Permeation lipid-soluble form

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. 

Apart from the properties of the cell membranes, certain physicochemical characteristics of the drugs can significantly influence the rate of their absorption. Most drugs are either weak acids or bases that exist in solution as a mixture of ionized and nonionized forms. Nonionized forms are more lipophilic whereas ionized forms more hydrophilic. Consequently, the nonionized forma are lipid soluble and able to permeate rapidly across cell membranes. This process is known as passive nonionic diffusion. 

Ammonia and simple aliphatic amines were among the first uncouplers reported for photophosphorylation by Krogmann, Jagendorf and Avron and by Good respectively. Ammonia and simple aliphatic amines in their lipid-soluble, unprotonated forms can freely permeate the thylakoid membrane. Once inside, they can take up protons and be converted to the corresponding ammonium ions [Fig. 10 (B)]. To maintain electrical neutrality, the accumulation of ammonium ions results in the influx of anions. The accumulation of ammonium salts inside consequently results in an osmotic influx of water and swelling of the thylakoids. 

Most of release studies are done in W/OAV multiple-emulsion systems where an active water soluble molecule is present in the inner aqueous phase. Several attempts have been made to explain the transport phenomena of entrapped addenda from the inner to the outer phase of multiple-emulsion droplets. It has been demonstrated that for lipid soluble material dissolved in the oil phase, the release obeys first-order kinetics and is diffusion controlled with excellent accordance to Pick s law. Two mechanisms for the permeation through the oil intermediate phase are well accepted, the first being via the reverse micellar transport (Figure 7.10 ) and the second via diffusion across a very thin lamellae of surfactant phase formed in areas where the oil layer is very thin (Figure 10b). 

Reduced AA exists predominantly as the ascorbate anion in most body fluids. Molecules that are comparably water soluble diffuse rapidly through nonspecific pathways in cell membranes, especially through the lipid bilayer. In contrast, ascorbate, because of its size and charge, does not readily permeate the lipid bilayer. Simple diffusion of DHAA into cells is negligible probably due to the structure and water nucleation around the molecule. Weak organic acids can enter cells by simple diffusion of their undissociated forms. Once in the cytoplasm, these acids dissociate into organic ions and protons. However, it has been demonstrated that this process did not occur for AA (Wilson and Dixon, 1989). 

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