WHAT SURFACE OF THE INTESTINAL EPITHELIUM IS EFFECTIVELY AVAILABLE TOPERMEATING DRUGS

A mathematical model is presented which examines the extent to which t he intestinal epithelium is accessed by drug molecules. Morphological information from the literature for the jejunum, ileum, and colon of t he rat and for human jejunum was incorporated. Perturbation theory was used to derive the limiting cases for total access to the entire epit helial surface, for transport by diffusion and by diffusion with conve ction, respectively. A parameter gamma = root(PH2)/(Db) was identified to provide a measure of the ability of drug molecules to access the e ntire epithelial surface down to the crypt wells, where P is the cell permeability, D the aqueous diffusion coefficient, h the channel depth between the villi, and b is half the width of the idealized intervill ous channel. When gamma much less than 1, diffusion is not a limitatio n and the entire surface is fully utilized for absorption of drug. Thi s condition arises with drugs of low permeability and is more likely t o be met with colonic than small intestinal epithelium. When gamma gre ater than or equal to 1 diffusion becomes a limitation and then not al l of the epithelial surface is functionally accessible to drug molecul es, a condition most likely to prevail with drugs of high permeability traversing the jejunum. Furthermore, water flux per se is predicted t o have relatively little influence on enhancing surface accessibility. This simple, but quantitative approach showed that the ranking order of permeability jejunum > ileum > colon for low permeable drugs can at least in part be explained by the differences in surface amplificatio n between these different epithelial regions. The analysis also indica tes that for highly permeable drugs extreme caution should be exercise d in extrapolating permeability measurements in vitro across various p reparations and to events in vivo.