Membrane models octanol-water system

The partition coefficient or its logarithm serves as a quantitative measure of a compound s lipophilicity. For pharmaceuticals, water and 1-octanol are the two solvents used most frequently to measure lipophilicity. The two-phase octanol/water system closely models the cell membrane/interstitial fluid interface. While Lipinski s rules do not specify a minimum lipophilicity, a log P value of 5 or less prevents a drug from effectively hiding within membranes. 

Numerous examples available from the application of the octanol-water system allow translation between different solvents or the modeling of a lipid membrane, provided the Collander relation [19] is valid. 

In 1962, Hansch, Maloney and Fujita [Hansch, Maloney et al, 1962] published their study on the structure-activity relationships of plant growth regulators and their dependency on Hammett constants and hydrophobidty. Using the octanol/water system, a whole series of partition coefficients was measured and, thus, a new hydrophobic scale was introduced for describing the inclination of molecules to move through environments characterized by different degrees of hydrophilicity such as blood and cellular membranes. The delineation of Hansch models led to explosive development in QSAR analysis and related approaches [Hansch and Leo, 1995]. This approach known with the name of Hansch analysis became and it still is a basic tool for QSAR modeling. 

The 1-octanol-water system is challenged as the only valid hydrophobicity scale. It may not be the best model for studying the partitioning process m biomembranes. Does not the retention in RPLC model better this partitioning It has been argued that the chemical bonded stationary phase resembles more the hydrocarbon chains of membranes, but the bonding density of almost all commercial columns may be too low to provide a suitable model. 

Thus, a comparison between HPLC-derived lipophilicity indices and calculated log P values for a series of 8-substituted xanthines showed a clear influence of conformational effects. 8 In this case, Rekker s method was unable to take 3D effects into account, but the difference between experimental and predicted values was structure dependent rather than constant. Conformational analyses confirmed that a smaller than predicted lipophilicity was associated with folded conformers stabilized by hydrophobic and van der Waals forces and having part of their nonpolar surface masked from the aqueous phase. A 4D theoretical approach (log P calculations by MLP for conformers generated by high temperature molecular dynamics) suggests that these effects should be lower in an w-octanol/water system than in RP-HPLC. Indeed, the n-octanol/water system is not the most suitable model to study intramolecular interactions in nonpolar media because a surprisingly high proportion of water is dissolved in the w-octanol. Recall, however, that w-octanol, despite some limitations, was selected by many workers in the field as a model for biological membranes. 

A CRO may also allow for the in-house introduction of specialized lipophilic scales by transferring routine measurements. While the octanol-water scale is widely applied, it may be advantageous to utilize alternative scales for specific QSAR models. Solvent systems such as alkane or chloroform and biomimetic stationary phases on HPLC columns have both been advocated. Seydel [65] recently reviewed the suitabihty of various systems to describe partitioning into membranes. Through several examples, he concludes that drug-membrane interaction as it relates to transport, distribution and efficacy cannot be well characterized by partition coefficients in bulk solvents alone, including octanol. However, octanol-water partition coefficients will persist in valuable databases and decades of QSAR studies. 

The distribution coefficient between a liposome phase (see above about the membrane phase) and a water phase also has been used instead of an octanol/water partition coefficient (log P). The liposome phase provides a biomimetic environment to a much larger degree compared with the octanol phase and has shown to the ability to predict in vivo permeability more precisely (13). Lipid bilayer-containing partition systems thus have been considered to model the hydrogen-bonding abU-... 

These studies with a polymeric membrane validate this barrier model. It is clear that the tendency to partition into the membrane will influence flux through the membrane and one might anticipate that the octanol-water partition coefficients will be useful predictors of absorption. However, if this model applies in biological systems, one would not expect to observe this relation at higher values of A ow- With weak acids and bases the neutral form would move across a membrane more readily than its charged counterpart, and, consequently, one would predict that variation in environmental pH will influence the uptake of these compounds. Also, if the environmental pH is relatively constant, such as is observed, say in the stomach, or small intestine, the pTta of the acid or base will determine the proportion in the neutral form at that pH and, hence, the absorption efficiency. These relations will be illustrated with examples from studies in animals and plants. 

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