Metabolism, pharmacokinetics, tissue distribution, and excretion of [14C]CP-424391 in rats.
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 C(max) of 1.44 microg/ml. CP-424391 accounts for about 40% of radioactivity area under the plasma concentration-time curve and C(max) 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. [(14)C]CP-424391 radioactivity was eliminated from most tissues by 9 h with the exception of liver, skin, and uvea. By 168 h, [(14)C]CP-424391 radioactivity remained localized only in the uvea.
Khojasteh-Bakht
S Cyrus
SC
Pfizer Inc., Global Research and Development, PDM Development, MS 4096, Eastern Point Road, Groton, CT 06340, USA.
O'donnell
John P
JP
Fouda
Hassan G
HG
Potchoiba
Michael J
MJ
D000284:Administration, Oral; D000818:Animals; D002250:Carbon Radioisotopes / Q000378:metabolism / Q000652:urine; D005243:Feces / Q000737:chemistry; D005260:Female; D006133:Growth Substances / Q000737:chemistry / Q000378:metabolism* / Q000652:urine; D008297:Male; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism* / Q000652:urine; D011720:Pyrazoles / Q000737:chemistry / Q000378:metabolism* / Q000652:urine; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution / Q000502:physiology
C433143:CP 424391; D002250:Carbon Radioisotopes; D006133:Growth Substances; D010880:Piperidines; D011720:Pyrazoles