Abstract
To document the disposition of hexarelin, a peptidyl growth hormone secretagogue, male Sprague-Dawley rats received a 5-μg/kg bolus i.v. dose or three single s.c. doses of 5, 10, and 50 μg/kg. To assess hexarelin tissue distribution and excretion, rats were given 1 μg/kg of [3H]hexarelin (9.4 Ci/mmol). Metabolism of [3H]hexarelin was assessed in bile duct-exteriorized rats given 50 μg/kg where radiolabeled hexarelin biliary and urinary excretion was quantified. After its i.v. injection, hexarelin displayed a half-life of 75.9 ± 9.3 min, a systemic clearance of 7.6 ± 0.7 ml/min/kg, and a volume of distribution at steady state of 744 ± 81 ml/kg. After s.c. administration, the area under the curve (477–3826 pmol·min/ml) estimated with increasing doses confirmed the absence of hexarelin accumulation. Clearance/F (12–15 ml/min/kg) and volume of distribution/F (1208–1222 ml/kg) were dose independent. Hexarelin bioavailability given s.c. was 64%. The highest radioactivity levels were detected in the kidney, liver, and duodenum. The pattern of hexarelin excretion was similar after i.v. or s.c. administrations. Total radioactivity in bile, urine, and feces corresponded to 60, 22, and 10% of the dose, respectively. Of the radioactivity excreted in bile and urine, 90 and 71% was unchanged hexarelin, respectively. These results suggest that: 1) the kinetics of hexarelin appear to be first order up to 50 μg/kg; 2) hexarelin is rapidly absorbed after s.c. administration; 3) biliary excretion is the primary route of hexarelin elimination; and 4) the high recovery of unchanged peptide in bile and urine demonstrates hexarelin stability toward proteolytic enzymes.
Footnotes
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Send reprint requests to: Huy Ong, Ph.D., Facultéde Pharmacie, Université de Montréal C.P. 6128, succursale Center-Ville, Montréal (Québec) Canada H3C 3J7. E-mail:ongh{at}ere.umontreal.ca.
- Abbreviations used are::
- GH
- growth hormone
- GHRPs
- growth hormone-releasing peptides
- LSC
- liquid scintillation counting
- AUC
- area under the curve
- CLp
- plasma clearance
- Vd
- volume of distribution
- TFA
- trifluoroacetic acid
- Received June 9, 1999.
- Accepted October 1, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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