Epithelial cells nucleosides

Both influx and efflux transporters are located in intestinal epithelial cells and can either increase or decrease oral absorption. Influx transporters such as human peptide transporter 1 (hPEPTl), apical sodium bile acid transporter (ASBT), and nucleoside transporters actively transport drugs that mimic their native substrates across the epithelial cell, whereas efflux transporters such as P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), and breast cancer resistance protein (BCRP) actively pump absorbed drugs back into the intestinal lumen. 

Members of the PepT family are located on the apical membranes of intestinal and renal epithelial cells and mediate the uptake of several peptidomi-metic drugs like (3-lactam antibiotics, angiotensin-converting enzyme inhibitors, and nucleoside analogs. Currently, two human PepTs have been identified. 

Walter E, Kissel T, Reers M et al. (1995) Transepithelial transport properties of peptidomimetic thrombin inhibitors in monolayers of a human intestinal cell fine (CACO-2) and their correlation to in vivo data. Pharm Res 12(3) 360-365 Walter E, Kissel T (1995) Heterogeneity in the human intestinal cell line CACO-2 leads to differences in trans-epithelial transport. Eur J Pharm Sci 3 215-230 Ward JL, Tse CM (1999) Nucleoside transport in human colonic epithelial cell lines evidence for two Na-l—independent transport systems in T84 and CACO-2 cells. Biochim Bio-phys Acta 1419 15-22... 

The major important organic electrolytes and nonelectrolytes transported by epithelial cells include sugars, amino acids, nucleosides, organic cations, and organic anions. Transport systems have significant implications for the absorption, distribution, elimination, and pharmacokinetic properties of many clinically important drugs. The major epithelial tissues... 

The Calu-3 human submucosal gland cell line forms polarized cell monolayers with tight junctions, produces mucus, and develops apical cilia when grown at an air interface. Transport studies can be performed after 10-14 days in culture, and it has been shown that Calu-3 cells express P-gp and actively transport amino acids, nucleosides, and dipeptide analogs organic anions, organic cations, polyamines, and efflux pump substrates are not actively transported.43,51,53-56 Because Calu-3 cells are not subject to the influence of multiple in vivo cell types, the expression of carrier proteins and enzymes may not reflect in vivo levels. Nevertheless, values obtained in Calu-3 permeability studies correlate well with those obtained from primary cultured rabbit tracheal epithelial cells and in vivo rat lung absorption studies.54 Mannitol permeation in Calu-3 cells is about 10 times less than that in vivo, but this is the same ratio difference between Caco-2 cells and in vivo intestinal epithelium.51... 

Mangravite, L.M., Lipschutz, J.H., Mostov, K.E., and Giacomini, K.M. (2001) Localization of GFP-tagged concentrative nucleoside transporters in a renal polarized epithelial cell line. American Journal of Physiology. Renal Physiology,... 

GNT are localized primarily in the luminal (brush border) membrane of renal epithelial cells. Three isoforms have been identified GNTl (SLG28A1), GNT2 (SLG28A2), and GNT3 (SLG28A3). CNTs are involved in unidirectional cellular uptake cotransport with sodium. These secondary active transporters mediate active uphill transport of nucleosides. 

Dietary uptake of purine and pyrimidine bases is minimal. The diet contains nucleic acids and the exocrine pancreas secretes deoxyribonuclease and ribonucle-ase, along with the proteolytic and lipolytic enzymes. This enables digested nucleic acids to be converted to nucleotides. The intestinal epithelial cells contain alkaline phosphatase activity, which will convert nucleotides to nucleosides. Other enzymes within the epithelial cells tend to metabolize the nucleosides to uric acid, or to salvage them for their own needs. Approximately 5% of ingested nucleotides will make it into the circulation, either as the free base or as a nucleoside. Because of the minimal dietary uptake of these important molecules, de novo synthesis of purines and pyrimidines is required. 

Nucleoside Transport in Mouse Intestinal Epithelial Cells. Two Transport Systems with Differing Substrate Specificities. 

Pastor-Anglada, M., et al. Complex regulation of nucleoside transporter expression in epithelial and immune system cells. Mol. Membr. Biol. 2001, 18, 81-85. 

Trifluridine (trifluorothymidine) is a fluorinated pyrimidine nucleoside that inhibits viral DNA synthesis in HSV-1, HSV-2, CMV, vaccinia, and some adenoviruses. It is phosphorylated intracellularly by host cell enzymes, and then competes with thymidine triphosphate for incorporation by the viral DNA polymerase (Figure 49-3). Incorporation of trifluridine triphosphate into both viral and host DNA prevents its systemic use. Application of a 1% solution is effective in treating keratoconjunctivitis and recurrent epithelial keratitis due to HSV-1 or HSV-2. Cutaneous application of trifluridine solution, alone or in combination with interferon alfo, has been used successfully in the treatment of acyclovir-resistant HSV infections. 

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