The Octanol-Water Partition Coefficient

In environmental work, extensive use is made of a special K value, the octanol-water partition coefficient. It describes the distribution of a solute between octanol and water i.e., it is defined by 

Octanol, or more properly 1-octanol, was chosen as a correlating substance because its carbon-to-oxygen ratio is similiar to that of lipids and, in general, mimics the dissolution of solutes in organic matter. is also a direct measure of hydrophobicity, i.e., the tendency of a chemical to partition out of water, and is consequently an inverse measure of the solubility of a substance in water. The higher the ICqc, the greater the effect of a chemical on an animal. A short list of Kqq values for various substances appears in Table 6.7. 

The following serves as an example of the application of octanol-water partition coefficients Suppose it is desired to estimate the effect on fish of the pesticide DDT dissolved in water. The lipid content of most fish clusters about a value of 4.8%. We can then define a fish-water partition coefficient 

This relation expresses the assumption that a fish is composed of 4.8% by volume octanol. Using the value for DDT listed in Table 6.7, we obtain 

Octanol—Water Partition Coefficients for Various Substances 

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Two approaches to quantify/fQ, i.e., to establish a quantitative relationship between the structural features of a compoimd and its properties, are described in this section quantitative structure-property relationships (QSPR) and linear free energy relationships (LFER) cf. Section 3.4.2.2). The LFER approach is important for historical reasons because it contributed the first attempt to predict the property of a compound from an analysis of its structure. LFERs can be established only for congeneric series of compounds, i.e., sets of compounds that share the same skeleton and only have variations in the substituents attached to this skeleton. As examples of a QSPR approach, currently available methods for the prediction of the octanol/water partition coefficient, log P, and of aqueous solubility, log S, of organic compoimds are described in Section 10.1.4 and Section 10.15, respectively. 

The octanol—water partition coefficient, which is used as an iadicator of the tendency of an organic chemical to accumulate ia living tissue, was low. This iadicates that naphthalene is unlikely to accumulate ia the body. 

Other evaluations (27,28) of environmental considerations report vapor pressure, water solubiHty, and the octanol/water partition coefficient for trimethylbenzenes. 

Silicones have been detected in water from various rivers and in effluent from wastewater treatment faciUties. They are barely detectable in water from municipal treatment faciUties. Water solubiUty (S) of siUcones has been found to correlate with the octanol—water partition coefficients for a... 

This expression can be used to predict solubiUties from the octanol-water partition coefficients. SolubiUty and data for four oligomeric siloxanes are hsted in Table 14. 

Octanol—Water Partition Coefficient. In environmental calculations, the octanol—water partition coefficient, is related to a chemical s Hpophilicity and... 

Once the composition of each equiHbrium phase is known, infinite dilution activity coefficients for a third component ia each phase can then be calculated. The octanol—water partition coefficient is directly proportional to the ratio of the infinite dilution activity coefficients for a third component distributed between the water-rich and octanol-rich phases (5,24). The primary drawback to the activity coefficient approach to estimation is the difficulty of the calculations involved, particularly when the activity coefficient model is complex. 

Closely related to water solubility as a polarity measure is the partition coefficient of a substance between water and an immiscible organic solvent. Most commonly the organic solvent is selected to be n-octanol, and the symbol P is given to the octanol/water partition coefficient. Then log P is a quantitative measure of hydro-phobicity and, therefore, of nonpolarity. Table 8-3 gives log P values for many of... 

The BUSES model provides an estimate of the organic carbon/water partition coefficient (Koc) based on the octanol/water partition coefficient (Kow)- From these data, it is evident that the methyltins are less likely to partition onto organic carbon (in sediments, soils, biota) than are the butyl- and octyltin compormds due to then-lower partition coefficients and higher water solubilities. The 7/oc value can then be used to derive sohds/water partition coefficients in suspended matter, in sediment, and in soil using values of 10%, 5%, and 2% for organie carbon, representing typical organic carbon contents of suspended matter, sediment, and soil, respeetively. 

Connell, D.W. (1994). The octanol-water partition coefficient, Chapter 13 ofVol. 2, in Calow (Ed.). Handbook of Ecotoxicology. Oxford, U.K. Blackwell. 

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. 

Polar surface area (PSA) - defined simply as the part of a molecular surface that is polar - is probably, together with the octanol-water partition coefficient, one of the most important parameters used to characterize the transport properties of drugs. PSA has been shown to provide very good correlations with intestinal... 

Usually aquatic toxicity of chemicals with general narcosis mechanism of action is described by the octanol/water partition coefficient [73]. However, log is a composite descriptor which has components of molecular volume and H-bond acceptor terms. Raevsky and Dearden [74] therefore used molecular polarizabihty (as a volume-related term) and the H-bond acceptor factor instead of log to model aquatic toxicity (log LC50) to the guppy for 90 chemicals with general narcosis mechanisms. This excellent correlation has statistical criteria better than that obtained for the same data using log Pofy, ... 

Almost all widely used, reliable prediction models for logarithmic partition coefficients, and especially for the octanol-water partition coefficient log P w, are linear regression models with respect to fragment counts, atom types, bond types or... 

