Abstract
Disposition and metabolism of cetrorelix was studied in intact and bile duct-cannulated rats and dogs after s.c. injection. An s.c. dose of 0.1 mg/kg [14C]cetrorelix was rapidly and completely absorbed in rats. Tmax in plasma and most tissues was at 2 h. Radioactivity at the injection site in rats declined to 10% by 24 h. The extent of 14C 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 higher level. Rats excreted 69.6% of radioactivity via feces and 24.3% into urine. Excretion was nearly complete within 48 h. No enteral reabsorption was detected. In dogs tmax in plasma was 1.3 h.14C- and cetrorelix-plasma levels 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 absorption phase (flip-flop). In dogs equal amounts of the 14C dose were found within 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 species qualitatively the same metabolites were found, characterized as truncated peptides of the parent decapeptide. The major metabolite occurring in bile of both species was the (1-7)heptapeptide. The amounts of the (1-4)tetrapeptide in feces of rats but not in that of dogs increase with time, suggesting additional degradation of the peptide in the gastrointestinal tract of rats by enteric metabolization.
Footnotes
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Send reprint requests to: Dr. Martin Schwahn, Department of Biological Research Biochemistry, Corporate Research and Development, ASTA Medica Group, Weismüllerstraβe 45, D-60314 Frankfurt/Main, Germany. E-mail: martin.schwahn{at}astamedica.de
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↵1 Part of this work was presented at the 5th International ISSX Meeting, October 25–29, 1998, Cairns, Australia (Hempel et al., 1998).
- Abbreviations used are::
- LH-RH
- luteinizing hormone-releasing hormone
- GI
- gastrointestinal
- PB
- protein binding
- LSC
- liquid scintillation counting
- SPHPLC
- semipreparative HPLC
- A/D
- adsorption/desorption chromatography
- MS
- mass spectrometry
- ESI-MS/MS
- electrospray mass spectroscopy
- ng-eq
- nanogram equivalents
- RIA
- radioimmunoassay
- Received May 13, 1999.
- Accepted September 8, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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