Unstirred water layer diffusion barrier

Smithson, K.W., and D.B. Millar. 1981. Intestinal diffusion barrier Unstirred water layer or membrane surface mucous coat Science 214 1241. 

The layer of water adjacent to the absorptive membrane of the enterocyte is essentially unstirred. It can be visualized as a series of water lamellas, each progressively more stirred from the gut wall toward the lumen bulk. For BCS class 2 compounds the rate of permeation through the brush border is fast and the diffusion across the unstirred water layer (UWL) is the rate-limiting step in the permeation process. The thickness of the UWL in human jejunum was measured and found to be over 500 pm [3]. Owing to its thickness and hydrophilicity, the UWL may represent a major permeability barrier to the absorption of lipophilic compounds. The second mechanism by which the UWL functions act as a barrier to drug absorption is its effective surface area. The ratio of the surface area of the UWL to that of the underlying brush border membrane is at least 1 500 [4], i.e., this layer reduces the effective surface area available for the absorption of lipophilic compounds and hence impairs its bioavailability. 

Molecules diffuse less readily across a given distance in a plasma membrane than in a cell wall or an adjacent unstirred water layer. For the previous numerical values, DjKj is 1 x 10-9 m2 s-1 in the aqueous solution and 2 x 10 1° m2 s-1 in the cell wall, but for a plasma membrane about 7 nm thick, DjKj is only 10-18 to 10-14 m2 s-1. Membranes do indeed provide very effective barriers to the diffusion of solutes. 

It has recently been discussed [61-63] whether the diffusional barrier at the intestinal surface can be accounted for solely by an unstirred water layer. It has been proposed that the mucus layer overlying the enterocytes should be regarded as an important diffusion barrier for uptake of lipid solutes from the luminal contents. The mucus adherent to the rat duodenal wall has been found to be approximately 80 jam thick in the fasted state [64]. The intestinal mucus coat is formed by proteoglycans produced by goblet cells, but so far very little is known about the molecular structure of the mucus layer [65]. The possible interaction between mucus constituents and luminal lipid solutes needs to be investigated in detail, since it might reveal key factors which constitute the diffusional barrier of the small intestine. 

Micellar solubilization of lipids within the intestinal lumen permits the lipids to diffuse to the surface of the intestinal epithelium and make contact with the microvillus membrane. This is important because there is a major physiological diffusion barrier called the unstirred water layer, that covers the surface of the epithelial cell membranes. The unstirred layer of water is a feature common to all biological membranes. Micelles penetrate this relatively immobile aqueous layer more readily, thus increasing the efficiency of lipid uptake into the intestinal mucosal cell. 

Within the interstices of the brush border is a hydrodynamic layer of unstirred water , which must act, to some extent, to modify the kinetics of the transport processes (Chapter 5). The significance of this layer as a diffusion barrier, is, however, a matter of dispute (458). 

The thickness of the mucus layer in the human stomach is about 570 pm [101], whereas in the human colon the thickness is about 100-150 pm [102], Ryu and Grim [103] suggested that there is little mixing between the villi and the unstirred layer over the tip of the villi of the canine jejunum, which is about 500-1000 pm thick. Therefore, for a solute to reach the lateral surfaces of the villi, an additional barrier of as much as 800 pm needs to be traversed [103]. It was shown that native mucus gel from rat small intestine reduced the diffusion coefficients of 3H-water, urea, benzoic acid, antipyrine, aminopyrine, alpha-methyl-glucoside, L-phenylalanine by 37%-53% compared with buffer solution [104], For high-molecular-weight substances, such as proteins or microparticulates, mucin can offer considerable resistance to diffusion [105],... 

The presence of an unstirred layer which may adhere to a given cell membrane can be treated operationally as a barrier with its own permeability property in series with the actual membrane. Its importance in membrane transport processes depends essentially on the permeability of the membrane itself relative to that of the unstirred layer to the particular molecule being transported. Consequently, only molecules which permeate membranes at high rates are affected, since diffusion in the unstirred layer is quite rapid. Water transfer across human red cell membrane and those of most other cells and tissues studied falls within this category. Dainty [22] has given the following equation by which the apparent diffusion permeability coefficient may be corrected for the effect of an unstirred layer of thickness, 8 ... 

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