Lipophilic parameters

In 1985 a major step in the theoretical analysis of oral drug absorption phenomena took place [156], when solubility and dose were also taken into account for the estimation of the absorption potential A P of a drug apart from the pH-partition hypothesis related parameters (lipophilicity, and degree of ionization). According to this concept, the AP is related proportionally to the octanol/water partition coefficient Pc, the fraction of the un-ionized species, at pH= 6.5, and the physiological solubility cs of the drug and inversely proportional to the dose r/o ... 

Physicochemical parameters are widely used in QSRR studies. Among the many physicochemical parameters, lipophilicity is one of the most widely used parameters in TLC QSRR studies. As is well known, there is a linear relationship between the =... 

Moriguchi model based on structural parameters - lipophilicity descriptors... 

The second set of parameters are compound specific and will determine its transport over barriers (e.g., between gut and blood, blood and tissues), its biotransformation, and its excretion. Most of the transport parameters can be described as partition coefficients [20] and are strongly determined by the compound s physicochemical parameters, lipophilicity and volatility being the most important ones. However, the role of transporter proteins present in cellular membranes and responsible for the partitioning over specific barriers needs special attention, e.g., in the gut, the kidney, and at the blood-brain barrier [22], the blood placenta barrier, and the liver-bile interface [23]. 

Using Eq. [4] and the A parameter, lipophilicity can thus be factorized into a polar and a nonpolar term, as exemplified by Eq. [5] for the oc-tanol/water system ... 

The amino group is readily dia2oti2ed in aqueous solution, and this reaction forms a basis for the assay of sulfas. Aldehydes also react to form anils, and the yellow product formed with 4-(dimethylamino)hen2a1dehyde can be used for detection in thiu-layer and paper chromatography. Chromatographic retention values have been deterrnined in a number of thiu layer systems, and have been used as an expression of the lipophilic character of sulfonamides (23). These values have corresponded well with Hansch lipophilic parameters determined in an isobutyl alcohol—water system. 

HPLC INVESTIGATION OF pH DEPENDENCY OF THE LIPOPHILICITY PARAMETER OF PARABENS... 

In this section we describe a cellular automata model of a semipermeable membrane separating two compartments [5]. A solute in one compartment has varied parameters to reflect its relative polarity or lipophilicity. The passage of this solute into and through the membrane is observed, as this property is varied. 

The importance of lipophilicity to bitterness has been well established, both directly and indirectly. The importance of partitioning effects in bitterness perception has been stressed by Rubin and coworkers, and Gardner demonstrated that the threshold concentration of bitter amino acids and peptides correlates very well with molecular connectivity (which is generally regarded as a steric parameter, but is correlated with the octanol-water partition coefficient ). Studies on the surface pressure in monolayers of lipids from bovine, circumvallate papillae also indicated that there is a very good correlation between the concentration of a bitter compound that is necessary in order to give an increase in the surface pressure with the taste threshold in humans. These results and the observations of others suggested that the ability of bitter compounds to penetrate cell membranes is an important factor in bitterness perception. 

Lipophilicity is intuitively felt to be a key parameter in predicting and interpreting permeability and thus the number of types of lipophilicity systems under study has grown enormously over the years to increase the chances of finding good mimics of biomembrane models. However, the relationship between lipophilicity descriptors and the membrane permeation process is not clear. Membrane permeation is due to two main components the partition rate constant between the lipid leaflet and the aqueous environment and the flip-flop rate constant between the two lipid leaflets in the bilayer [13]. Since the flip-flop is supposed to be rate limiting in the permeation process, permeation is determined by the partition coefficient between the lipid and the aqueous phase (which can easily be determined by log D) and the flip-flop rate constant, which may or may not depend on lipophilicity and if it does so depend, on which lipophilicity scale should it be based ... 

However, Clog P and, more generally, Hpophilidty descriptors referring to octanol-water are not the only lipophilicity parameters to be taken into account As mentioned above, isotropic and anisotropic Hpophilidty values gave rise to two different Hpophilidty scales for ionized compounds and thus it is recommended to test both of them (after checking the absence of any coHnearity) when looking for a QSAR model involving ions. 

Relationships between lipophilicity and retention parameters obtained by RPLC methods using isocratic or gradient condition are reviewed. Advantages and limitations of the two approaches are also pointed out, and general guidelines to determine partition coefficients in 1-octanol-water are proposed. Finally, more recent literature data on Hpophilicity determination by capillary electrophoresis of neutral compounds and neutral forms of ionizable compounds are compiled. Quotation is restricted to key references for every method presented - an exhaustive listing is only given for the last few years. 

The different organic modifiers used to derive the most suitable mobile phases lead to different parameters namely isocratic logfe and extrapolated logkw. The extrapolation method has no reality in terms of chromatographic behavior of solutes. However, mainly by correlation with log Pod (Eqs. 2 and 3) several studies have demonstrated the interest of these extrapolated retention factors as predictors of the lipophilicity of solutes. 

A thorough review, even with a very superflcial mention of the vast literature on ADME, QSPR and QSAR applications involving the use of lipophilicity, would be a daunting task and it is far beyond the scope of this chapter. However, it is no surprise that three international conferences, in recent years, have been specifically dedicated to this topic, and that the development of newer and faster screening methods, in some cases seeking to produce alternative lipophilicity parameters to the classical or nonclassical log Pod determinations are still an active area of interest [6]. 

We also note, in closing, that lipophilicity is a key parameter of the well-known Rule-of-5 [19] and it represents probably the single most broadly used parameter in these efforts whether the approach is experimental or in silica [20]. 

We have tried to cover some of the important aspects of the determination and use oflog P and log D parameters. Far from being exhaushve, this chapter attempted to offer some considerations and perspective in a field where, after 40 years from its beginning at the hand of Corwin Hansch et al, there does not seem to be much alternative to the balance of forces encoded by the octanol-water system to model lipophilicity. 

L. G. Reevaluating equilibrium and kinetic binding parameters for lipophilic drugs based on a structural model for drug interaction with biological membranes. 

---