Lipid Partition coefficients

As mentioned earlier, ascorbate and ubihydroquinone regenerate a-tocopherol contained in a LDL particle and by this may enhance its antioxidant activity. Stocker and his coworkers [123] suggest that this role of ubihydroquinone is especially important. However, it is questionable because ubihydroquinone content in LDL is very small and only 50% to 60% of LDL particles contain a molecule of ubihydroquinone. Moreover, there is another apparently much more effective co-antioxidant of a-tocopherol in LDL particles, namely, nitric oxide [125], It has been already mentioned that nitric oxide exhibits both antioxidant and prooxidant effects depending on the 02 /NO ratio [42]. It is important that NO concentrates up to 25-fold in lipid membranes and LDL compartments due to the high lipid partition coefficient, charge neutrality, and small molecular radius [126,127]. Because of this, the value of 02 /N0 ratio should be very small, and the antioxidant effect of NO must exceed the prooxidant effect of peroxynitrite. As the rate constants for the recombination reaction of NO with peroxyl radicals are close to diffusion limit (about 109 1 mol 1 s 1 [125]), NO will inhibit both Reactions (7) and (8) and by that spare a-tocopherol in LDL oxidation. 

Processing of the triolein alone (i.e., without analyzing the LDPE as well) is not encouraged for a number of reasons. First of all, the LDPE constitutes a significant part of the total SPMD sorption capacity, in contrast to biota, where the sorption capacity of the non-lipid phase is often considered to be negligible. Data on membrane-lipid partition coefficients (/fmc) is very limited, but the available... 

Data from McLachlan, 1996. Also given are the estimated air-lipid partition coefficients and the used Aa jpH, values.)... 

In recent years there has been an increased interest in the utility of lipid-based delivery systems to enhance oral bioavailability (4). It is generally known that membrane permeability is directly correlated to a drug s water-lipid partition coefficient however, the systemic availability of highly lipophilic drugs is impeded by their low aqueous solubility. In an effort to improve this solubility-limited bio-availabiliy,formulators have turned to the use of lipid excipients to solubilize the compounds before oral administration. Several formulations are currently on the market, for example, Sandimmun/Neoral (cyclosporin microemulsion), Norvir (ritonavir), and Fortovase (saquinavir)... 

Bocasch, W. D., Cornford, E. M. and Oldendorf, W. H. (1981) Schistosoma mansoni correlation between lipid partition coefficient and transintegumental uptake of non-electrolytes. Exp. Parasitol. 52 396-403. 

Other characteristics, which influence percutaneous absorption, are solvent concentration gradients, solvent partitioning (water/lipid partition coefficient) and permeability constants. 

General anaesthetics have been in use for the last 100 years, yet their mechanism of action are still not yet clearly defined. For many years it was thought that general anaesthetics exerted their effects by dissolving in cell membranes and perturbing the lipid environment in a non-specific manner. This theory derived from the observation that for a number of drugs which induced anaesthesia, their potency correlated with their oil-water partition coefficients. This Meyer-Oveiton correlation was accepted for a number of years, however in the last 15-20 years evidence has shown that a more likely theory is that of specific interactions of anaesthetics with proteins, particularly those within the CNS that mediate neurotransmission [1]. 

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). 

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] ... 

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. 

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 ... 

Such a parabolic relation has the following incidence on drug delivery a molecule with a low partition coefficient will partition slowly from water into a lipid membrane. If the receptor is within or beyond that membrane, such a molecule will have a low probability of reaching it in the time interval under study. Conversely, molecules which are highly lipophilic will readily partition into the first of a series of lipid membranes, but will be held there and thus slowed down in their random walk to their site of action. Hence, optimal transport conditions are clearly achieved by drugs of intermediate partition coefficient, with no transfer step being too low. 

The lipophilicity of a solute affects its permeability in lipid bilayers. Lipophilicity is usually expressed in terms of its partitioning between water and an organic solvent, such as olive oil [95], oleyl alcohol [96], ether [97], or octanol [98]. Partition coefficient (PC) of a compound is expressed as its concentration ratio between organic medium and water at equilibrium ... 

Absorption. No studies were located regarding the mechanism of absorption in humans or animals after inhalation, oral, or dermal exposure to diisopropyl methylphosphonate. Both facilitated transport and diffusion through the lipophilic portions of the membrane could be involved in absorption processes. No data were found regarding lipid solubility or partition coefficients. 

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