Abstract
Colon-specific delivery of metabolically labile molecules, such as proteins and peptides, is of particular interest in pharmaceutical research. Among the factors that may influence the permeability of drug molecules across colonic mucosa are their molecular weight and geometry. The purpose of this study was to evaluate the influence of molecular geometry on in vitro permeability across rabbit distal colonic epithelia. Permeability of radiolabeled hydrophilic probes with different molecular weights and geometries across isolated rabbit distal colonic tissue was evaluated by means of the Ussing chamber technique. The hydrodynamic radii of the probes (an indicator of molecular geometry) were estimated by theoretical models as well as dynamic light scattering. We conducted the permeability studies in the presence and absence of the epithelial cells to evaluate the contribution of the underlying connective tissue to the overallin vitro permeability across the colonic mucosa. The rank order of the permeability of the markers was mannitol > lactulose > polyethylene glycol (PEG) 400 > PEG 900 > PEG 4000, which is consistent with their molecular weights and estimated hydrodynamic radii. The permeability of inulin, a polyfructose molecule with a molecular weight of about 5000, however, was approximately the same as that of PEG 900 (molecular weight about 900). When the epithelial cells were removed, for the homologous series of PEGs, the permeabilities were proportional to their free diffusion coefficients in water. It appears that for the PEG and lactulose probes, theoretical estimation of the hydrodynamic radii, which assumes the molecules to be spherical in shape, provides a good basis for the dependence of permeability on geometry. The relatively high permeability of inulin seems to be due to its compact structure. The PEG permeability values in the absence of epithelial cells, in combination with their diffusion coefficients, indicate that the underlying connective tissue does not contribute to the overall permeability of these molecules across colonic mucosa in vitro.
Footnotes
-
Send reprint requests to: Jindřich Kopeček, Center for Controlled Chemical Delivery, University of Utah, Biopolymers Research Building, #205, Salt Lake City, Utah, 84112
-
↵1 Department of Pharmaceutics and Pharmaceutical Chemistry/CCCD, University of Utah, Salt Lake City, Utah 84112.
-
↵2 Present address: Department of Pharmaceutics, University of Mississippi, University, Mississippi, 38677.
-
↵3 Department of Drug Delivery, SmithKline Beecham, King of Prussia, Pennsylvania, 19406.
- Abbreviations:
- DLS
- dynamic light scattering
- FPLC
- fast-protein liquid chromatography
- ISC
- short circuit current
- Mn
- number average molecular weight
- Mw
- weight average molecular weight
- PD
- spontaneous transepithelial potential difference
- Pd
- polydispersity (Mw/Mn)
- PEG
- polyethylene glycol
- Rt
- transepithelial resistance
- Received January 25, 1996.
- Accepted October 15, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|