What Surface of the Intestinal Epithelium Is Effectively Available to Permeating Drugs?

Abstract

A mathematical model is presented which examines the extent to which the intestinal epithelium is accessed by drug molecules. Morphological information from the literature for the jejunum, ileum, and colon of the rat and for human jejunum was incorporated. Perturbation theory was used to derive the limiting cases for total access to the entire epithelial surface, for transport by diffusion and by diffusion with convection, respectively. A parameter gamma = square root of (Ph2)/(Db) was identified to provide a measure of the ability of drug molecules to access the entire 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 intervillous channel. When gamma << 1, diffusion is not a limitation and the entire surface is fully utilized for absorption of drug. This condition arises with drugs of low permeability and is more likely to be met with colonic than small intestinal epithelium. When gamma >/= 1, diffusion becomes a limitation and then not all of the epithelial surface is functionally accessible to drug molecules, a condition most likely to prevail with drugs of high permeability traversing the jejunum. Furthermore, water flux per se is predicted to 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 amplification between these different epithelial regions. The analysis also indicates that for highly permeable drugs extreme caution should be exercised in extrapolating permeability measurements in vitro across various preparations and to events in vivo.

Intestinal Secretion Is a Major Route for Parent Ivermectin Elimination in the Rat

“…However, the intestinal elimination capacity (expressed per unit of intestinal length) appeared to decrease gradually from proximalto-distal small intestine, with maximal values in the duodenum. Regional differences could possibly be attributed to differences in passive diffusion, expression levels of efflux transporters, or carrier affinity (Makhey et al, 1998), but other factors should be considered as well in interpretation of data such as a different proportion of villi in the intestinal segments (Olivier et al, 1998). Data were expressed per unit of intestinal length and not of intestinal area, since the loop diameter along the segments was too variable to be properly assessed.…”

Leakiness and Size Exclusion of Paracellular Channels in Cultured Epithelial Cell Monolayers–Interlaboratory Comparison

“…The human stomach surface is usually classed as "tight," with a 2,000 Ω. cm 2 TEER value; the small intestine is thought to be "leaky," indicated by 50-100 Ω.cm 2 ; the colonic TEER is "intermediate" in tightness, with 300-400 Ω.cm 2 values (3). Usually, the surface area assumed in the intestinal resistance measurement is based on the "smooth cylinder" model (4,5). However, the fold and villus structures in the small intestine can effectively expand the available surface area by up to 30 times (4)(5)(6)(7)(8)(9), and if this were taken into account, the intestinal TEER values could more closely match those of the stomach, given the smoother gastric surface (4)(5)(6)(7)(8)(9)(10)(11).…”

Membrane Permeability – Measurement and Prediction in Drug Discovery

“…In humans, the fold expansion (FE) of the surface area is about threefold, and villi expansion (VE) is about 10-fold [7]. In the case of high epithelial membrane permeability (P ep ) absorption occurs at the top of the villi before diffusing down the villi channels, whereas low P ep compound may diffuse down the villi channels to the crypts (Figure 6.1).…”

“…In the case of high epithelial membrane permeability (P ep ) absorption occurs at the top of the villi before diffusing down the villi channels, whereas low P ep compound may diffuse down the villi channels to the crypts (Figure 6.1). Therefore, accessibility (Acc) to the surface depends on P ep and diffusion coefficient [7,8]. The effective membrane permeability can be expressed as:…”