Anion transport processes

Following intravenous injection, the Tc-IDA complex is bound to plasma protein (mainly albumin) and carried to the liver (Nicholson et al. 1980). Accumulation in the liver involves the same carrier-mediated, non-sodium-dependent organic anion transport processes as for the uptake of bilirubin. In the space of Disse, the albumin- Tc-IDA conjugate is dissociated to facilitate active transport of the Tc-IDA complex into hepatocytes (Krishnamurthy and Krishnamurthy 1989). In patients with normal hepatobiliary function, maximal liver uptake is measured at 12 min ( Tc-mebrofenin, 10.9 1.9 min Tc-disofenin, 11.5 3.1 min) (Fritzberg 1986). The radioactivity is half this value within approximately 20 min. The gallbladder is well visualized 20 min postinjection. Intestinal activity appears on the average at 15-30 min. The common bile duct may be visualized after 14 min. The upper limit of normal for visualization of these structures is 1 h (Weissmann et al. 1979). 

Probenecid appears to completely inhibit the renal tubular secretion of the active metabolite of oseltamivir via the anionic renal transporter process. Oseltamivir does not alter amoxicillin pharmacokinetics, suggesting minimal potential to inhibit the renal anionic transport process. Cimetidine, which inhibits the renal tubular secretion of drugs via the cationic secretion transport process, had no effect on oseltamivir. 

Electrically assisted transdermal dmg deflvery, ie, electrotransport or iontophoresis, involves the three key transport processes of passive diffusion, electromigration, and electro osmosis. In passive diffusion, which plays a relatively small role in the transport of ionic compounds, the permeation rate of a compound is deterrnined by its diffusion coefficient and the concentration gradient. Electromigration is the transport of electrically charged ions in an electrical field, that is, the movement of anions and cations toward the anode and cathode, respectively. Electro osmosis is the volume flow of solvent through an electrically charged membrane or tissue in the presence of an appHed electrical field. As the solvent moves, it carries dissolved solutes. 

The gradients of H, Na, and other cations and anions established by ATPases and other energy sources can be used for secondary active transport of various substrates. The best-understood systems use Na or gradients to transport amino acids and sugars in certain cells. Many of these systems operate as symports, with the ion and the transported amino acid or sugar moving in the same direction (that is, into the cell). In antiport processes, the ion and the other transported species move in opposite directions. (For example, the anion transporter of erythrocytes is an antiport.) Proton symport proteins are used by E. coU and other bacteria to accumulate lactose, arabinose, ribose, and a variety of amino acids. E. coli also possesses Na -symport systems for melibiose as well as for glutamate and other amino acids. 

Radiotracer techniques involving lsO in the anodization process are used with subsequent neutron activation analysis84 or SIMS.85 Another method involves implantation of inert ion markers into the surface layer of the sample prior to anodization and examination of the position of the markers after the oxide film has grown to a certain thickness.86 Assuming immobility of the inert species, the ratio of the cation to the anion transport number, t+/, should be equal to the ratio of the outer to the inner layer thickness. Numerous experimental determinations72,87 suggest t+ and f to be 0.4 and 0.6, respectively. 

In cell lines, the organic anion transporters (OAT and OATP) have been identified and cloned into cells of kidney origin such as LLC-PK1, MDCK, HK-2, and Caco-2 [129]. The most well-known uptake transporters, which transport the substrate over the membrane into the organism are the amino acid- [35, 42, 139] and oligopeptide-carriers (PepTl and PepT2) [139-142]. These two transporter families are abundantly expressed in the small intestine of most animals, and can therefore be involved in the absorption process of pharmaceutical drugs. The PepTl is expressed in the cell lines Caco-2 and HT-29 [140-142]. 

Another important vitamin is folate, which is required for purine and pyrimidine nucleotide synthesis. Since folate and its derivatives are generally lipo-phobic anions, they do not traverse biological membranes via simple diffusion but rather have to be taken up into the cells by specific transport processes... 

Langridge-Smith, J. E. and Field, M. (1981). Sulfate transport in rabbit ileum characterisation of the serosal border anion exchanger process, J. Membr. Biol., 63, 207-214. 

Figure 9.13 Examples of mitochondrial transport systems for anions. 0 The anb port system transfers malate into but oxo-glutarate out of the mitochondrion. The symport system transfers both pyruvate and protons into the mitochondrion across the inner membrane. Both transport processes are electroneutral.

Biliary excretion of certain anions (S25) and cations (N2) may be by an active transport process, and many drugs are excreted into bile against a bile blood concentration gradient exceeding 50 1 (Gll). 

As has already been pointed out, the solubility properties of the anion, its lipophilicity, are extremely important for the dissolution of the complex in solvents of low polarity. Large and soft inorganic and, much more so, organic anions very strongly increase the solubility. Anion activation and cation transport processes both depend on such anion effects. 

Due to the ionic nature of cephalosporin molecules, the interfacial chemical reaction may in general be assumed to be much faster than the mass transfer rate in the carrier facilitated transport process. Furthermore, the rate controlling mass transfer steps can be assumed to be the transfer of cephalosporin anion or its complex, but not that of the carrier. The distribution of the solute anion at the F/M and M/R interfaces can provide the equilibrium relationship [36, 69]. The equilibrium may be presumably expressed by the distribution coefficients, mf and m at the F/M and M/R interfaces, respectively and these are defined as... 

Certain molecules, such as p-aminohippuric acid (Fig. 3.18), a metabolite of p-aminobenzoic acid are actively transported from the bloodstream into the tubules by a specific anion transport system. Organic anions and cations appear to be transported by separate transport systems located on the proximal convoluted tubule. Active transport is an energy-requiring process and therefore may be inhibited by metabolic inhibitors, and there may be competitive inhibition between endogenous and foreign compounds. For example, the competitive inhibition of the active excretion of uric acid by compounds such as probenecid may precipitate gout. 

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