Amino acids carrier-mediated transport

The most efficient rectal absorption enhancers, which have been studied, include surfactants, bile acids, sodium salicylate (NaSA), medium-chain glycerides (MCG), NaCIO, enamine derivatives, EDTA, and others [45 17]. Transport from the rectal epithelium primarily involves two routes, i.e., the paracellular route and the transcellular route. The paracellular transport mechanism implies that drugs diffuse through a space between epithelial cells. On the other hand, an uptake mechanism which depends on lipophilicity involves a typical transcellular transport route, and active transport for amino acids, carrier-mediated transport for (3-lactam antibiotics and dipeptides, and endocytosis are also involved in the transcellular transport system, but these transporters are unlikely to express in rectum (Figure 8.7). Table 8.3 summarizes the typical absorption enhancers in rectal routes. 

Enalaprilat and SQ27,519 are angiotensin-converting enzyme (ACE) inhibitors with poor oral absorption. Enalapril and fosinopril are dipeptide and amino acid derivatives of enalaprilat and SQ27,519, respectively [51] (Fig. 10). Both prodrugs are converted via deesterification to the active drug by hepatic biotransformation. In situ rat perfusion of enalapril indicated a nonpassive absorption mechanism via the small peptide carrier-mediated transport system. In contrast to the active parent, enalapril renders enalaprilat more peptide-like, with higher apparent affinity for the peptide carrier. The absorption of fosinopril was predominantly passive. Carrier-mediated transport was not demonstrated, but neither was its existence ruled out. 

Depending upon the mechanism that is employed by the organism to accumulate the solute, internalisation fluxes can vary both in direction and order of magnitude. The kinetics of passive transport will be examined in Section 6.1.1. Trace element internalisation via ion channels or carrier-mediated transport, subsequent to the specific binding of a solute to a transport site, will be addressed in Section 6.1.2. Finally, since several substances (e.g. Na+, Ca2+, Zn2+, some sugars and amino acids) can be concentrated in the cell against their electrochemical gradient (active transport systems), the kinetic implications of an active transport mechanism will be examined in Section 6.1.3. Further explanations of the mechanisms themselves can be obtained in Chapters 6 and 7 of this volume [24,245]. 

The inhibition of amino-acid transport has been regarded as the main toxic effect of mercury compounds [82], The biochemical mechanism underlying the inhibition is unclear. In unfertilized sea-urchin eggs an interaction with the amino-acid carrier was found, whereas in fertilized eggs inhibition of amino-acid transport was indirect and might result from an elevation of the Na + content of the egg caused by the inhibition of the Na+ pump [83]. The action on the diffusional process could be mediated by an effect on membrane phospholipids or on membrane proteins, or by interaction with Ca2+ which stabilizes membrane structure. Mercuric chloride in skate liver cells inhibited amino acid transport, decreased Na + /K + -ATPase (adenosinetriphosphatase) activity, impaired volume regulatory mechanisms and increased the permeability of the plasma membrane to potassium [84]. It has been suggested that... 

The existence of a carrier-mediated transport in nasal mucosa was first suggested by Kimura et al. [34], P-glycoprotein, organic cation transporter, dopamine transporter, and amino acid transporters have all been identified in the nasal mucosa, especially in the olfactory mucosa [31, 32, 35, 36], These transporters determine the polarized absorption and excretion of their substrates including amino acids, amines, and cations. 

P. Tornquist and A. Aim. Carrier-mediated transport of amino acids through the blood-retinal and the blood-brain barriers. Graefes Arch, Clin. Exp. Ophthalmol. 224 21-25 (1986). 

FIGURE 1.35 SLM process using O-9-(l-adamantylcarbamoyl)-10,ll-dihydro-ll-octadecylsulfinylquinme and corresponding quinidine derivative as chiral carriers for the preparative separation of enantiomers of Al-derivatized amino acids (e.g., DNB-Leu). (a) ftinciple of the carrier SLM process with carrier-mediated transport (top) and (nonstereoselective) nonspecific transport processes (bottom), (b) General experimental setup of the SLM production unit with two membrane modules, (c) Multistage SLM purification process. P, permeate QD/QN, membrane modnles snpported with quinidine-derived and quinine-derived chiral carriers. R, S, D, L refers to the respective enantiomers of the selectand (DNB-Leu). (Reproduced from A. Maximini et al., J. Membr. ScL, 276 221 (2006). With permission.)... 

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]. 

Proteolysis of peptides and proteins commences in the stomach when pepsin is present. As a result, protein or peptide drugs will be hydrolyzed into smaller fragments like amino acids or oligopeptides, which are absorbed through the mucosa either by diffusion or by a carrier-mediated transport [18], In an average individual, 94-98% of the total protein is completely digested and absorbed [19], Proteolysis continues in the intestine with pancreatic enzymes like trypsine and brush-border enzymes. 

