Lipid-aqueous partition coefficient

The lipid-aqueous partition coefficient of a drug molecule affects its absorption by passive diffusion. In general, octanol/pH 7.4 buffer partition coefficients in the 1-2 pH range are sufficient for absorption across lipoidal membranes. However, the absence of a strict relationship between the partition coefficient of a molecule and its ability to be absorbed is due to the complex nature of the absorption process. Absorption across membranes can be affected by several diverse factors that may include the ionic and/or polar characteristics of the drug and/or membrane as well as the site and capacity of carrier-mediated absorption or efflux systems. 

The simplest way to predict the lipid/ water partition coefficient, Kiw, of a drug is based on measurements of the surface pressure, ttd, of the drug as a function of its concentration in the aqueous subphase (Gibbs adsorption isotherm). The Gibbs adsorption isotherm provides the air/water partition coefficient, Kaw, and the cross-sectional area, Ad of the drug and allows calculation of the lipid/water partition coefficient, K]w, according to Eq. (6) [59] ... 

For compounds that have either a very low diffusion coefficient or a very low lipid-water partition coefficient, the lipid barrier of the stratum corneum is a formidable impediment to penetration through the skin. However, for such compounds it has been observed that there is no longer a correlation between skin permeation and lipid solubility further, there also appears to be little dependence on molecular weight. It has therefore been hypothesized that such compounds make use of an alternative, low-permeability, and essentially aqueous pathway through the stratum corneum. Although direct physical evidence for such pores is lacking, the notion of a... 

The classic experiments were those performed by Ernest Overton and Hans Meyer at the turn of the twentieth century, where tadpoles were placed in solutions containing alcohols of increasing hydrophobicity. They found a correlation between the concentration of the alcohol required to cause cessation of movement and the concentration of the alcohol distributed into the lipid phase of a lipid-water mixture. The ratio of the concentration in the lipid phase to the concentration in the aqueous phase at equilibrium is known as the Overton-Meyer or lipid-water partition coefficient. The higher the partition coefficient, the less alcohol was needed to cause cessation of movement. 

The value of the biota-water partition coefficient, ftfBW.i. is more difficult to compute since we do not know how to chemically characterize a fish, a plant, or other biota. For animals or fish the assumption generally made is that the hydrophobic chemicals of interest partition mainly into the organic lipid (fat) portion of the biota, rather than the aqueous fluid, inorganic bone, or fibrous tissue of the body. Further, it is assumed that the lipids are chemically similar to octanol, so that the lipid-water partition coefficient... 

Despite the work of Overton and Meyer, it was to be many years before structure-activity relationships were explored further. In 1939 Ferguson [10] postulated that the toxic dose of a chemical is a constant fraction of its aqueous solubility hence toxicity should increase as aqueous solubility decreases. Because aqueous solubility and oil-water partition coefficient are inversely related, it follows that toxicity should increase with partition coefficient. Although this has been found to be true up to a point, it does not continue ad infinitum. Toxicity (and indeed, any biological response) generally increases initially with partition coefficient, but then tends to fall again. This can be explained simply as a reluctance of very hydrophobic chemicals to leave a lipid phase and enter the next aqueous biophase [11]. An example of this is shown by a QSAR that models toxicity of barbiturates to the mouse [12] ... 

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 ... 

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 ... 

One of the key parameters for correlating molecular structure and chemical properties with bioavailability has been transcorneal flux or, alternatively, the corneal permeability coefficient. The epithelium has been modeled as a lipid barrier (possibly with a limited number of aqueous pores that, for this physical model, serve as the equivalent of the extracellular space in a more physiological description) and the stroma as an aqueous barrier (Fig. 11). The endothelium is very thin and porous compared with the epithelium [189] and often has been ignored in the analysis, although mathematically it can be included as part of the lipid barrier. Diffusion through bilayer membranes of various structures has been modeled for some time [202] and adapted to ophthalmic applications more recently [203,204]. For a series of molecules of similar size, it was shown that the permeability increases with octa-nol/water distribution (or partition) coefficient until a plateau is reached. Modeling of this type of data has led to the earlier statement that drugs need to be both... 

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 first of these environmentally-important parameters can be expressed as a partition coefficient. In aqueous solution many, but not all pesticide compounds exhibit strong affinity for soil organic matter or concentrate in the lipid phase of soil organisms. Some, notably the cationic group, also exhibit marked affinity for clay or other mineral surfaces. An overall partition (or distribution) coefficient (kD) can be defined ... 

In developing some of the relationships, it is helpful to use a four-quadrant diagram in which each quadrant represents a species in a lipid or water phase. The diagram below shows a typical distribution of an acid, AH, between two phases where ion partitioning is assumed to be negligible. The partition coefficent, P, is the ratio of the concentration of AH in the octanol to the concentration of AH in the aqueous phase. The distribution coefficient, D, is the ratio of the concentration in the octanol to that of all forms in the water. This is also called the apparent partition coefficient. 

When the ion-pair partitioning is indicated in the quadrant diagram (below) it becomes obvious that a circle of equilibria is present. Knowing the octanol pKa, the log P and the aqueous pKa should allow one to calculate the partition coefficient of the ion pair. From these equilibria one can write that the difference in log P between the acid and its salt is the same as the difference between the pKa s (Equation 9). The closer the pKa s, the more lipid soluble the ion pair will be, relative to the acid. Internal hydrogen bonding or chelation that stabilizes an ion pair will affect the octanol stability more than the aqueous stability, where it is less needed, and so will decrease the delta pKa. Chelation should therefore favor biolipid solubility of ion pairs. Ultimate examples are available in some ionophores. This is one of the properties of some of the herbicides I pointed out earlier. 

The effect of solubility on drug action is, however, usually a question of equilibration of the drug between the aqueous phase and the lipid phase of the cell membrane. This leads us to a discussion of partition coefficients. 

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