Transport of deslorelin, an LHRH agonist, is vectorial and exhibits regional variation in excised bovine nasal tissue

Abstract

The nasal route is a non-invasive alternative route for the delivery of a number of macromolecules, including peptides, proteins and vaccines. The purpose of this study was to determine the regional variation in excised bovine nasal tissue permeability to deslorelin, a nonapeptide luteinizing hormone releasing hormone (LHRH) agonist, and to further elucidate its mechanisms of transport. To this end, this study determined the permeability of deslorelin across different regions of freshly excised bovine nasal mucosa, including the medium turbinate anterior (MTA), medium turbinate posterior (MTP) and the inferior turbinate posterior (ITP) regions. At 37°C, mucoal-to-serosal (m-s) transport of deslorelin across excised bovine nasal mucosa exhibited regional variation, with the % cumulative transport in 6 h being in the order: MTA (0.2 ± 0.06%) < MTP (1.6 ± 0.1%) < ITP (2.85 ± 0.3%). In addition, at 37°C, deslorelin transport across all these nasal regions was vectorial and the mucosal-to-serosal:serosal-to-mucosal (m-s:s-m) transport ratios across MTA, MTP and ITP regions were 1.5, 5.4 and 3.7, respectively. At low temperature (4°C) and at 37°C in the presence of 2,4-dinitrophenol, an energy depletor, the m-s deslorelin transport across the MTP region decreased to 0.32 ± 0.12 and 0.13 ± 0.05%, respectively, and the directionality was abolished. Sodium fluorescein transport also exhibited regional variation but no directionality. Histology and scanning electron microscopy studies indicated non-ciliated columnar epithelium in the MTA region and ciliated respiratory epithelium in the MTP and ITP regions. The thickness of the various regions, as visualized using histology, was in the order: MTA > MTP > ITP. Thus, deslorelin transport across excised bovine nasal mucosa is vectorial, temperature- and energy-dependent and exhibits regional variation. The regional differences in s-m transport are likely due to differences in the passive transport. Differences in m-s:s-m flux ratios may be due to differential expression of carriers.