Nasal delivery of peptides: an in vitro cell culture model for the investigation of transport and metabolism in human nasal epithelium.
We investigated the transport- and metabolism properties of three peptides in monolayers of human nasal epithelial cells. The effective permeability coefficients of thyrotropin-releasing hormone, met-enkephalin and human recombinant insulin were found to be 4.5, 4.4 and 0.4 x 10(-7) cm/s, respectively. The permeability was inversely proportional to the molecular weight and one order of magnitude lower than in excised nasal mucosa of rabbits. The metabolic cleavage of thyrotropin-releasing hormone (TRH) to the free acid by cytosolic prolyl-endopeptidase was also detected in human nasal cell monolayers, suggesting that ca. 10% of the total amount of TRH is transported via a transcellular pathway. Met-enkephalin is a substrate for aminopeptidases, located on the apical membrane of nasal epithelial cells. Metabolites and enzyme activity are comparable with literature data. Our studies demonstrate that not only morphological, but also functional properties of human nasal epithelial cells are preserved under in vitro conditions. Such a cell culture model based on human nasal cells could be beneficial for the characterization of peptide transport on a cellular level and for investigation of the absorption enhancer mechanism. Further studies are necessary, however, to establish correlations between in vitro permeabilities in cell cultures and nasal drug absorption in animals and humans.
Kissel
T
T
Department of Pharmaceutics and Biopharmacy, Philipps University of Marburg, Germany. kissel@mailer.uni-marburg.de
Werner
U
U
D000281:Administration, Intranasal; D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport; D002478:Cells, Cultured; D004744:Enkephalin, Methionine / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics; D009831:Olfactory Mucosa / Q000378:metabolism*; D011817:Rabbits; D013973:Thyrotropin-Releasing Hormone / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics
D007328:Insulin; D004744:Enkephalin, Methionine; D013973:Thyrotropin-Releasing Hormone