Partition coefficient lipophilicity

Hansch and Toshio Fujita, a postdoctoral researcher in Hansch s group, designed a parameter, ttr, to estimate the lipophilicity of an R-group.3 Hansch s parameter relies on partition coefficients to measure lipophilicity. Partition coefficients, P, are equilibrium constants describing the degree to which a molecule distributes into a biphasic mixture of two immiscible solvents. Hansch used 1-octanol and water as the model solvents because these were known to simulate the lipid membrane-cytosol interface. The partition coefficient of a molecule is defined as the ratio of a molecule s concentration in an octanol layer to its concentration in an aqueous layer (Equation 12.12). 

Dissolution of the compound also depends on its physicochemical properties notably, its aqueous solubility, ionizability (pKa), and lipophilicity (partition coefficient log Pfor neutral species or log P74 for partially ionized compounds). In addition to its effect on solubility, log Pis a crucial factor that governs passive membrane partitioning. However, while an increase in log P enhances permeability, it indicates a reduced solubility and... 

As stated, the development of complexes has been dictated by systematic changes based on empirical observations — the d5-Pt(am)2 unit works. A more quantitative approach takes into account a mathematical equation with electronic and steric factors and such parameters as lipophilicity. The idea that biological response was a function of chemical composition was first advanced in 1869 and a review of these developments is available in Albert s book (Chapter 1, Ref. 1). An account of the quantitative approach which correlates concentration to obtain a given response with electronic factors (e.g. Hammett constants) and lipophilicity (partition coefficients) has been given by Hansch [85]. Few QSAR relationships have been applied to the platinum complexes. 

Dmg distribution into tissue reservoirs depends on the physicochemical properties of the dmg. Tissue reservoirs include fat, bone, and the principal body organs. Access of dmgs to these reservoirs depends on partition coefficient, charge or degree of ionization at physiological pH, and extent of protein binding. Thus, lipophilic molecules accumulate in fat reservoirs and this accumulation can alter considerably both the duration and the concentration—response curves of dmg action. Some dmgs may accumulate selectively in defined tissues, for example, the tetracycline antibiotics in bone (see Antibiotics,tetracyclines). 

The partition coefficient P, defined as the equilibrium concentration of the compound in n-octanol divided by that in the aqueous phase, has been measured for pyrazole and indazole (B-79MI40416). It was found that log F = 0.13-0.26 for pyrazole and 1.82 for indazole, clearly showing the greater hydrophobicity (lipophilicity) of the indazole ring, due to the benzenoid moiety. 

The lipophilicity (7 m value) and specific hydrophobic surface area of pyrido[l,2-a]pyrazinium-l-olates 342 and -3-olate 343, and l-(4-chlorophe-nyl)-l-hydroxy-l,2-dihydropyrazino[2,l-a]isoquinolinium salt (344) has been measured by reversed-phase thin-layer chromatography (98MI13). Partition coefficient (log/ ) of 9-bromo-5-[(A-phenylaminocarbonyl)-methyl]-l,2,3,5,6,7-hexahydropyrido[l,2,3- fc]quinoxaline-2,3-dione was calculated to be 2.78 (97JMC4053). 

The ending caine stems from cocaine, the first clinically employed local anaesthetic. Procaine and tetracaine are ester-linked substances, the others are amides. Amide bonded local anaesthetics usually contain two i s in their name, ester-bonded only one. In the structure drawings, the lipophilic portion of the molecule is depicted at the left, the amine at the right. The asterisk marks the chiral centre of the stereoisomeric drugs. Lipid solubility is given as the logarithm of the water octanol partition coefficient, log(P). 

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 ... 

Compounds with high values are of low polarity and are described as being lipophilic and hydrophobic. Compounds with high values are of high polarity and are hydrophilic. Although the partition coefficient between octanol and water is... 

An analysis of partition coefficient data and drug solubilities in PCL and silicone rubber has been used to show how the relative permeabilities in PCL vary with the lipophilicity of the drug (58,59). The permeabilities of copolymers of e-caprolactone and dl-lactic acid have also been measured and found to be relatively invariant for compositions up to 50% lactic acid (67). The permeability then decreases rapidly to that of the homopolymer of dl-lactic acid, which is 10 times smaller than the value of PCL. These results have been discussed in terms of the polymer morphologies. 

In 1868 two Scottish scientists, Crum Brown and Fraser [4] recognized that a relation exists between the physiological action of a substance and its chemical composition and constitution. That recognition was in effect the birth of the science that has come to be known as quantitative structure-activity relationship (QSAR) studies a QSAR is a mathematical equation that relates a biological or other property to structural and/or physicochemical properties of a series of (usually) related compounds. Shortly afterwards, Richardson [5] showed that the narcotic effect of primary aliphatic alcohols varied with their molecular weight, and in 1893 Richet [6] observed that the toxicities of a variety of simple polar chemicals such as alcohols, ethers, and ketones were inversely correlated with their aqueous solubilities. Probably the best known of the very early work in the field was that of Overton [7] and Meyer [8], who found that the narcotic effect of simple chemicals increased with their oil-water partition coefficient and postulated that this reflected the partitioning of a chemical between the aqueous exobiophase and a lipophilic receptor. This, as it turned out, was most prescient, for about 70% of published QSARs contain a term relating to partition coefficient [9]. 

