Figure 7.51 Effect of bile salt on permeability in donor well at pH 6.5.

significantly elevated Pe, consistent with effects (1) and (3). The four acids in the Table 7.19 behave according to effect (1) listed above; both Pe and %R are elevated. The two ampholytes may also be affected this way, judging by the increased %R.

7.7.10 Effects of Bile Salts in Donor Wells

An alternative method to overcome the solubility problem mentioned in the last section is to use bile salts to solubilize lipophilic molecules in the donor wells. Figure 7.51 shows a plot of relative permeability (Pe without bile/Pe with bile) versus membrane retention, which is related to lipophilicity (Section 7.7.2). As the plot shows, the most lipophilic molecules (carvedilol, propranolol, and verapa-mil) have attenuated permeabilities (by a factor of 3 in the case of carvedilol). The effective partition coefficient between the PAMPA membrane phase and the aqueous phase containing bile salt micelles [577] is expected to be lower for lipophilic molecules, which should result in lower Pe values. This is evident in the figure.

7.7.11 Effects of Cyclodextrin in Acceptor Wells

The method for creating acceptor sink condition discussed so far is based on the use of a surfactant solution. In such solutions, anionic micelles act to accelerate the transport of lipophilic molecules. We also explored the use of other sink-forming reagents, including serum proteins and uncharged cyclodextrins. Table 7.20 compares the sink effect of 100 mM p-cyclodextrin added to the pH 7.4 buffer in the acceptor wells to that of the anionic surfactant. Cyclodextrin creates a weaker sink for the cationic bases, compared to the anionic surfactant. The electrostatic binding force between charged lipophilic bases and the anionic surfactant micelles

TABLE 7.20 Effect of 100 mM ß-Cyclodextrin in Acceptor Wells, pH 7.4"
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