Systematic investigations of the influence of molecular structure on the transport of peptides across cultured alveolar cell monolayers

Purpose. To determine how the structures of peptides influence their alveol ar permeability. Methods. The studies were performed using 14 synthetic 'model' peptides, la belled with a novel, non-intrusive amino acid fluorophore, and their transp ort studied using rat alveolar cell monolayers cultured on permeable suppor ts. Results. The passage of the peptides across the epithelial cell monolayers is shown to be primarily paracellular, with an inverse dependence on molecu lar size, and an enhanced flux observed for cationic peptides. The apparent permeability coefficients (P-app) for the peptides (together with those fo r other organic solutes, taken from the literature) are shown to be well-mo delled assuming two populations of 'pores' in the monolayers, modelled as c ylindrical channels of radii 15 Angstrom and 22 nm. The former pores are sh own to be numerically equatable with the monolayer tri-junctional complexes , and the latter are taken as monolayer defects. Conclusions. The various monolayer P-app values correlate well with the res ults from in vivo transport experiments, and the conclusion is drawn that t he pulmonary delivery of peptide drugs is perfectly exploitable.