Hexarelin--evaluation of factors influencing oral bioavailability and ways to improve absorption

Hexarelin, a hexapeptide with growth hormone-releasing activity, has been found in man to have a biological bioavailability (estimated from growth hormone levels) of 0.3+/-0.1% after oral administration. The cause of the low oral efficacy of hexarelin and means of improving its absorption have been evaluated. It was found that hexarelin was degraded in the presence of the contents of the intestine. The metabolite was identified as hexarelin deamidated at the lysine residue. The degradation of hexarelin in the contents of rat ileum was inhibited by the addition of chymostatin, Pefabloc SC, EDTA, and EGTA. Furthermore, the presence of pancreatic proteases from pancrease substitute drugs caused a degradation of hexarelin that could be inhibited by the addition of Pefabloc SC. The same hexarelin metabolite that was found with the contents of rat ileum was found in the presence of human, porcine and bovine trypsin. Hexarelin permeability across rat ileum and in Caco-2 cell monolayers was low. An increase in hexarelin permeability was observed in the presence of different permeability enhancing agents.