Carrier-mediated transport systems

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. 

State of carrier-mediated transport system for xenobiotics elimination... 

On the other hand, several probe substrates of carrier-mediated transport systems in the small intestine have been reported to be not absorbed by carrier-mediated mechanism in the rat colon in situ. Those include L-carnitine [23], methotrexate [18], cephradine [18], and 5-fluorouracil [18], as substrates of the L-carnitine carrier, folate carrier, peptide carrier, and pyrimidine carrier, respectively (Table 3.3). It is based on the nonsaturable nature of their transport. Particularly, the apparent membrane permeabilities of L-carnitine and methotrexate are negligibly low, suggesting that these compounds are practically unabsorbable from the colon. In the case of 5-fluorouracil, Na+-independence of transport was observed in situ [18] and also in everted sacs in vitro in the colon [21], while its carrier in the small intestine is known to be Na+-dependent. Furthermore, for ascorbate and nicotinate, as described in everted sacs in vitro [21], and L-dopa, as described in situ [24], carrier-mediated transport cannot be observed in the rat colon. 

Tomei S, Hayashi Y, Inoue K, Torimoto M, Ota Y, Morita K, Yuasa H, Watanabe J (2003) Search for carrier-mediated transport systems in the rat colon. Biol Pharm Bull 26 274-277... 

Oyama Y, Yamano H, Ohkuma A, Ogawara K, Higaki K, Kimura T (1999) Carrier-mediated transport systems for glucose in mucosal cells of the human oral cavity. J Pharm Sci 88 830-834... 

M. Takano, K. Inui, T. Okano, H. Satio, and R. Hori. Carrier-mediated transport systems of tetraethylammonium in rat renal brush-border and basolateral membrane vesicles. Biochim Biophys Acta 773 113-124 (1984). 

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... 

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... 

Other transcellular mechanisms of absorption include carrier-mediated transport and endocytic processes. Although it is well known that carrier-mediated transport systems exist for di- and tripeptides in the intestine, there is still no evidence for carrier-mediated transport of peptides across the vaginal mucosa, although prostaglandins have been demonstrated to utilize such a mechanism. Although there must be some type of endocytic transport of endogenous peptides into the epithelial cells in order to regulate proliferation, no receptor-mediated or bulk-fluid mechanisms have been reported. 

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. 

Table 13.1 Carrier-mediated transport systems within the BBB...

Explain how carrier-mediated transport systems may be exploited in CNS drug delivery. 

The studies reported here using the isolated, vascularly perfused rat intestine system and isolated brush border membrane vesicles fail to support a role for a specific zinc-binding ligand involved in zinc uptake in the rat. Rather, the extent of zinc uptake involves the interaction of several phenomena, including both extracellular and intracellular reactions. It appears that the major pathway of zinc uptake under normal dietary conditions involves the transfer of zinc from various dietary components to a carrier mediated transport system at the brush border membrane. The net absorption of zinc from the lumen could involve a competition between various dietary components, zinc binding ligands and the membrane carrier for zinc. Thus, in some cases, those compounds in the lumen with a higher affinity for zinc than the membrane component will be less likely to permit transfer of zinc to the carrier, while compounds with a lower affinity for zinc will increase the amount of zinc made... 

Theoretically, a lipophilic drug may pass through the cell or go around it. If drug has a low molecular weight and is lipophilic, the lipid cell membrane is not a barrier to drug diffusion and absorption. In the intestine, molecules smaller than 500 MW may be absorbed by paracellular drug absorption. Numerous specialized carrier-mediated transport systems are present in the body especially in the intestine for the absorption of ions and nutrients required by the body. 

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