Lipophilicity octanol-water partition

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. 

Octanol-water partition (log P) and distribution (log D) coefficients are widely used to make estimates for membrane penetration and permeability, including gastrointestinal absorption [77, 78], BBB crossing [60, 69] and correlations to pharmacokinetic properties [1]. The two major components of lipophilicity are molecular size and H-bonding [57], which each have been discussed above (see Sections 2.5 and 2.6). 

Each of these scales produce a lipophilicity index related but not identical to octanol-water partitioning. 

Sangster, J. Octanol-Water Partition Coefficients Fundamentals and Physical Chemistry, Wiley, Chichester, 1997. n Valko, K. Application of high-performance liquid chromatography based measurements of lipophilicity to model biological distribution. J. Chromatogr. A 2004, 1037, 299-310. 

The importance of molecular size and H-bond strength for octanol-water partitioning is used by the SLIPPER model [13, 14], which calculates lipophilicity for... 

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. 

Rekker, R. E., Mannhold, R., Bijloo, G., De Vries, G Dross, K. The lipophilic behaviour of organic compounds 2. The development of an aliphatic hydrocarbon/ water fragmental system via interconnection with octanol-water partitioning data. Quant. Struct.-Activ. Rel. 1998, 37, 537-548. 

The diphenyl ether herbicides are nonvolatile compounds, generally very lipophilic and insoluble in water. Solubility in water and octanol-water partition coefficients (logXow) of the various diphenyl ether herbicides range from 120mgL (acifluorfen) to 0.16 mg (oxyfluorfen) and from 2.9 (fomesafen) to 5.4 (acifluorfen), respectively. Diphenyl ether herbicides are stable in an acidic or alkaline condition, but some compounds are gradually degraded under the sunlight. ... 

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]. 

The procedure takes as input parameters the measured (or calculated) pKa and the measured (or calculated) octanol-water partition coefficient, log P. The latter parameter is used to estimate the intrinsic solubility So, using the Hansch-type expression [38], log So = 1.17 — 1.38 log P, or an improved version for ionizable molecules of moderate lipophilicity (Fig. 6.6) ... 

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. 

Several approaches for higher-throughput lipophilicity measurements have been developed in the pharmaceutical industry [38], including automated shake-plate methods [46], and some of these are now available commercially [47]. A convenient method to measure octanol/water partitioning is based on potentiometric titration this is called the pH-method [48],... 

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... 

The importance of physical properties in drug action underlies many aspects of modern drug discovery in particular, compound lipophilicity (as estimated by LogP, the logarithm of the 1-octanol-water partition... 

The logarithm of the 1 -octanol - water partition coefficient, denoted log Kq j or log P, indicates the distribution of the compound between the organic and the water phase. For highly lipophilic compounds, the log P is determined via reversed-phase thin-layer chromatography, giving the so-called log P tlc value1. 

The relationship between the herbicidal activity of 1,2,5-oxadiazole iV-oxides and some physicochemical properties potentially related to this bioactivity, such as polarity, molecular volume, proton acceptor ability, lipophilicity, and reduction potential, were studied. The semi-empirical MO method AMI was used to calculate theoretical descriptors such as dipolar moment, molecular volume, Mulliken s charge, and the octanol/water partition coefficients (log Po/w) <2005MOL1197>. 

Wame, M., St. J., Connell, D. W., Hawker, D. W. (1990) Prediction of aqueous solubility and the octanol-water partition coefficient for lipophilic organic compounds using molecular descriptors and physicochemical properties. Chemosphere 16, 109-116. 

The SPs have been shown to be highly toxic to fish and aquatic invertebrates, particularly arthropods, with toxicities as low as the nanogram per liter range in laboratory studies (see Sect. 3). However, due to their high lipophilicity and octanol water partition coefficient (Koc) values, they are rapidly adsorbed to suspended and bottom sediments [1], effectively limiting the exposure of water column organisms. 

Litman etal. [ 391 analyzed a set of 34 diverse drugs and their effect on the kinetics of the ATPase activity of the microsomal membrane fraction of a P-gp overexpressing CHO cell line. They found a correlation (r=0.75) between the affinity of the modulators and their van der Waals surface area, while the affinity data did not correlate with the lipophilicity of the compounds, expressed as calculated octanol/ water partition coefficients. 

LogP (the octanol/water partition coefficient, which indicates lipophilic-ity) >5, or... 

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