Figure 5.6 The difference between liposome-water and octanol-water partitioning as a function of the octanol-water partition coefficient for a series of unrelated structures [149,385,386,429]. For example, acyclovir partitions into liposomes over 3000 times more strongly than into octanol, and amiodarone partitions into liposomes 100 times more weakly than into octanol. [Avdeef, A., Curr. Topics Med. Chem., 1, 277-351 (2001). Reproduced with permission from Bentham Science Publishers, Ltd.]

At the opposite extreme is the example of amiodarone. The log octanol partition coefficient is 7.8 [162], whereas the membrane constant is reported as 6.0 [429], surprisingly, almost two orders of magnitude smaller (8 = —1.8).

Although the relationship in Fig. 5.6 is somewhat coarse, it is still useful in predictions. Since octanol-water log P prediction programs are omnipresent and adequately reliable, it can now be said that they can predict membrane-water partitioning, by using the equation in Fig. 5.6. Better yet, if one measures the value of log PoNct, one can estimate the membrane partition coefficient with the confidence of the variance expressed in Fig. 5.6.

5.10 log Dmem, diffmem, AND THE PREDICTION OF log Pmem FROM log P1

In the preceding section, we explored the relationship between log PNct and log Pmem- We now focus on the partitioning of the charged species into phospholipid bilayer phases. More surprises are in store.

Figure 5.7 shows lipophilicity profiles (log D vs. pH) for an acid (warfarin), a base (tetracaine), and an ampholyte (morphine). The dashed curves correspond to the values determined in octanol-water and the solid curves, to values in liposome-water. As is readily apparent, the major differences between octanol and liposomes

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