Exceptions from Lipinski s rule, i.e., molecules of PSA values > 140 A2 are found to be actively absorbed by carrier-mediated transport systems (Wessel et al. 1998), as shown in Fig. 3. IB. As further detailed in Fig. 3.2, the intestinal epithelium expresses a number of such transport systems for amino acids, organic anions and cations, nucleosides, and hexoses. Among these systems are the apical sodium-dependent bile acid transporter (ASBT Annaba et al. 2007), the monocarboxylate transporter (MCT Halestrap and Price 1999), the sodium-D-glucose co-transporter (SFGT1 Kipp et al. 2003), and the nucleotide transporter SPNT1 (Balimane and Sinko 1999). In addition, the expression of a specialized transporter system for small peptides has been found in the intestinal epithelium with the di/tripeptide transporter, PepTl (Tsuji 2002), after previous functional studies by Hu et al. (1989), and the cloning of PepTl... 

Facilitated diffusion involves carrier-mediated transport down a concentration gradient. The existence of the carrier molecules means that diffusion down the concentration gradient is much greater than would be expected on the basis of the physicochemical properties of the drag. A much larger number of substances are believed to be transported by facilitated diffusion than active transport, including vitamins such as thiamine, nicotinic acid, riboflavin and vitamin B6, various sugars and amino acids. 

Several carrier systems have been shown to be present in the brain endothelium, allowing for the selective transport of a group of common substrates (Table 13.1). The most common system is the one that mediates the transport of glucose, which provides the brain with virtually all its energy. Carrier-mediated mechanisms are also responsible for the absorption of two other energy sources ketone bodies, which are derived from lipids, and lactic acid, a by-product of sugar metabolism. Carrier-mediated transport systems are also involved in the uptake of amino acids by the brain. The brain can manufacture its own small neutral and acidic amino acids however, large neutral and basic amino acids are obtained from the bloodstream. 

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. 

Drags which have structures similar to that of endogenous nutrients may be taken up by a specialized transport system (carrier-mediated transport, receptor-mediated transcytosis) existing in the brain endothelium for nutrients. For example, drags having a molecular structure similar to a large neutral amino acid may cross the BBB via the neutral amino acid carrier such drags include melphalan (phenylalanine mustard), L-dopa, a-methyldopa, and p-chlorophenylalanine. 

As discussed above, certain nutrients are taken up into the brain by carrier-mediated systems. If a dmg possesses a molecular structure similar to that of a nutrient which is a substrate for carrier-mediated transport (Table 13.1), the pseudo-nutrient dmg may be transported across the BBB by the appropriate carrier-mediated system. For example, the dmg L-dopa crosses the BBB via the neutral amino acid carrier system. Other neutral amino acid dmgs that are transported through the BBB on this transport system are a-methyldopa, a-methylparatyrosine, and phenylalanine mustard. 

The distinction between facilitated diffusion through channels and carrier-mediated transport is somewhat artificial/ but may be justified on the basis of specificity. For example/ 3-lactams in general can pass through nonselective bacterial outer membrane porin (e.g./ OmpF) channels via passive diffusion/ whereas imipenem (and related zwitterionic carbapenems) can also utilize OprD channels/ which preferentially recognize basic amino acids and dipeptides. The identification of mutants that selectively confer imipenem resistance suggests that more intimate protein-drug associations are involved in carrier-mediated transport than in facilitated diffusion/ which may be limited only by pore diameter. 

Pardridge WM. 1998. Blood-brain barrier carrier-mediated transport and brain metabolism of amino acids. Neurochem. Res. 23 635 14... 

Carrier-mediated transport (e.g. glucose, amino acids, purines]... 

A similarly depressing picture exists with tumours in the brain. Conventional anticancer chemotherapy often cannot penetrate the barrier to attack the tumour. The CNS, however, does require low-molecular-weight molecules to grow and function and these small polar molecules (e.g. amino acids, sugars) have their own transport proteins located at the blood-brain barrier that act to transfer the essential compound through the barrier in a process called carrier-mediated transport. 

Other polar molecules may be substrates for carrier-mediated transport (Fig. 1, Path 2a) by amino acid [8,9], peptide [10,11], bile acid [12], sugar [13],... 

Bucci R, Canepari S, CardareUi E, GireUi AM, Pietrodangelo A, Valiente M. Carrier-mediated transport of amino acids through bulk hquid membranes. Sep Sci Technol 2004 39 3821-3838. 

The second method in this group is the intestinal rings or slices. This method for studying drug absorption has been used extensively for kinetic analysis of carrier-mediated transport of glucose, amino acids and peptides (Kararli 1989 Osiecka et al. 1985 Porter et al. 1985 Kim et al. 1994 Leppert and Fix 1994). The method is easy to use the intestine of the animal is cut... 

Note that the most powerful method of improving solubility, adding in carboxylic acids or amines in order to form soluble salts, should have quite an adverse effect on permeability, unless it reduces overall charge as for lisinopril or coincidentally produces a substrate for carrier-mediated transport (e.g. via an amino acid or dipeptide transporter). In short, structure property relationships for solubility and cell permeability, like many properties that need to be optimized in going from a hit to a clinical candidate, operate by different rules, and often go in opposite directions. 

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