Paschke, A., Manz, M., Schtiurmann, G. Application of different RP-HPLC methods for the determination of the octanol/water partition coefficient of selected tetrachlorobenzyltoluenes. Chemosphere 2001, 45, 721-728. 

Poole, S. K., Durham, D., Kibbey, C. Rapid method for estimabng the octanol-water partition coefficient (logPow) fiy microemulsion electrokinetic... 

Broto, P., Moreau, G., Vandycke, C. Molecular structures, perception, autocorrelation descriptor and SAR studies system of atomic contributions for the calculation of the octanol-water partition coefficient. Eur. J. Med. Chem. 1984, 79, 71-78. 

The pKa of a molecule, a charge-state-related parameter, is a descriptor of an acid-base equilibrium reaction [34,35]. Lipophilicity, often represented by the octanol-water partition coefficient Kp is a descriptor of a two-phase distribution equilibrium reaction [36]. So is solubility [37-39]. These three parameters are thermodynamic constants. On the other hand, permeability Pe is a rate coefficient, a kinetics parameter, most often posed in a first-order distribution reaction [40-42]. 

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.]...

Winters and Lee134 describe a physically based model for adsorption kinetics for hydrophobic organic chemicals to and from suspended sediment and soil particles. The model requires determination of a single effective dififusivity parameter, which is predictable from compound solution diffusivity, the octanol-water partition coefficient, and the adsorbent organic content, density, and porosity. 

The binding constants of a number of compounds were measured using dialysis, solubility and sorption techniques. The solubility technique was used for compounds which were not radiolabeled. All data was collected at pH = 8.3. The binding constants were then compared to the octanol/water partition coefficients for the compounds and the molar solubilities of the compounds. The data is presented in Table II. The Kow values were taken from the literature.18 22-2 The solubility values were determined in this research with the exception of DDT and Lindane, which were taken from the literature. A plot of log Kc vs. log Kow is presented in Figure 5. The slope of this line is 0.71, the intercept is 0.75 and the value of the correlation coefficient is 0.9258. The regression is highly significant... 

The data presented here indicates that the extent of binding for a particular compound is related to the octanol/water partition coefficient for that compound. This is very similar to the sorption of compounds from water to sediment. Compounds with log Kow values less than four (such as Lindane) will probably not be bound to an appreciable extent in the environment. Compounds with very high log Kow values (DDT and DEHP) may be bound to a significant extent. The extent of binding will depend on both the concentration of humic material and on the nature of the humic material. The humic materials used in this research showed dramatically different affinities for DDT. The reasons for this are poorly understood and deserve further study. 

Transport of the herbicides by vapor diffusion on moist soil was shown to be directly related to vapor pressure and inversely related to water solubility. Transport of the herbicides by leaching was shown to be inversely related to the Freundlich adsorption coefficient which in turn was directly related to the octanol/water partition coefficient and inversely related to water solubility (16). 

For substituents on benzene, lipophilicities are given by values of kx, as measured by the following equation (Scheme 1.1), where P values are the octanol/water partition coefficients. 

McFarland et al. recently [1] published the results of studies carried out on 22 crystalline compounds. Their water solubilities were determined using pSOL [21], an automated instrument employing the pH-metric method described by Avdeef and coworkers [22]. This technique assures that it is the thermodynamic equilibrium solubility that is measured. While only ionizable compounds can be determined by this method, their solubilities are expressed as the molarity of the unionized molecular species, the intrinsic solubility, SQ. This avoids confusion about a compound s overall solubility dependence on pH. Thus, S0, is analogous to P, the octanol/water partition coefficient in both situations, the ionized species are implicitly factored out. In order to use pSOL, one must have knowledge of the various pKas involved therefore, in principle, one can compute the total solubility of a compound over an entire pH range. However, the intrinsic solubility will be our focus here. There was one zwitterionic compound in this dataset. To obtain best results, this compound was formulated as the zwitterion rather than the neutral form in the HYBOT [23] calculations. 

Many groups have discussed the correlation between solubility and molecular properties [14-19], and the octanol/water partition coefficient, the molecular volume and surface area, the boiling point and charge distribution in the molecules are well-documented molecular descriptors that correlate strongly with experimental solubility. 

Second, P-gp differs from other transporters in that it recognizes its substrates when dissolved in the lipid membrane [52], and not when dissolved in aqueous solution. The site of recognition and binding has been shown to be located in the membrane leaflet facing the cytosol [53, 54], This implies that the membrane concentration of the substrate, Csm, determines activation [57]. Since the nature of a molecular interaction is strongly influenced by the solvent, the lipid membrane must be taken into account as the solvent for the SAR analysis of P-gp. Under certain conditions, the effect of additional solvents or excipients (used to apply hydrophobic substrates or inhibitors) on the lipid membrane and/or on the transporter must also be considered. Lipophilicity of substrates has long been known to play an important role in P-gp-substrate interactions nevertheless, the correlation of the octanol/water partition coefficients with the concentration of half-maximum... 

Absorption, in general, is treated as a physicochemical transport process based on computations of logP (the octanol/water partition coefficient) and solubility governed by factors such as polar surface area on the molecule. It is conceivable that SNPs in drug transporter genes will affect the pharmacokinetic properties of compounds and, therefore, these may have to be taken into consideration in the design process. 

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