Carrier-mediated transport ionization

Lipophilic compounds will cross the placenta most readily by passive diffusion, whereas those ionized at plasma pH will generally not, unless they are substrates for a carrier-mediated transport system. Most foreign compounds will enter the embryonic bloodstream by passive diffusion, and the exposure of the embryo of fetus will therefore depend on the concentration of the compound in the maternal bloodstream and the blood flow, which increases as pregnancy progresses. The ability of the maternal organism to metabolize and excrete the compound, reflected in the plasma level and half-life, will therefore be a major determinant of... 

Certain ionized and hydrophilic molecules that are unable to partition into the hydrophobic environment of the membrane lipids may utilize the facilitated transport mechanisms that are present for ions and small molecules, such as glucose. For example, carrier-mediated transport can be an absorption mechanism for peptides and amino acids. The amino acid L-tyrosine is absorbed through the nasal cavity via a carrier-mediated process, which can be increased by esterification of its carboxyl group [16]. 

The ionization state of a drag may be affected by factors other than pH. When citrate, a tricarboxylic acid, chelates metals such as aluminum, the tetravalent citrate-aluminum complex leaves a free non-complexed monocarboxylic acid which is a substrate for the monocarboxylic acid or lactate carrier in the brain endothelium. When citrate is not chelated, it has no affinity for these carriers and, as there is no di- or tricarboxylic acid carrier within the BBB, citrate is not significantly transported through the BBB via carrier-mediated transport. 

The ionization state of the substrate can affect BBB transport of carrier-mediated substrates. For example, histidine is an imidazole amino acid that is highly charged under acidic conditions and crosses the BBB via the basic amino acid carrier. However, under neutral conditions, histidine is 90% neutral and traverses the BBB via the neutral amino acid carrier. 

At a physiological pH of 7.2, 99 percent of the ammonia is in the ionic form. The un-ionized form diffuses across cell membranes while the ammonium ion is transported more slowly via carrier-mediated processes. 

At physiological pH, 7.2, 99% of anunonia is in the ionic form. The lui-ionized form diffuses across cell membranes. It was previously thought to simply pass via the phospholipid bilayer but it is now known to use specific transporters in human erythrocytes it is one of the rhesus-antigen proteins (rhesus associated glycoprotein) that mediates the exchange. The NH4+ ion is transported much more slowly via another carrier-mediated process. 

These membranes differ by the presence of a specific carrier, to effect facilitated diffusion (also called mediated transport). As a result, transport is faster than can be calculated for simple diffusion, but at equilibrium no difference exists between the concentrations inside and outside the cell (contrast with Type 3 membranes). Type 2 membranes exist not only to hasten the absorption of a limited number of vital nutrients, but also to effect absorption of those metabolites which could not be expected to penetrate a Type 1 membrane because of ionization or an excessively hydrophilic structure. 

The absorption and transport of the majority of drugs across biological membranes occurs by passive diffusion, a process dependent upon physicochemical properties, i.e., lipophilicity, ionization, and molecular size. Since enantiomers have identical physicochemical properties, stereoselectivity would not be expected even though membrane phospholipids are chiral, the significance of lipophilieity appears to outweigh that of compound chirality. In contrast, differences between diastereoisomers may occur as a result of their differential solubility. However, in the case of compounds transported via earrier-mediated meehanisms, e.g., facilitated diffusion or active transport, proeesses involving a direct interaction between a substrate and a carrier maeromoleeule, stereoselectivity is expected. Preferential absorption of the l- eompared to the D-enantiomers of dopa [96] and methotrexate [97,98] have been reported. In the case of the above examples, enantioseleetivity in absorption is observed, whereas in the case of eephalexin, a eephalosporin antibiotic, diastereoselectivity for the L-epimer oeeurs. The L-epimer has shown a greater affinity than, and acted as a competitive inhibitor of o-eephalexin transport [99]. The L-epimer is also more suseeptible to enzyme-mediated hydrolysis, with the result that it cannot be detected in plasma [99]. 

At least seven carriers control entry through the mitochondrial membrane. One carrier facilitates entry of succinate, D- and L-malate, malonate, and w 5o-tartrate anions, but not tartrate, maleate, or fumarate. Another mediates the entry of citrate, c/s-aconitate, wocitrate, and d- or L-tartrate, but not furmarate or maleate. A third carrier transports adenosine nucleotides. Also phosphate anions can enter mitochondria whereas other inorganic anions cannot (Chappell, 1966). Apart from these processes, many substances (e.g. ammonia) enter by simple diffusion as non-ionized substances, and many anions flow in and out of mitochondria if cations are present (Pressman, 1970). 

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