Figure 5.10 Comparison of membrane to octanol pKa values of compounds with unrelated structures [149,385,386]. [Avdeef, A., Curr. Topics Med. Chem., 1, 277-351 (2001). Reproduced with permission from Bentham Science Publishers, Ltd.]

However, when the IAM log k7AMw were compared to liposome log Dmem70, there was no direct correlation when all of the compounds were used. It was clear that multi—mechanisms were operative, in the Lipinski sense [1].

For the series of large molecules, such as, p blockers or the long-chain (p-methylbenzyl)alkylamines, IAM retention correlated with liposome partitioning. Hydrophobic recognition forces was thought to be responsible for the partitioning process. In addition, the formation of an H bond between the hydroxy group of the p blocker and the ester bond of phospholipids (Fig. 5.1) may explain why the p blockers partitioned into the liposomes more strongly than the alkylamines. For the more hydrophilic short-chain (p-methylbenzyl)alkylamines (n = 0-3 in Fig. 5.5), the balance between electrostatic and hydrophilic interactions was different in the IAM and liposome systems. Electrostatic interactions are thought to play only a minor role for the IAM retention of the model solutes, presumably due to the smaller density of phospholipids in IAM resin surfaces, compared to liposomes. The solute's capacity to form H-bonds, which is important for partitioning in liposomes, plays only a minor role in the IAM system.


In the early literature, it was a common practice to make a single measurement of log D, usually at pH 7.4, and use a simplified version of Eq. (4.10) (with log P1

neglected) along with the known pKa to calculate log PN. (The practice may still persist today. We have intentionally omitted these simplified equations in this book.) Most of the time this produced the correct log PN, often because ion pairing was not extensive at the pH of measurement. This is true for the p blockers whose pKa is about 9.5; the diff 3-4 rule would suggest that ion pair partitioning should be extensive only below pH 6.5.

With liposome partitioning, however, the rule slips to diff 1-2. This means SIP partitioning starts at about pH 8.5 for weak bases whose pKa values are near 9.5 (e.g., Figs. 5.7b, 5.11). So, all who published ''anomalous'' values of log P^em may need to get out their slide rules [429-432]! (What we know now was not known then.)

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