Octanol-water partition coefficient factor

An overview of some basic mathematical techniques for data correlation is to be found herein together with background on several types of physical property correlating techniques and a road map for the use of selected methods. Methods are presented for the correlation of observed experimental data to physical properties such as critical properties, normal boiling point, molar volume, vapor pressure, heats of vaporization and fusion, heat capacity, surface tension, viscosity, thermal conductivity, acentric factor, flammability limits, enthalpy of formation, Gibbs energy, entropy, activity coefficients, Henry s constant, octanol—water partition coefficients, diffusion coefficients, virial coefficients, chemical reactivity, and toxicological parameters. 

An important factor in determining the course of uptake, transport, and distribution of xenobiotics is their polarity. Compounds of low polarity tend to be lipophilic and of low water solubility. Compounds of high polarity tend to be hydrophilic and of low fat solubility. The balance between the lipophilicity and hydrophilicity of any compound is indicated by its octanol-water partition coefficient (K J, a value determined when equilibrium is reached between the two adjoining phases ... 

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. 

Niimi AJ, HB Lee, GP Kissoon (1989) Octanol/water partition coefficients and bioconcentration factors of chloronitrobenzenes in rainbow trout Salmo gairdneri) Environ Toxicol Client 8 817-823. 

From an analysis of the key properties of compounds in the World Dmg Index the now well accepted Rule-of-5 has been derived [25, 26]. It was concluded that compounds are most Hkely to have poor absorption when MW>500, calculated octanol-water partition coefficient Clog P>5, number of H-bond donors >5 and number of H-bond acceptors >10. Computation of these properties is now available as a simple but efficient ADME screen in commercial software. The Rule-of-5 should be seen as a qualitative absorption/permeabiHty predictor [43], rather than a quantitative predictor [140]. The Rule-of-5 is not predictive for bioavail-abihty as sometimes mistakenly is assumed. An important factor for bioavailabihty in addition to absorption is liver first-pass effect (metaboHsm). The property distribution in drug-related chemical databases has been studied as another approach to understand drug-likeness [141, 142]. 

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, ... 

The Rvalues are partition coefficients. The assumption that these are real constants Is seldom completely true, of course, because equilibrium Is rarely achieved and because the equilibrium ratios generally are not the same for all concentration levels. Moreover, It Is difficult to find the needed Information, and one must often accept a single literature value as typical of a given Intermedia transfer. When the organic content of the soli Is known or can be accurately estimated, one can usually derive Kgw from a compound s aqueous solubility, S, or Its octanol/water partition coefficient, KQW (14) Values of Kpa, namely "bloconcentratlon factors" between feed and meat animals (15,16), can also be derived from S or KQW. Bloconcentratlon factors between water and fish are well documented (14) A considerable weakness exists In our perception of the proper estimates to use for partition coefficients between soli and edible crop materials. Thus, at one time, two of the present authors used a default value of Kgp = 1 for munitions compounds that are neither very soluble In water nor very Insoluble (4) at another time, a value of was assumed for compounds with very low values of Ksw, l.e., polybromoblphenyls (6). 

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. 

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. 

Briggs GG (1981) Theoretical and experimental relationships between soil adsorption, octanol-water partition coefficients, water solubilities, bioconcentration factors, and the parachor. J Agric Food Chem 29 1050-1059... 

De Wolf, W, De Bruijn, J H M, Seinen W, Hermens JLM (1992) Influence of biotransformation on the relationship between bioconcentration factors and octanol water partition-coefficients. Environ Sci Technol 26(6) 1197-1201... 

There is a continuing effort to extend the long-established concept of quantitative-structure-activity-relationships (QSARs) to quantitative-structure-property relationships (QSPRs) to compute all relevant environmental physical-chemical properties (such as aqueous solubility, vapor pressure, octanol-water partition coefficient, Henry s law constant, bioconcentration factor (BCF), sorption coefficient and environmental reaction rate constants from molecular structure). 

Hawker, D. W. (1990a) Vapor pressures and Henry s law constants of polychlorinated biphenyls. Environ. Sci. Technol. 23, 1250-1253. Hawker, D. W. (1990b) Description of fish bioconcentration factors in terms of solvatochromic parameters. Chemosphere 20, 267-477. Hawker, D. W., Connell, D. W. (1988) Octanol-water partition coefficients of polychlorinated biphenyl congeners. Environ. Sci. Technol. 22, 382-387. 

Isnard, R, Lambert, S. (1988) Estimating bioconcentration factors for octanol-water partition coefficient and aqueous solubility. 

Sherblom, P.M., Eganhouse, R.P. (1988) Correlations between octanol-water partition coefficients and reversed-phase high-performance liquid chromatography capacity factors. J. Chromtogr. 454, 37-50. 

Polychlorinated biphenyls structure, retention times, response factors, and octanol/water partition coefficients (log Kow)... 

Laskowski [1] has thoroughly reviewed the physico-chemical properties of the SPs, and these are summarized briefly below. SPs are typically of low water solubility (in the low microgram per liter range) and are highly nonpolar (logarithmic octanol water partition coefficients of around 6-7), indicating potential for bioaccumulation. Fish bioconcentration factors (BCF) of several hundred to several thousand are reported however metabolism limits the amount of bioaccumulation,... 

In a recent study of twenty disperse and solvent dyes, data for water solubility, octanol/ water partition coefficient, entropy of fusion and melting point were subjected to regression analysis. Complicating factors such as impurities, polymorphism, tautomerism, polarisation and hydrogen bonding precluded the development of reliable predictions of solubility and partition coefficient. Anthraquinone dyes exhibited much lower entropy of fusion than many of the azo dyes [64,65]. 

The dominant transport process from water is volatilization. Based on mathematical models developed by the EPA, the half-life for M-hexane in bodies of water with any degree of turbulent mixing (e.g., rivers) would be less than 3 hours. For standing bodies of water (e.g., small ponds), a half-life no longer than one week (6.8 days) is estimated (ASTER 1995 EPA 1987a). Based on the log octanol/water partition coefficient (i.e., log[Kow]) and the estimated log sorption coefficient (i.e., log[Koc]) (see Table 3-2), ii-hexane is not expected to become concentrated in biota (Swann et al. 1983). A calculated bioconcentration factor (BCF) of 453 for a fathead minnow (ASTER 1995) further suggests a low potential for -hcxanc to bioconcentrate or bioaccumulate in trophic food chains. 

The most notable correlation found for the organic carbon partition coefficient (Koc) of hydrophobic chemicals is that obtained with the octanol/water partition coefficient (Kow). Recently, a single correlation has been proposed for all these compounds based on previous data (log(Koc/Kow) versus logAow) the specific approximation proposed was Koc = 0.35 Kow, but this could vary by a factor of 2.5 in either direction [39]. 

Estimation is easier and less time-consuming because use is made of empirical relationships between the BCF and physicochemical properties of the compound, such as water solubility (S) [42-48], Km, (solid organic carbon/water partition coefficient) [48], Kmw (membrane water partition coefficient), iipw (liposome water partition coefficient) [49], critical micelle concentration (CMC) [45], steric factors, molecular weight [47,48], and others. The most common regression method is the estimation of BCF from the octanol-water partition coefficient (Kovl) [18,42,44-48,50,51],... 

Kd is difficult to define when dealing with actual field conditions. Laboratory studies have demonstrated that an approximation of Kd can be made based on the more easily determined factors such as organic carbon content of the soil and the octanol-water partitioning coefficient of the compound. For sediment particles <50 pm ... 

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