Lipophilicity of a substance

The lipophilicity of a substance, that is, the tendency of a substance to become dissolved in a lipid, is often measured by the tendency of a substance to become dissolved in a nonpolar solvent, for example, by the n-octanol-water distribution coefficient. The lipophilicity of a substance is inversely proportional to its water solubility. 

The log -octanol-water partition coefficient (log Kow) is a measure of the lipophilicity of a substance. As such, log Kow is a key parameter in the assessment of environmental fate. Many distribution processes are driven by log Kow, e.g. sorption to soil and sediment and bioconcentration in organisms. 

Figure 9.29. The lipophilicity of a substance, as measured by the octanol-water distribution coefficient, is an essential parameter for predicting biomagnification (biostorage and accumulation in the food chain) (Calculated from data by Chiou et al., 1977.)...

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]. 

In order for a substance to be absorbed, it must cross biological membranes. Most substances cross by passive diffusion. This process requires a substance to be soluble both in lipid and water. The most useful parameters providing information on the potential for a substance to diffuse across biological membranes are the octanol/water partition coefficient (Log P) value and the water solubility. The Log value provides information on the relative solubility of the substance in water and the hydrophobic solvent octanol (used as a surrogate for lipid) and is a measure of lipophilicity. Log P values above zero indicate that the substance is more soluble in octanol than water, i.e., is lipophilic, and values below zero (negative values) indicate that the substance is more soluble in water than octanol, i.e., is hydrophilic. In general, moderate Log P values (between 0 and 4) are favorable for absorption. However, a substance with a Log P value around 0 and low water solubility (around 1 mg/1) will also be poorly soluble in lipids and hence not readily absorbed. It is therefore important to consider both the water solubility of a substance and its Log P value when assessing the potential of that substance to be absorbed. 

From an acid-base titration curve, we can deduce the quantities and pK.d values of acidic and basic substances in a mixture. In medicinal chemistry, the pATa and lipophilicity of a candidate drug predict how easily it will cross cell membranes. We saw in Chapter 10 that from pKa and pH, we can compute the charge of a polyprotic acid. Usually, the more highly charged a drug, the harder it is to cross a cell membrane. In this chapter, we learn how to predict the shapes of titration curves and how to find end points with electrodes or indicators. 

Partition coefficient represents the equilibrium ratio of the molar concentrations of a chemical substance (the solute) in a system containing two immiscible liquids. The octanol / water partition coefficient is expressed as either Kow or P and is a descriptor of a substance s relative affinity for lipids and water. For purposes of simplification, Kow is usually reported as its common logarithm (log Kow or log P). A large log Kow value for a chemical (relative to other substances) indicates that the chemical has a greater affinity for the n-octanol phase and, hence, is more hydrophobic (lipophilic). A negative log Kow value indicates that a chemical has a greater affinity for the water phase and, hence, is more hydrophilic. 

Bioaccumulation The accumulation of a substance in a biological organism, usually due to its lipophilicity. 

Lipophilicity A term used to describe the ability of a substance to dissolve in or associate with fat and therefore living tissue. This usually applies to compounds that are nonionized or nonpolar or have a nonpolar portion. Therefore, high lipid solubility usually implies low water solubility. 

A negative linear correlation between k2 (depuration constant) and log Kow (or BCF) has been shown in fish by several authors (e.g. Spade and Hamelink, 1982 Gobas et al., 1989 Petersen and Kristensen, 1998), whereas k (uptake rate constant) is more or less independent of the lipophilicity of the substance (Connell, 1990). The resultant BCF will thus generally increase with increasing lipophilicity of the substances, i.e. log BCF and log Kow correlate for substances which do not undergo extensive metabolism. 

Bioaccumulation The accumulation of xenobiotic substances in organisms and the food chain is important in the assessment of the harmfiilness of a substance in the environment. The accumulation of organic substances in organisms occurs often in accordance with their lipophilicity (Figure 9.29) A ow often serves as a measure of lipophilicity and as a predictive parameter for bioaccumulation in the food chain. One also speaks of biomagnification to describe progressive accumulation of xenobiotic substances in the food chain. 

For lipophilic substances this factor can be quite high, but theoretically, there will always be an equilibrium concentration, where no net uptake takes place. The factor is quite versatile as a simple parameter that describes the tendency of a substance to accumulate. 

Octanol/water partition coefficient (K J quantifies the lipophilic-ity of a substance and is therefore assumed to be an index of the ability to pass through biological membranes and to bioaccumulate in living organisms. It is therefore used as a measure of the affinity for the biota. For most pesticides ranges from... 

The bioaccumulation of a substance into an organism is not an adverse effect hazard in itself. Bioconcentration and bioaccumulation may lead to an increase in body burden which may cause toxic effects due to direct and/or indirect exposure. Bioaccumulative substances characterized by high persistence and toxicity, negligible metabolism and a log ATow between 5 and 8 may represent a concern when widely dispersed in the environment. The potential of a substance to bioaccumulate is primarily related to its lipophilicity. A surrogate measure of this quality is the n-octanol - water partition coefficient (/fow), which is correlated with bioconcentration potential. Therefore, /fow values are normally used as predictors in quantitative structure - activity relationships (QSARs) for bioconcentration factors (BCFs) of organic non-polar substances. 

Lipophilicity has emerged as the key parameter for assessing the potential environmental impact of contaminants. This property constitutes a measure for the preference of a substance for either aqueous or non-aqueous phases. The partitioning between compartments of different polarity determines the rate and the direction of the transport of chemicals in the environment and thus their accumulation in some of its components. Therefore, lipophilicity appears in QSARs in environmental studies in two ways - as an endpoint by itself as well as a chemical descriptor to model further distribution-related parameters. 

Many works have illustrated that there is a linear relationship between R values and log P. R o values also can be used to measure the lipophilicities of chemical substances. In general, the chromatographic method is an excellent alternative to the traditional flask-shaking method for lipophilicity determination. It avoids the difficulties that one may encounter in the flask-shaking method. It is simple and rapid and requires only minute amounts of substances (which need not necessarily be very pure) it does not need quantitative analysis the nature of the organic modifier does not affect the measurement of the lipophilic character, as the value is not affected by the organic modifier. 

Any dissolved substance lowers the solidification range of the base [8m] and therefore will affect the solidification point of the mass. This may cause a problem when large quantities of lipophilic active substances are added. For example, chloral hydrate in a concentration of 5 % in hard fat lowers the solidification point by more than 5 °C. Sometimes textbooks advise the addition of a substance with a high melting point [5fj. Such an addition bears risks for bioavailability however. The substance, such as beeswax, may separate upon cooling [8m]. Glycerol monostearate does better but increases the viscosity of the mass as well and may therefore retard the release of the active substance. Furthermore the increase of the solidification point may affect the bioavailability as well. 

Besides in the crystalline form, a substance may also exist in the glassy state. In the glassy state, the molecules are not oriented in a specific manner towards each other as they are in a crystal lattice, but randomly (amorphous). The aqueous solubility and thereby also the dissolution rate of a substance in the glassy state is better and higher than in crystalline form [35, 36]. Therefore, the bioavailability of lipophilic active substances after oral administration, which is limited due to their slow dissolution, can be improved by converting them into the glassy state. 

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