Lipophilicity profiles

Lewis DFV. Structural characteristics of human P450s involved in drug metabolism QSARs and lipophilicity profiles. Toxicology 2000 144 197-203. 

C-IS lactones are examples of this class the structure consists mainly of a lipophilic profile. These may, perhaps, interact as for the tautomeric form discussed earlier (see Section 11,4). 

In the traditional shake-flask method, the apparent partition coefficient, log D, is measured, usually at pH 7.4 (sometimes at pH 6.5). Different buffers are used to control each pH used in the determinations [70]. Usually, in a comprehensive study, several pH measurements are made, and values of log are plotted against the pH. This plot is often called the lipophilicity profile . One can determine the true partition coefficients (log P ) and the ionization constants from the features in such a curve. 

Figure 3.1 shows an example of a monoprotic base, pindolol, lipophilicity profile, as a function of pH. The two limiting slopes in the curve are zero and the slope in between is -i-l (-1 for acids). The maximum value of log Doa is equal to logPoa... 

The lipophilicity profile of an acid is a mirror image of the shape in Fig. 3.1, i.e. the maximum (neutral-species) partitioning occurs at low pH and the minimum (ion-pair) partitioning at high pH. Other shapes are described in the review by Avdeef [18]. 

The Jamieson paper reports the results of a number of studies, some successful, others not. Failures can be ascribed to the difficulties encountered in log P control. The first evident trouble concerns the choice of the lipophilicity descriptor many prefer log P, but this choice is questionable as has been outlined by Lombardo (see Chapter 16). Secondly, variations in lipophilicity profile influence not only hERG activity, but also target selectivity and also ADMET properties. Lipophilicity is a bulk property and its modification can involve different moieties of the molecules. Once the chemical modulation has been designed, but before moving to the bench, the research group should predict the consequences of this change on each step of the drug s action, but unfortunately this is not always done. 

The log D value at a single pH is often influenced by ion partitioning, especially at neutral pH where log D may be used in quantitative structure-permeation relationships. Therefore, the lipophilicity profile may be essential to interpreting PK... 

Of course, the shape of the lipophilicity profiles becomes much more complicated for molecules with multiple ionized forms. Nevertheless, the partition coefficients may be calculated from the distribution coefficient using the general equation [113] ... 

General equations may be derived to express the above correction term, and it is easy to demonstrate that, in the case of a monoprotic substance, the lipophilicity profile on the entire pH range reads ... 

However, recent studies on the variation of the distribution coefficient of ionizable drugs as a function of pH (pH-lipophilicity profiles) shows that the partitioning of charged species cannot be neglected [143]. In other words, the general relationship between distribution and partition coefficients [Eq. (15)] cannot be simplified. 

FIG. 5 pH-lipophilicity profiles (on the left) and errors (curves in bold on the right) made by using the simplified Eq. (14) instead of the complete Eq. (15) when estimating log/ . The calculation is made for a monobase (top), a monoacid (middle), and a zwitterion (bottom) with a difference of three units between log/ and log/. (Adapted from Ref. 143.)... 

Figure 4.2 (a) Lipophilicity profile of a weak acid at two values of background salt and... 

Figure 4.4 (a) Lipophilicity profile of an ampholyte at two values of background salt and (b) log-log speciation plot at 0.15 M KC1. [Avdeef, A., Curr. Topics Med. Chem., 1, 277-351 (2001). Reproduced with permission from Bentham Science Publishers, Ltd.]... 

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... 

Comer, J. Tam, K., Lipophilicity profiles theory and measurement, in Testa, B. van de Waterbeemd, H. Folkers, G. Guy, R. (eds.), Pharmacokinetic Optimization in Drug Research, Verlag Helvetica Chimica Acta, Zurich and Wiley-VCH, Weinheim, 2001, pp. 275-304. 

The general form of the equation for lipophilicity profiles is shown below ... 

Fig. 2.1. Lipophilicity profiles for diclofenac (acid), propranolol (base) and morphine (ampholyte). Dashed lines indicate the pH range where molecule may partition in its ionized form.

Lipophilicity profiles are readily calculated from pH-metric data, as pH, P and Ka are known and can be used in Eq. (1). 

Figure 2. Lipophilicity profiles of (a) dinitro-o-cresol and (b) 3,4-dimethylaniline. Dow values were calculated with the data and model described by Jafvert et al. [129], and Johnson and Westall [130], Dmw values were calculated with the data and model described by Escher et al. [140]...

Figure 4. Scheme of lipophilicity profile of zwitterionic compounds. The line drawn represents the case where the neutral tautomer predominates or the zwitterion is rather hydrophobic, resulting in a bell-shaped profile. The dashed line represents the case where the zwitterion predominates and intramolecular interactions are not possible, resulting in a U-shaped profile. Adapted with permission from [133] Pagliara, A. et al. (1997). Lipophilicity profiles of ampholytes , Chem. Rev., 97, 3385-3400 copyright (1997) American Chemical Society... 

Particularly interesting examples are also the lipophilicity profiles of ampholytes. Depending on the ratio between the neutral tautomer and the zwitterionic tautomer, the log Dow versus pH profile may be bell-shaped or U-shaped [133] (Figure 4). For zwitterions, the shape of the lipophilicity profile depends upon the structure and conformation of the molecule. If the charged groups are situated in proximity and can interact with each other, the zwitterion might be more hydrophobic than the anionic and the cationic species, resulting in a bell-shaped lipophilicity profile. If, however, intramolecular interactions are not possible for steric reasons, the lipophilicity profile is U-shaped [133],... 

The pA is consequently equal to the pshifted by Amw and can be directly deduced from the lipophilicity profile (Figure 6). Since Amw is generally smaller in the membrane-water system as compared to the octanol water... 

Figure 6. Derivation of the pfrom a lipophilicity profile, a refers to acid, b to a base...

Figure 7. Lipophilicity profile of propranolol in liposomes composed of zwitterionic and charged lipids (phosphatidyl ethanolamine (PE), oleic acid (OA), phosphatidyl inositol (PI)). Conditions of measurements are described in [113]. The dotted line indicates the partitioning profile of propranolol in the egg PC liposome system. The bars show the pH-dependent charge profile of propranolol (hatched bars positively charged propranolol) and the lipids in the membrane (black bars negatively charged lipids). Reprinted from [113] Kramer, S. (2001). Liposome/water partitioning , In Pharmacokinetic Optimization in Drug Research, eds. Testa, B. et al. Reproduced by permission of Verlag Helvetica Chimica Acta, Zurich...

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