Partition coefficient
Conversely, hydrophilic drugs (low octanol/water partition coefficients) are found primarily in aqueous regions such as blood serum.
In areas such as drug discovery—areas involving partition phenomena in biological systems such as the human body—the log D at the physiologic pH = 7.4 is of particular interest.
[citation needed] It is often convenient to express the log D in terms of PI, defined above (which includes P0 as state I = 0), thus covering both un-ionized and ionized species.
indicates the pH-dependent mole fraction of the I-th form (of the solute) in the aqueous phase, and other variables are defined as previously.
[15][better source needed] They are sorted by the partition coefficient, smallest to largest (acetamide being hydrophilic, and 2,2',4,4',5-pentachlorobiphenyl lipophilic), and are presented with the temperature at which they were measured (which impacts the values).
[26] Likewise, it is used to calculate lipophilic efficiency in evaluating the quality of research compounds, where the efficiency for a compound is defined as its potency, via measured values of pIC50 or pEC50, minus its value of log P.[27] In the context of pharmacokinetics (how the body absorbs, metabolizes, and excretes a drug), the distribution coefficient has a strong influence on ADME properties of the drug.
More specifically, for a drug to be orally absorbed, it normally must first pass through lipid bilayers in the intestinal epithelium (a process known as transcellular transport).
[29][30] Likewise, hydrophobicity plays a major role in determining where drugs are distributed within the body after absorption and, as a consequence, in how rapidly they are metabolized and excreted.
[31][32] On the other hand, hydrophobic drugs tend to be more toxic because they, in general, are retained longer, have a wider distribution within the body (e.g., intracellular), are somewhat less selective in their binding to proteins, and finally are often extensively metabolized.
Hence it is advisable to make the drug as hydrophilic as possible while it still retains adequate binding affinity to the therapeutic protein target.
[33] For cases where a drug reaches its target locations through passive mechanisms (i.e., diffusion through membranes), the ideal distribution coefficient for the drug is typically intermediate in value (neither too lipophilic, nor too hydrophilic); in cases where molecules reach their targets otherwise, no such generalization applies.
[35] In the field of hydrogeology, the octanol–water partition coefficient Kow is used to predict and model the migration of dissolved hydrophobic organic compounds in soil and groundwater.
Hydrophobic agrochemicals in general have longer half-lives and therefore display increased risk of adverse environmental impact.
[36] In metallurgy, the partition coefficient is an important factor in determining how different impurities are distributed between molten and solidified metal.
It is a critical parameter for purification using zone melting, and determines how effectively an impurity can be removed using directional solidification, described by the Scheil equation.
[6] Many other industries take into account distribution coefficients, for example in the formulation of make-up, topical ointments, dyes, hair colors and many other consumer products.
[citation needed] The pH-metric set of techniques determine lipophilicity pH profiles directly from a single acid-base titration in a two-phase water–organic-solvent system.
[44][45] This strategy requires methods for the determination of concentrations in individual cells, i.e., with Fluorescence correlation spectroscopy or quantitative Image analysis.
For example, tens of thousands of industrially manufactured chemicals are in common use, but only a small fraction have undergone rigorous toxicological evaluation.
[50] As discussed in more detail below, estimates of partition coefficients can be made using a variety of methods, including fragment-based, atom-based, and knowledge-based that rely solely on knowledge of the structure of the chemical.
Standard approaches of this type, using atomic contributions, have been named by those formulating them with a prefix letter: AlogP,[51] XlogP,[52] MlogP,[53] etc.
It has been shown that the log P of a compound can be determined by the sum of its non-overlapping molecular fragments (defined as one or more atoms covalently bound to each other within the molecule).
Molecule mining approaches apply a similarity-matrix-based prediction or an automatic fragmentation scheme into molecular substructures.
, in the case where partition of ionized forms into non-polar phase can be neglected, can be formulated as[13][14] The following approximate expressions are valid only for monoprotic acids and bases:[13][14] Further approximations for when the compound is largely ionized:[13][14] For prediction of pKa, which in turn can be used to estimate log D, Hammett type equations have frequently been applied.
