The influence of lipophilicity upon the nasal absorption of a series of hexapeptides

A series of glycine (G) and phenylalanine (F) containing hexapeptides have been synthesised that vary only in the proportions of their constituent amino acids, The peptides FGGGGG (F(1)G(5)), FFGGGG (F(2)G(4)) and FFFGGG (F(3)G(3)) were characterised by their distribution coefficients and it was found that a linear relationship existed between logo and the number of phenylalanine residues. Metabolism by aminopeptidases is a major barrier to the nasal absorption of labile peptides. To overcome this the peptides were synthesised with D-phenylalanine that rendered the peptides totally resistant to metabolism by leucine aminopeptidase. The extent of nasal absorption of the peptides was measured by a nasal perfusion technique. The peptides were generally poorly absorbed with only 20.2% (D-F(1)G(5)), 19.7% (D-F(2)G(4)) and 25.9% (D-F(3)G(3)) disappearing from the perfusate after 105 min. The results also illustrate that the extent of absorption does not correspond closely with differences in lipophilicity of the peptides.