SIZE-DEPENDENT PERMEABILITY OF HYDROPHILIC PROBES ACROSS RABBIT COLONIC EPITHELIUM

Colon-specific delivery of metabolically labile molecules, such as pro teins and peptides, is of particular interest in pharmaceutical resear ch. Among the factors that may influence the permeability of drug mole cules across colonic mucosa are their molecular weight and geometry. T he purpose of this study was to evaluate the influence of molecular ge ometry on in vitro permeability across rabbit distal colonic epithelia . Permeability of radiolabeled hydrophilic probes with different molec ular weights and geometries across isolated rabbit distal colonic tiss ue was evaluated by means of the Ussing chamber technique. The hydrody namic radii of the probes (an indicator of molecular geometry) were es timated 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 connec tive tissue to the overall in vitro permeability across the colonic mu cosa. 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 mol ecular weight of about 5000, however, was approximately the same as th at of PEG 900 (molecular weight about 900). When the epithelial cells were removed, for the homologous series of PEGs, the permeabilities we re proportional to their free diffusion coefficients in water. It appe ars that for the PEG and lactulose probes, theoretical estimation of t he hydrodynamic radii, which assumes the molecules to be spherical in shape, provides a good basis for the dependence of permeability on geo metry. The relatively high permeability of inulin seems to be due to i ts compact structure. The PEG permeability values in the absence of ep ithelial cells, in combination with their diffusion coefficients, indi cate that the underlying connective tissue does not contribute to the overall permeability of these molecules across colonic mucosa in vitro .