Sink Condition to Offset the Attenuation of Permeability

Since lipophilic molecules have affinity for both the membrane lipid and the serum proteins, membrane retention is expected to decrease, by the extent of the relative lipophilicities of the drug molecules in membrane lipid versus serum proteins, and by the relative amounts of the two competitive-binding phases [see Eqs. (7.41)-(7.43)]. Generally, the serum proteins cannot extract all of the sample molecules from the phospholipid membrane phase at equilibrium. Thus, to measure permeability under sink conditions, it is still necessary to characterize the extent of membrane retention. Generally, this has been sidestepped in the reported literature. 

We found that the negatively charged surfactant, sodium laurel sulfate, can be successfully substituted for the serum proteins used previously. In low ionic strength solutions, the cmc of the surfactant is 8.1 mM [577]. We explored the use of both sub-CMC (data not shown) and micelle-level concentrations. Saturated micelle solutions are most often used at pION. 

The effect of the surfactant is most dramatic for the bases and neutral molecules studied, as shown in Tables 7.13 and 7.14. Permeabilities increased by up to fourfold for the lipophilic bases and neutral molecules, and membrane retentions were decreased by 50% in most cases of bases and neutral compounds (Figs. 7.31 and 7.32). 

The transport properties of the acids did not respond significantly to the presence of the sink. This may be because at pH 7.4 the acids are negatively charged, as are the phospholipid membranes and also the surfactant micelles electrostatic repulsions balanced out the attractive forces due to increased membrane lipophilicity. Lowered surface pH may also play a balancing role [457]. 

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