Lipophilicity and Membrane Permeation

Permeability is a kinetic property expressed by the permeability coefficient (centimeters per second), a number indicating the rate at which molecules pass from aqueous solution across a membrane to another solution on the other side. Permeability is a molecular property used to screen for more complex absorption processes (i.e. in vitro permeabihty is measured to estimate in vivo absorption). 

Lipophilicity is intuitively felt to be a key parameter in predicting and interpreting permeability and thus the number of types of lipophilicity systems under study has grown enormously over the years to increase the chances of finding good mimics of biomembrane models. However, the relationship between lipophilicity descriptors and the membrane permeation process is not clear. Membrane permeation is due to two main components the partition rate constant between the lipid leaflet and the aqueous environment and the flip-flop rate constant between the two lipid leaflets in the bilayer [13]. Since the flip-flop is supposed to be rate limiting in the permeation process, permeation is determined by the partition coefficient between the lipid and the aqueous phase (which can easily be determined by log D) and the flip-flop rate constant, which may or may not depend on lipophilicity and if it does so depend, on which lipophilicity scale should it be based  

It is our opinion that, among isotropic systems, alongside the standard octanol-water, the alkane-water system (partihoning between water and different alkanes is relahvely independent of the alkane used [14]) is the only system that can be successfuUy used in ADMET predichon, because of its completely different nature from octanol-water. The situahon is much more confused for arhsohopic systems (see Ref. [7] for a brief review) since no standard system has been defined to date. 

However, it is clear that anisotropic systems become relevant in the presence of ionic species (see Section 12.1.4). 

To sum up, lipophilicity is only one component of permeability, and thus any relationships found between passive permeation and log D] are reliable for the investigated series of compounds, but cannot be used to make general predictions. 

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