Unstirred water layer structure

The glycocalyx and the mucus layer make up the structure of the unstirred water layer (UWL) [73]. The thickness of the UWL is estimated to be 30-100 pm in vivo, consistent with very efficient stirring effects [74]. In isolated tissue (in the absence of stirring), the mucus layer is 300-700 pm thick [73]. The pH in the unstirred water layer is 5.2-6.2, and might be regulated independently of the luminal pH (Section 2.3). The mucus layer may play a role in regulating the epithelial cell surface pH [73]. 

Figure 6.1 Schematic representation of the intestinal membrane structure. The singlet arrow in the figure illustrate the permeation pathways, (a) Villous structure of intestine. Unstirred water layer is adjacentto villi, (b) Permeation pathways of compounds across the intestinal epithelial membrane. (Adapted from [14] and modified from Bentham Science Publishers, Ltd.)...

Any enhancing effect of surfactants on drug absorption appears to be related to increased drug solubilization, modification of mucosal permeability, or reduction of resistance of the unstirred water layer at the GI membrane surface. In general, unionic surfactants have little effect on membrane structure but cationic surfactants have been associated with reversible cell loss and loss of goblet cells. These effects must limit consideration of surfactants as absorption promoters, particularly for long term treatment. 

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. 

In summary, a lipid molecule on its route from the luminal bulk phase into the intracellular compartment of an enterocyte has to overcome two unstirred water layers and one plasma membrane of lipid bilayer structure. The unstirred water layer on the luminal side partly coincides with the mucus gel and the glycocalyx relatively little is known of the importance of these diffusional barriers. 

To reach the systemic circulation, a drug must move from the intestinal lumen through an unstirred water layer and mucous coat adjacent to the epithelial cell structure. Movement across the epithelial layers takes place by two independent routes, transcellular flux (i.e., movement across the cells) and paracellular flux or movement between adjacent epithelial cells. The solute molecules then encounter a basement membrane, interstitial space, and mesenteric capillary wall to access the mesenteric circulation. Any and all of these microenvironments can be considered a resistance to solute molecule movement, each with an associated permeability coefficient. Therefore, the overall process consists of a number of resistances (i.e., reciprocal of permeability) in series. Furthermore, the influence of drug structure with permeability in these different domains may be different. For example, permeability in an unstirred water layer is inversely related to solute size, whereas paracellular permeability Is a function of both size and charge. Furthermore, cations exhibit greater permeability than neutral species, which in turn manifest greater permeability than anions. 

The digestion products encounter two main barriers to their absorption. The first is the layer of unstirred water at the surface of the microvillus membrane and this is thought to be the rate-limiting step in the uptake process. The second barrier is the microvillus membrane (brush-border membrane) itself. As mentioned in section 6.5.2, this membrane has a particularly robust structure. After many years of research, it is still not entirely clear how the lipid digestion products cross this barrier. 

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