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SIP - log Pmem
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diffmem = log Pmem
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diffmem = 0875 diffOCT - 189
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2 r = 078 n = 20
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Figure 58 Comparison of liposome diff to octanol diff functions of substituted phenols [382,383] [Avdeef, A, Curr Topics Med Chem, 1, 277 351 (2001) Reproduced with permission from Bentham Science Publishers, Ltd]
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groups of the phospholipids, an effect they preferred not to call ion pairing Undeniably, the nature of the charged-species partitioning into phospholipid bilayers is different from that found in octanol In a later study, Austin et al [442] effectively were able to reconcile the ionic strength differences between their study and that of Alcorn et al [433], using a Gouy Chapman model When the drug concentration in the membrane is plotted against the drug concentration in water, the resultant hyperbolic curve shows a lessening slope (log D) with increasing drug concentration (10 6 to 10 4 M) when there is no background salt This is consistent with the interpretation that surface-bound charged drug repulsion attenuates additional charged drug partitioning Bauerle and Seelig [395] and Thomas and Seelig [397] observed hyperbolic curves with drug concentrations exceeding 1 mM The addition of 015 M NaCl mitigates the effect substantially, allowing for higher drug concentrations to be used Avdeef et al [149] and Balon et al [385,386] reported log PN and log PSIP mem mem values of a number of drugs, determined by the pH-metric method, using both LUVs and SUVs, in a background of 015 M KCl Escher and colleagues [383,384] reported SIP values for a large series of substituted phenols, using DOPC SUVs and the equilibrium dialysis/centrifugation method Figure 58 is a plot of diffmem versus diffoct for the series of phenols studied by Escher It appears that knowing the octanol diff values can be useful in predicting the membrane values, and for phenols the relationship is described by diffmem 0:88 diffoct 1:89 5:3
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THREE INDICES OF LIPOPHILICITY: LIPOSOMES, IAM, AND OCTANOL
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pKamem = 099 pKaOCT - 221 r2 = 099 s = 026 n = 20
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Figure 59 The remarkable relationship between the octanol and the membrane pKa values of a series of substituted phenols [382,383] [Avdeef, A, Curr Topics Med Chem, 1, 277 351 (2001) Reproduced with permission from Bentham Science Publishers, Ltd]
The offset of 189 indicates that surface ion pairing in membranes is about 100 oct times greater than that of octanol Scherrer suggested that comparisons of pKa mem to pKa may be more predictive [276] Indeed, this is true for the phenols, as indicated in Fig 59 It is remarkable that the relation for the phenols
mem oct pKa 0:99 pKa 2:21
5:4
has an r 2 of 099, for 20 compounds Again, we see the 221 offset, indicating that the 100-fold slippage from the diff 3-4 rule to the diff 1-2 rule This harbors good prediction relations The well-behaved prediction of charged phenol partitioning is less certain when carried over to unrelated structures, as shown in Fig 510, for the molecules reported by Avdeef et al [149] and Balon et al [385,386]
511 THREE INDICES OF LIPOPHILICITY: LIPOSOMES, IAM, AND OCTANOL Taillardat-Bertschinger et al [311] explored the molecular factors in uencing retention of drugs on IAM columns, compared to partitioning in liposomes and octanol Twenty- ve molecules from two congeneric series (b-blockers and ( p-methylbenzyl)alkylamines; see Fig 55) and a set of structurally unrelated drugs were used Liposome-buffer partitioning was determined by the equilibrium dialysis and the pH-metric methods The intermethod agreement was good, with r 2 087
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Correlation Between Octanol pKa & Membrane pKa
11 10
BASES
9 8 7 6 5 4 3 0
OCT mem = 085 pKa + 279 a
r =075 s=074 n=19
ACIDS
r2=087 s=063 n=9 pKamem = 117 pKaOCT - 368
pKaOCT
Figure 510 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]
7:0 However, when the IAM log kIAMw were compared to liposome log Dmem, 70, 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, b 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 b blocker and the ester bond of phospholipids (Fig 51) may explain why the b blockers partitioned into the liposomes more strongly than the alkylamines For the more hydrophilic short-chain (p-methylbenzyl)alkylamines (n 0 3 in Fig 55), 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
512 GETTING IT WRONG FROM ONE-POINT log Dmem MEASUREMENT In the early literature, it was a common practice to make a single measurement of log D, usually at pH 74, and use a simpli ed version of Eq (410) (with log PI