Kinetics and disposition of hexarelin, a peptidic growth hormone secretagogue, in rats

To document the disposition of hexarelin, a peptidyl growth hormone secreta gogue, male Sprague-Dawley rats received a 5-mu g/kg bolus i.v. dose or thr ee single s.c. doses of 5, 10, and 50 mu g/kg. To assess hexarelin tissue d istribution and excretion, rats were given 1 mu g/kg of [H-3]hexarelin (9.4 Ci/mmol). Metabolism of [H-3]hexarelin was assessed in bile duct-exteriori zed rats given 50 mu g/kg where radiolabeled hexarelin biliary and urinary excretion was quantified. After its i.v. injection, hexarelin displayed a h alf-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) estimat ed with increasing doses confirmed the absence of hexarelin accumulation. C learance/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 h ighest radioactivity levels were detected in the kidney, liver, and duodenu m. The pattern of hexarelin excretion was similar after i.v. or s.c. admini strations. Total radioactivity in bile, urine, and feces corresponded to 60 , 22, and 10% of the dose, respectively. Of the radioactivity excreted in b ile and urine, 90 and 71% was unchanged hexarelin, respectively. These resu lts suggest that: 1) the kinetics of hexarelin appear to be first order up to 50 mu g/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 hexar elin stability toward proteolytic enzymes.