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. 

Further supporting evidence for the importance of lipophilicity in bitter response is provided by the taste of isohumulone (118), the principal, bitter-tasting component of beer, and some of its derivatives. Isohumulone can exist in both cis and trans forms. Clarke and Hilderbrand reported that the cis form, having a partition coefficient of 0.78, is more bitter than... 

Absorption of trichloroethylene in humans is very rapid upon inhalation exposure. Trichloroethylene has a blood/gas partition coefficient that is comparable to some other anesthetic gases (i.e., chloroform, diethylether, and methoxyfluorene), but it is much more lipophilic than these gases. As a consequence of these properties, the initial rate of uptake of inhaled trichloroethylene in humans is quite high, with the rate leveling off after a few hours of exposure (Fernandez et al. 1977). The absorbed dose is proportional to the inhaled trichloroethylene concentration, duration of exposure, and alveolar ventilation rate at a given inhaled air concentration (Astrand and Ovrum 1976). Several studies indicate that 37-64% of inhaled trichloroethylene is taken up from the lungs (Astrand and Ovrum 1976 Bartonicek 1962 Monster et al. 1976). 

Lipophilicity represents the affinity of a molecule or a moiety for a lipophilic environment. It is commonly measured by its distribution behavior in a biphasic system, either liquid-liquid (e.g. partition coefficient in 1-octanol-water) or solid-liquid (retention on reversed-phase high-performance liquid chromatography or thin-layer chromatography system). 

In the traditional shake-flask method, the apparent partition coefficient, log D, is measured, usually at pH 7.4 (sometimes at pH 6.5). Different buffers are used to control each pH used in the determinations [70]. Usually, in a comprehensive study, several pH measurements are made, and values of log are plotted against the pH. This plot is often called the lipophilicity profile . One can determine the true partition coefficients (log P ) and the ionization constants from the features in such a curve. 

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 ... 

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. 

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 quantitative descriptor of lipophilicity, the partition coefficient P, is defined as the ratio of the concentrations of a neutral compound in organic and aqueous phases of a two-compartment system under equilibrium conditions. It is commonly used in its logarithmic form, logP. Whereas 1-octanol serves as the standard organic phase for experimental determination, other solvents are applied to better mimic special permeation conditions such as the cyclohexane-water system for BBB permeation. Measurement of log P is described in Chapters 12 and 13 as well as in Ref [22]. 

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. 

However, as stated above, the partition coefficients measured by the shake-flask method or by potenhometric titration can be influenced by the potenhal difference between the two phases, and are therefore apparent values which depend on the experimental condihons (phase volume ratio, nature and concentrahons of all ions in the solutions). In particular, it has been shown that the difference between the apparent and the standard log Pi depends on the phase volume raho and that this relationship itself depends on the lipophilicity of the ion [80]. In theory, the most relevant case for in vivo extrapolation is when V /V 1 as it corresponds to the phase ratio encountered by a drug as it distributes within the body. The measurement of apparent log Pi values does not allow to differentiate between ion-pairing effect and partihoning of the ions due to the Galvani potential difference, and it has been shown that the apparent lipophilicity of a number of quaternary ion drugs is not due to ion-pair partitioning as inihally thought [80]. 

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. ... 

Lipophilicity is a molecular property expressing the relative affinity of solutes for an aqueous phase and an organic, water-immiscible solvent. As such, lipophilicity encodes most of the intermolecular forces that can take place between a solute and a solvent, and represents the affinity of a molecule for a lipophilic environment. This parameter is commonly measured by its distribution behavior in a biphasic system, described by the partition coefficient of the species X, P. Thermodynamically, is defined as a constant relating the activity of a solute in two immiscible phases at equilibrium [111,112]. By convention, P is given with the organic phase as numerator, so that a positive value for log P reflects a preference for the lipid phase ... 

Of course, the shape of the lipophilicity profiles becomes much more complicated for molecules with multiple ionized forms. Nevertheless, the partition coefficients may be calculated from the distribution coefficient using the general equation [113] ... 

However, recent studies on the variation of the distribution coefficient of ionizable drugs as a function of pH (pH-lipophilicity profiles) shows that the partitioning of charged species cannot be neglected [143]. In other words, the general relationship between distribution and partition coefficients [Eq. (15)] cannot be simplified. 

Although experimental partition coefficients are the values of reference, drug design often necessitates log evaluations before the compound has been synthesized. Consequently, various methods have been developed to predict lipophilicity [188], and they generally apply only to neutral compounds in the water-OCT system. 

The first attempt for calculating logP was proposed by Hansch and Fujita [189] who considered partition coefficients as an additive-constitutive property. This means that lipophilicity of a given compound is given by that of the unsubstituted parent compound plus a 7T term representing the difference in partition coefficient between a particular substituent X and the hydrogen atom which it replaces ... 

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