Details

Autor(en) / Beteiligte

• Garren, Kevin W

Titel

In vitro evaluation of some barriers to buccal absorption and drug delivery using rodent models

Ort / Verlag

ProQuest Dissertations & Theses

Erscheinungsjahr

1987

Quelle

ProQuest Dissertations & Theses A&I

Beschreibungen/Notizen

• In this thesis efforts were made to characterize physical and enzymatic barriers of the buccal mucosa to drug absorption to assess the potential of the buccal route as an alternate route for drug delivery. In vitro permeability of hamster cheek pouch was found to increase with increasing lipophilicity for a series of p-substituted acetanilides. The epithelial cell layer of the cheek pouch appeared to be the physical barrier to diffusion for these compounds. In vitro permeabilities correlated well with in vivo buccal absorption of the same compounds in humans, suggesting hamster cheek pouch may be a useful model of human buccal mucosa. Levels of esterase, aminopeptidase, carboxypeptidase and endopeptidase activities in rat and hamster buccal and intestinal mucosal homogenates were determined. Relative levels and distributions of activities were found to vary between the species, but in all cases there were appreciable levels in buccal mucosa. Carboxypeptidases excepted, the enzyme activity present in intestinal mucosal homogenates equalled or exceeded those of the buccal mucosa. Simultaneous in vitro diffusion and metabolism of a synthetic aminopeptidase substrate in the hamster cheek pouch were studied. No intact substrate was found to traverse the tissue. The enzymatic barrier to diffusion appeared to be in the epithelial cell layer. Use of structural modification of the substrate, a stereoisomer of the substrate, and an enzyme inhibitor were approaches which enhanced absorption of the intact substrate. A mathematical model describing the simultaneous diffusion and metabolism of substrate agreed well with experimental data and indicated the capacity for substrate degradation to be three times the rate of diffusion in the tissue. Application of the model to diffusion and metabolism of substrate in the serosal-to-mucosal direction allowed estimation of the relative permeabilities of the keratinized epithelium and the viable cell layer to the hydrolysis product. Results of this work suggest that the delivery of drug via the buccal route will be limited to drugs which are highly potent and which are either not readily metabolized or can be protected by metabolic inhibitors.