Lipid permeability

It was soon recognized that gastric HVK -ATPase is the site of action for omeprazole [27,43] and that enzyme inhibition parallels inhibition of gastric acid secretion in laboratory animals [38]. Physico-chemically, omeprazole represents a lipid-permeable weak base with a pK of 4 [42]. At physiological pH, it is predominantly unionized and this neutral form passes freely across biological membranes. However, in an acidic environment with a pH below 4, it is predominantly protonated. This results in a limited permeability of the drug [28]. Due to the unique structure of the gastric... 

Most foodborne pathogenic bacteria are neutrophiles with their optimum growth pH ranging from pH 6-pH 7. These bacteria will only encounter acid-related stress in food systems as a result of the presence of lipid-permeable weak acids (Hill, O Driscoll, and Booth, 1995). 

It is unlikely that the effect of valinomycin is due to a conductance change which would stimulate an electrogenic pump, since protonophores like TCS have much less effect than ionophores and lipid-permeable cations do not substitute for these ionophores [58]. The effect of K -ionophores must be attributed to a requirement of the pump enzyme for internal K" ". Under certain conditions transport could be shown to be driven by a large gradient in the absence of ATP [66],... 

The gastric vesicles showed also a temperature-sensitive Rb and C1 uptake with approximately equal half times, indicating that these uptake processes are coupled [66,68]. Addition of ATP to the vesicles resulted in a transient release of Rb, but the C1 content did not change. This indicates that the Rb efflux is accompanied by proton uptake. The effect of ATP on the Rb efflux is rather specific for this nucleotide [68]. The pH dependence of this efflux process corresponds to that of the (K + H + )-ATPase, while some of the ATPase inhibitors also inhibit the Rb efflux. The effect of ATP on the Rb efflux is not due to a potential difference, since neither vahnomycin nor lipid-permeable cations affect the... 

Porcine skin flow-through diffusion cells (PSFT) also sensitive to changes in lipid permeability... 

Lipoidal or lipid permeability has been used to define the disposition characteristics of molecules (Wu and Benet, 2005). This permeability can be related to physicochemical properties as outlined earlier. The relationship can be extended to also the likely interaction sites for a molecule. Small, nonlipophilic molecules will rely on the paracellular pathway. Such molecules will be absorbed from the... 

TABLE 5.1 Physicochemistry and Lipid Permeability Classification of Drug Absorption, Bioavailability, Target Access, and Clearance... 

Four pharmacophores have been identified in CCR5 antagonists 6, namely, a tertiary basic amine, two tail hydrophobes one of which tolerates some polarity, and a (hetero)aryl head (Figure 3.5). In a series of these inhibitors, lipid permeability was very low and strategies to remove the amide function in tail hydrophobe 1 were progressed. Replacement of the secondary amide with a piperidine 7 or azetidine 8 moiety led to the discovery of compounds with increased intrinsic lipoidal membrane permeability and overall an improved in vivo pharmacokinetic profile [7]. 

In special cases (as in colloidal solutions) some particles can be considered as essential and other particles as irrelevant , but in most cases the essential space will itself consist of collective degrees of freedom. A reaction coordinate for a chemical reaction is an example where not a particle, but some function of the distance between atoms is considered. In a simulation of the permeability of a lipid bilayer membrane for water [132] the reaction coordinate was taken as the distance, in the direction perpendicular to the bilayer, between the center of mass of a water molecule and the center of mass of the rest of the system. In proteins (see below) a few collective degrees of freedom involving all atoms of the molecule, describe almost all the... 

Cell membrane The cell membrane is composed of about 45% lipid and 55% protein. The lipids form a bilayer that is a continuous nonpolar hydrophobic phase in which the proteins are embedded. The cell membrane is a highly selective permeability barrier that controls the entry of most substances into the cell. Important enzymes in the generation of cellular energy are located in the membrane. 

The prespective to be gained thus far is that in order to pass through a lipid layer an ion must have an appropriate polar shell provided in large part by the carrier or channel structure which by virtue of its conformation and by also having lipophilic side chains provides for the polar shell to lipid shell transition. While the relative permeability of monovalent vs divalent and trivalent ions can be qualitatively appreciated from the z2 term in Eqn 2, as indicated in Figure 1B, it is essential to know structural and mechanistic detail in order even qualitatively to understand anion vs cation selectivity and to understand selectivity among monovalent cations. 

Hurst (19) discusses the similarity in action of the pyrethrins and of DDT as indicated by a dispersant action on the lipids of insect cuticle and internal tissue. He has developed an elaborate theory of contact insecticidal action but provides no experimental data. Hurst believes that the susceptibility to insecticides depends partially on the cuticular permeability, but more fundamentally on the effects on internal tissue receptors which control oxidative metabolism or oxidative enzyme systems. The access of pyrethrins to insects, for example, is facilitated by adsorption and storage in the lipophilic layers of the epicuticle. The epicuticle is to be regarded as a lipoprotein mosaic consisting of alternating patches of lipid and protein receptors which are sites of oxidase activity. Such a condition exists in both the hydrophilic type of cuticle found in larvae of Calliphora and Phormia and in the waxy cuticle of Tenebrio larvae. Hurst explains pyrethrinization as a preliminary narcosis or knockdown phase in which oxidase action is blocked by adsorption of the insecticide on the lipoprotein tissue components, followed by death when further dispersant action of the insecticide results in an irreversible increase in the phenoloxidase activity as a result of the displacement of protective lipids. This increase in phenoloxidase activity is accompanied by the accumulation of toxic quinoid metabolites in the blood and tissues—for example, O-quinones which would block substrate access to normal enzyme systems. The varying degrees of susceptibility shown by different insect species to an insecticide may be explainable not only in terms of differences in cuticle make-up but also as internal factors associated with the stability of oxidase systems. 

The blood-brain barrier (BBB) forms a physiological barrier between the central nervous system and the blood circulation. It consists of glial cells and a special species of endothelial cells, which form tight junctions between each other thereby inhibiting paracellular transport. In addition, the endothelial cells of the BBB express a variety of ABC-transporters to protect the brain tissue against toxic metabolites and xenobiotics. The BBB is permeable to water, glucose, sodium chloride and non-ionised lipid-soluble molecules but large molecules such as peptides as well as many polar substances do not readily permeate the battier. 

FIGURE 6-15 Schematic representation of the ion permeability modulation for cation-responsive voltammetric sensors based on negatively charged lipid membranes. Complexation of the guest cation to the phospholipid receptors causes an increase of the permeability for the anionic marker ion. (Reproduced with permission from reference 49.)... 

Figure 41-6. Permeability coefficients of water, some ions, and other small molecules in lipid bilayer membranes. Molecules that move rapidly through a given membrane are said to have a high permeability coefficient. (Slightly modified and reproduced, with permission, from Stryer L Biochemistry, 2nd ed. Freeman, 1981.)...

The actions of proteins isolated from sea anemones, or other coelenterates, involve mechanisms different from those described for saponins. Thus, hemolysins from sea anemone R macrodactylus are capable of forming ion channels directly in membranes (98). The basic protein from S. helianthus also forms channels in black-lipid membranes. These channels are permeable to cations and show rectification (99). This ability of S. helianthus toxin III to form channels depends upon the nature of the host lipid membrane (100). Cytolysin S. helianthus binds to sphingomyelin and this substance may well serve as the binding site in cell membranes (101-106). 

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