Transport system dipeptide

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. 

Wenzel, U., B. Meissner, F. Doring, and H. Daniel. PEPTl-mediated uptake of dipeptides enhances the intestinal absorption of amino adds via transport system b(0, +), J. Cell. Physiol. 2001, 386, 251-259... 

Chong, S., S. A. Dando, K. M. Soucek, and R. A. Morrison. In vitro permeability through caco-2 cells is not quantitatively predictive of in vivo absorption for peptide-like drugs absorbed via the dipeptide transporter system, Pharm. Res. 1996, 13, 120-123... 

Several active transport systems that are normally found in the small intestinal enterocytes have been characterized in the Caco-2 cell model [13]. These include transport systems for glucose [32, 33], amino acids [34-37], dipeptides [38-40], vitamins [41], and bile acids [42, 43]. 

Inui, K., et al. H+ coupled active transport of bestatin via the dipeptide transport system in rabbit intestinal brush-border membranes. J. Pharmacol. Exp. Ther. 1992, 260, 482-486. 

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. 

Tsuji Tsuji A, Tamai I, Nakanishi M et al. (1993) Intestinal brush-border transport of the oral cephalosporin antibiotic, cefdinir, mediated by dipeptide and monocarboxylic acid transport systems in rabbits. J Pharm Pharmacol 45(11) 996—998... 

An active dipeptide transport system that depends on hydrogen ions takes up non-ester amino-beta-lactams (penicillin, amoxicillin, and oral first-generation cephalosporins) (337-339) and specific cephalosporins that lack the alpha-amino group (cefixime, ceftibuten, cefdinir, cef-prozil) (340,341). Nifedipine increases amoxiciUin and cefixime absorption, probably by stimulating the dipeptide transport system, since the serum concentrations of passively absorbed drugs and intestinal blood flow did not change (342-344). 

Matsumoto S, Saito H, Inui K. TransceUular transport of oral cephalosporins in human intestinal epithehal cells, Caco-2 interaction with dipeptide transport systems in apical and basolateral membranes. J Pharmacol Exp Ther 1994 270(2) 498-504. 

Intestinal absorption of beta-lactams occurs at least in part by an active mechanism involving a dipeptide carrier, and this pathway can result in interactions with dipeptides and tripeptides (196,197), which reduce the rate of absorption of the beta-lactams. In particular, angiotensin-converting enzyme (ACE) inhibitors, which have an oligopeptide structure, are absorbed by the same carrier (198) and interact with beta-lactams in isolated rat intestine (199). However, there might be a second site of interaction between ACE inhibitors and beta-lactams. Both groups of substances are excreted by the renal anionic transport system, and concomitant administration of both drugs sometimes results in pronounced inhibition of the elimination of beta-lactams (200). In the case of cefalexin, it may not lead to toxic effects. However, when more toxic beta-lactams are used, the possibility of this interaction has to be kept in mind. 

The carrier-mediated uptake of p-aminohippuric acid (PAH) into BBMV (Figure 7) and PAH accumulation by renal cortical slices [69,77] were also significantly reduced by CPH treatment (1200 mg/kg/d for 3d). Furthermore, the transport of other cephalosporins across the renal brush border membrane is also affected by CPH-treatment the uptake of cephalexin and cefotiam into BBMV was greatly reduced whereas the uptake of CPH remained unaffected [77]. Secretion of cephalosporins across the brush border membrane is assumed to occur by the PAH-system as well as by the organic cation/H+-antiporter [127,133]. Reabsorption of many cephalosporins is performed by the dipeptide transport system [69, 133]. The unaffected uptake of CPH into BBMV from CPH-treated rats indicates that CPH is transported by a system different from the... 

Since cephalexin is transported by the dipeptide transport system [75,133], the question arose whether or not the reduction of cephalexin transport activity following CPH treatment could be caused by either reduction in the number of transport sites or an impairment of the transport system for -lactam antibiotics and dipeptides 77]. Using photoaffinity labeling, two membrane polypeptides of brush border membrane of molecular weight of 130,000 and 95,000 were identified as constituents of the dipeptide transport system 77]. The results of this study demonstrated that CPH-treatment of rats greatly reduced the photoaffinity la-... 

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