Abstract
CP-424391, 2-amino-N-[3aR-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1R-benzyloxymethyl-2-oxoethyl]-isobutyramide, is an orally active growth hormone secretagogue currently being developed. In this study, we investigated the metabolic fate and disposition of radiolabeled CP-424391 in rats. Following 15 mg/kg single oral administration to Sprague-Dawley rats, 91% of the radiolabeled dose was recovered. Feces was the major route of excretion: 77% of the dose recovered in feces of the female rat and 84% in the male. Excretion in the urine was 15% in the female rat compared with 7% in the male. Both fecal and urinary metabolic profiles were consistent in both genders. The metabolic pathways of CP-424391 were oxidation at the benzyl group of the O-benzylserine moiety, N-demethylation of pyrazolidine, and/or O-debenzylation. In circulation, CP-424391 was absorbed within the first hour to an average apparent Cmax of 1.44 μg/ml. CP-424391 accounts for about 40% of radioactivity area under the plasma concentration-time curve and Cmax in circulation. The plasma terminal elimination half-life of CP-424391 was 2.4 h and for total radioactivity was 2.8 h. The radioactivity was widely distributed in all tissues except for the central nervous system. [14C]CP-424391 radioactivity was eliminated from most tissues by 9 h with the exception of liver, skin, and uvea. By 168 h, [14C]CP-424391 radioactivity remained localized only in the uvea.
Footnotes
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↵1 Retired.
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doi:10.1124/dmd.104.001065.
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ABBREVIATIONS: CP-424391, 2-amino-N-[3aR-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1R-benzyloxymethyl-2-oxo-ethyl]-isobutyramide; amu, atomic mass unit(s); CID, collision-induced dissociation; CQCS, cryosection quality control sample(s); GH, growth hormone; GIT, gastrointestinal tract; HPD, hours postdose; HPLC, high performance liquid chromatography; LLOQ, lower limit of quantification; WBAL, whole-body autoradioluminography.
- Received June 18, 2004.
- Accepted October 1, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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