormone-releasing hormone antagonist, in rats and dogs

Disposition and metabolism of cetrorelix was studied in intact and bile duc t-cannulated rats and dogs after s.c. injection. An s.c. dose of 0.1 mg/ kg [C-14]cetrorelix was rapidly and completely absorbed in rats. T-max in pla sma and most tissues was at 2 h. Radioactivity at the injection site in rat s declined to 10% by 24 h. The extent of C-14 absorption in rats calculated from excretion until 264 h was 94%. Exposure of the target organ pituitary gland was demonstrated with a time course similar to plasma but on a highe r level. Rats excreted 69.6% of radioactivity via feces and 24.3% into urin e. Excretion was nearly complete within 48 h. No enteral reabsorption was d etected. In dogs t(max) in plasma was 1.3 h. C-14- and cetrorelix-plasma le vels were similar until 24 h, indicating a negligible amount of metabolites . A dose of 1 mg/kg in dogs showed an increasing influence of a slow absorp tion phase (flip-flop). In dogs equal amounts of the C-14 dose were found w ithin 192 h in feces and urine, 46 and 48%, respectively. In urine of both species, only intact cetrorelix was detected. In bile and feces of both spe cies qualitatively the same metabolites were found, characterized as trunca ted peptides of the parent decapeptide. The major metabolite occurring in b ile of both species was the (1-7)heptapeptide. The amounts of the (1-4)tetr apeptide in feces of rats but not in that of dogs increase with time, sugge sting additional degradation of the peptide in the gastrointestinal tract o f rats by enteric metabolization.