Octanol: water partition coefficients lipophilicity/hydrophilicity

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 ... 

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. 

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. 

Common unspecific mode of action of all organic compounds has been taken up in quantitative structure-activity relationships (QSARs see Chapter 5) as the concept of baseline toxicity and in toxicokinetics as the body burden concept (see Chapter 2). Baseline toxicity refers to the idea that a minimum toxicity expectation may be formulated for any given organic compound based on considerations of a compound s partition properties between hydrophilic and lipophilic chemicals (e.g., between water and octanol). Commonly, this is expressed in terms of the octanol-water partition coefficient (K0,J of a chemical. The partition coefficient allows estimations of a local concentration or body burden for each individual chemical in the mixture. Assuming that this produces the same toxic effect (disturbances of cell membranes), it is then possible to anticipate joint narcotic action by adding together the respective local concentrations or body burdens for each individual mixture component. 

Cornea The cornea is an important mechanical barrier protecting the intraocular tissues. It is considered to be the main pathway for ocular penetration of topically apphed drugs. However, due to its unique structure, with the hydrophilic stroma sandwiched between the highly lipophilic epithelium and the less lipophilic endothelium, the penetration of compounds through the cornea depends on their n-octanol-water partition coefficient. Only drugs with a partition coefficient between 10 and 100 that show both lipid- and water-soluble properties can readily pass through the cornea. 

According to Kaur and Smitha [36], the optimum lipophilicity for corneal absorption is found in drugs with an n-octanol-water partition coefficient between 10 and 100. For drugs with smaller partition coefficients (highly hydrophilic drugs), the lipophilic epithelium forms the rate-limiting barrier, whereas the hydrophilic stroma... 

The relative differences in lipophilicity and hydrophilicity are reflected by the octanol water partition coefficients of the chemicals, KoW 28 w is indicative of the relative lipophilic character of a given chemical. It is defined as the ratio of that quantity of a chemical dissolved in the octanol phase to that dissolved in the water phase of an ocatanol-water mixture. Because it is a ratio, Kjw has no units and is expressed as a logarithm of that ratio because of the wide range of values for different compounds. A K(m value of 3.0 for a compound means that the compound is 1000 times more soluble in octanol than in water. 

In almost all of the studies presented here (as well as in most others not reported here) the chemical mixtures that produced unanticipated toxic effects contained at least one lipophile (K > 2.00) and one hydrophile ( CW < 2.00). The octanol water partition coefficients (7T w) are given in parentheses for each of the chemicals identified to point out the lipophilic and hydrophilic species. 

Mixtures of pesticides, heavy metals, or organic solvents often produce unanticipated neurotoxic effects. The following are published examples of such effects. Octanol water partition coefficients (W w) are given for all chemicals cited to demonstrate lipophilicity or hydrophilicity. 

At the other end of the spectrum, however, in transdermal systemic delivery, the molecular attributes required are rather different. In this case, compounds are required to partition into the relatively lipophilic stratum corneum, diffuse rapidly across the stratum corneum and partition easily into the more hydrophilic viable epidermis and dermis prior to vascular removal. The intrinsic requirements of compounds for transdermal delivery are, therefore, a medium polarity (a log octanol-water partition coefficient of 1-3), a low molecular volume and a lack of potential to bind to skin components (e.g., via hydrogen bonding). 

The lipophilicity of an active substance, and thereby its tendency to pass lipophilic membranes, can be described in terms of the octanol-water partition coefficient and the polar surface area. The octanol-water partition coefficient, the log P value, should be within the 0.4—5.6 range and preferably below 3. The polar surface area of a compound is the total sum of the surface of the polar atoms in the molecule. In general this will refer to the oxygen and nitrogen atoms in the molecules and include the hydrogen atoms attached. Co-inclusion of sulfur and phosphor atoms in the calculations was shown to add little to the predictive value of the results. When the polar surface area of a molecule exceeds 140 A the molecule is too hydrophilic and cmisid-ered to be unsuitable for absorption after oral administration. For special barriers such as the highly lipophilic blood brain barrier the threshold is 60 A. ... 

Medicinal products can be applied on the skin to treat local skin diseases (topical application) or to systemically administer an active substance (transdermal application). In the first case, the active substance should accumulate in or even on the skin and display its effect there. When transdermal administration is intended, the active substance should be transported through the skin followed by absorption into the systemic circulation. In the skin the stratum comeum (the most outer layer of 5-50 layers of dead cells, a homed layer of comeocytes, see Fig. 12.1 and Sect. 12.3.1) forms the major barrier for absorption of active substances. The layer is highly lipophilic in nature and is fully impermeable for hydrophilic active substances. Lipophilic active substances, when adequately formulated, may be absorbed via the skin. Typical characteristics which make an active substance suitable for transdermal transport are an octanol-water partition coefficient (expressed as log Pq/w) between 1 and 3 and a molecular mass below 500 Da [10, 11]. Moreover the dose should not exceed 20 mg per day. Hydrophilic active... 

The relative differences in lipophilicity and hydrophilicity are reflected by the -octanol water partition coefficients of the chemicals, [28], is indicative of the... 

Generally, biodegrability of the compounds decrease with a drop of water solubility and with an increase of molecular weight and complexity of bond structure (Devinny et al. 1999). The microbial removal of the compounds is limited by its hydrophobicity (lipophilicity), determining the water solubility and thereby pollutant transfer from the gas to the aqueous phase. The hydrophobicity is characterized by the octanol-water partition coefficients. It is a ratio of concentrations of the un-ionized compound in a mixture of two immiscible phases (octanol and water) at equilibrium. It determines the difference in solubility of the compound in these two phases. Estimation of hydrophobicity of the compounds is assessed on the base of logarithm of the ratio (logP). It is assumed, that the compound is hydrophilic... 

Figure 15.37. Lock-in mechanism for estradiol-CDS (128). Experimental and calculated logarithms of the octanol-water partition (log P) and distribution (log D) coefficients are shown to illustrate the significant changes in partition properties. The lipophilic CDS (logP > 4) can easily cross the BBB, whereas the hydrophilic intermediate (logD < 0) is no longer able to come out, providing a sustained release of the active estradiol (130).

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... 

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