Lipophilic drug absorption enterocyte barriers

To enhance absorption, it is important to identify the rate-limiting step in this process and to counter the relevant barrier in each case. The possible solutions for the absorption barriers facing lipophilic drug absorption are presented according to their physiological order, i.e., issues concerning the GI lumen (preenterocyte), followed by issues associated with the enterocyte and onward. However, it should be noted that a few concepts affect more than one step of the absorption process. 

FIGURE 6.1 The barriers that a lipophilic drug has to transverse along the intestinal absorption process (1) dissolution and solubilization in the intestinal milieu, (2) narrow absorption window, (3) unstirred water layer, (4) efflux pumps, (5) intra-enterocyte metabolism, and (6) first pass hepatic metabolism. 

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. 

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