Lipophilic compounds, unstirred water layer

In the same way, o-nitrophenyl octyl ether (o-NPOE) was immobilized on polycarbonate (PC) filters and the apparent permeability measured after 5 h incubation time was correlated to log Pnpoe for a series of reference compounds (log Pnpoe ranging from —1 to 3.6) [90]. Lipophilicity values in the alkane/water system were also determined using PAMPA with hexadecane-PC coated filters [89]. In this case, a correlation was found between intrinsic permeability (log Pq, permeability corrected for ionization and for unstirred water layer contribution, which particularly affects permeability of lipophilic compounds) and log P ik. However, log Pq is obtained from the knowledge of the pJC, value(s) and the permeability pH profile and therefore requires the full permeability pH profile to be measured for each compound, which negatively impacts the assay throughput. 

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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