Abstract
The current therapy for growth hormone deficiency in children is subcutaneous administration of growth hormone. Attempts to develop alternative delivery forms for this hormone have not yet resulted in new products. Recently a hexapeptide, His- d-Trp-Ala-Trp- d-Phe-Lys-NH 2 (SK&F 110679), has been discovered which elicits growth hormone release in vitro and in vivo in both animals and man. SK&F 110679 may provide an alternative therapy for the treatment of growth hormone deficiency, especially if the delivery form is more convenient. In this study, membrane permeability and systemic absorption of SK&F 110679 have been determined from either the plasma growth hormone concentra- tions or from direct quantitation of the peptide. Intestinal transport in both small and large intestinal segments is approximately equal to the rate of transport of the passively transported marker, mannitol. As predicted from this low rate of transepithelial transport, the oral bioavailability of SK&F 110679 is less than 1% in both animals and man. Hepatic first pass effects were estimated from measurement of plasma growth hormone concentrations following intraportal adminstration in the rat or from measurement of plasma concentrations of SK&F 110679 in the dog. Results from these studies suggest that SK&F 110679 may be subject to significant first pass elimination. Thus, bioavailability following intratracheal administration was investigated to determine whether it could provide a more optimal pharmacokinetic/pharmacodynamic profile for SK&F 110679. In rats, intratracheal administration of SK&F 110679 elicited dose related increases in plasma growth hormone concentrations and in the dog, resulted in a bioavailability of ≈43% compared to intravenous administration. These results confirm previous reports that peptides are better absorbed from the lung than from the gastrointestinal tract and suggest that aerosol delivery of peptides may provide a convenient alternative to subcutaneous administration.
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