The mucus layer and other barriers to intestinal drug absorption
1997 (English)Doctoral thesis, comprehensive summary (Other academic)
The extraepithelial mucus layer acts as a barrier to the absorption and diffusion of drugs. Three in vitro models have been used for studies of this and other intestinal barriers to drug transport. A drug absorption model based on monolayers of the mucus-producing human intestinal goblet HT29-H cell line was developed. The goblet cells produced mucin molecules and a mucus layer that covered the surface of the cells. The permeability of the gobletcell monolayers to the lipophilic molecule testosterone increased after removal of the mucus layer while the permeability to the small hydrophilic molecule mannitol was not altered.
The mucus layer contributed 78% of the total resistance to absorption of testosterone in the HT29-H model, while the corresponding values for the unstirred water layer, the cell monolayer and the filter were 16%, 5% and 1%, respectively.
A co-culture model containing absorptive Caco-2 cells and goblet HT29-H cells (the two most abundant epithelial cell types) was developed. A seeding density of 1% HT29-H cells resulted in co-cultures comprising 30% goblet cells in small clusters after 4 weeks in culture. Tight junctions were formed between the two cell types as revealed by electron microscopy and transepithelial electrical resistance measurements. The permeability of the monolayers tohydrophilic drugs increased with increasing numbers of goblet cells. The specific tight junction permeability, adjusted for junctional path length, was higher in HT29-H cells than Caco-2 cells.
A relationship between the octanol/water distribution ratio and the self-diffusion coefficient of drugs was found in a native pig intestinal mucus model (PIM) but not in a purified pig gastric mucin model (PPGM), indicating that mucus components other than mucin molecules interact with drugs. PIM was thus found to be a more complete model of the barrier properties of gastrointestinal mucus than PPGM.
The major components of PIM, other than water, were lipids and proteins; concentrations of mucin and DNA were lower. Of the individual components of native intestinal mucus, lipids were found to have the greatest influence on the diffusion of drugs.
Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 1997. , 50 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 0282-7484 ; 162
Research subject Pharmaceutics
IdentifiersURN: urn:nbn:se:uu:diva-836ISBN: 91-554-3950-0OAI: oai:DiVA.org:uu-836DiVA: diva2:171190
1997-04-25, Lecture hall, B41, Biomedical Center, Uppsala University, Uppsala, 14:15