title: Metabolism of [Des-Gly10,D-Trp6]LHRH ethylamide in rabbit nasal tissue.
abstract: The objective of this study was to determine whether [Des-Gly10, D-Trp6] LHRH ethylamide, a nonapeptide LHRH agonist known as deslorelin, is degraded by the rabbit nasal tissue. Deslorelin was incubated with nasal tissue either alone or in the presence of 0.1 mM ouabain, 0.1% 2,4-dinitrophenol, 0.1 mM phosphoramidon, 0.1 mM N-tosyl-L-phenylalanine chloromethylketone (TPCK) or 2% EDTA at 37 degrees C. Furthermore, deslorelin alone was incubated with nasal tissue at 4 degrees C. All incubation solutions were adjusted to isotonicity and pH 5.0. At the end of 90 min, the supernatants were analyzed using a reversed-phase HPLC. Metabolite peaks could be detected in all the above experiments except the low temperature study, suggesting inhibition of metabolism at low temperature. Intact drug remaining in the supernatant was elevated by about 32% by ouabain and dinitrophenol, suggesting that energy-dependent cellular uptake is likely for deslorelin. Phosphoramidon and TPCK failed to alter deslorelin levels, suggesting that phosphoramidon and TPCK sensitive endopeptidases did not contribute to the observed deslorelin metabolism. However, EDTA significantly elevated the intact deslorelin levels in a dose-dependent manner, with an elevation of 113% with 2% EDTA. With 2% EDTA, the metabolite peaks almost completely disappeared, indicating a possible role for either metal-activated peptidases or metallo-endopeptidases in the nasal metabolism of deslorelin.
authors.affiliation: Department of Pharmacal Sciences, School of Pharmacy, Auburn University, AL 36849-5503, USA. udayako@mail.auburn.edu
authors.forename: U B
authors.initials: UB
authors.lastname: Kompella
authors.forename: B A
authors.initials: BA
authors.lastname: Dani
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000378:metabolism*; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000378:metabolism; D008969:Molecular Sequence Data; D009297:Nasal Mucosa / Q000378:metabolism*; D011817:Rabbits; D017329:Triptorelin Pamoate / Q000031:analogs & derivatives
chemical_list: D004791:Enzyme Inhibitors; D017329:Triptorelin Pamoate; D007987:Gonadotropin-Releasing Hormone; C066438:deslorelin