Peptides transporters

During the past 10 years, one of the most exciting developments in the oral peptide drug delivery was the identification of PEPT1. This is a significant finding because this carrier protein is known to play a critical role in the absorption of 

Peptide transporters PEPT1, PEPT2 PTR3, hPT-1, PHT1 SLC15A members 

Amino acid transporters CATs (4), LATs (3), b(° + AT SLC7A 

Organic cation transporters OCTs (3), OCTNs (3) SLC22A 

Bile acid transporters NTCP, ISBT SLC10A 

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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. 

Leibach FH and Ganapathy V. Peptide transporters in the intestine and the kidney. Anna Rev Nutr 1996 16 99-119. 

A peptide, once released, is not subject to reuptake like most transmitters, but is broken down by membrane peptidases. There are no known peptide transporters so that reuptake and re-use are not likely. The peptidases are predominantly membrane bound at the synapse and many are metalloproteases in that they have a metal moiety, most often zinc, near the active site. These enzymes are generally selective for particular... 

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Shepard, I. L. Jenkins, D. C. Duckworth, J. R. Sportsman et al. Association of intestinal peptide transport with a protein related to the cadherin superfamily, Science 1994, 264, 430-433... 

Leibach, F. H., Differential recognition of fl-lactam antibiotics by intestinal and renal peptide transporters, PEPT1 and PEPT2,... 

Guo, A., Hu, P., Balimane, P., Leibach, F. H., Sinko, P. J., Interactions of a nonpeptidic drug, valacyclovir, with the human intestinal peptide transporter (hPePTl) expressed in a mammalian cell line,... 

Wenzel, U., Gebert, I., Weintraut, H., Weber, W.-M., Clauss, W., Daniel, H., Transport characteristics of differently charged cephalosporin antibiotics in oocytes expressing the cloned intestinal peptide transporter PepTl and in human intestinal Caco-2 cells, J. Pharmacol. Exp. Ther. 1996, 277, 831-839. 

Shiraga, T., Miyamoto, K., Tanaka, H., Yamamoto, H., Taketani, Y. et al, Cellular and molecular mechanisms of dietary regulation on rat intestinal H+/Peptide transporter PepTl, Gastroenterology 1999, 3 36, 354-362. 

As shown in Table 11.1, there are various membrane transporters and isoforms. Many of these transporters are expressed in the GI tract. Among them, the peptide transport systems have received the most attention. Di-, tri-peptide trans-... 

Fig. n.i. Human duodenal expression variability of peptide and amino acid transporters (our unpublished data). Shaded box indicates 25-75% of expression range, the line within the box marks the median, and error bars indicate 10-90% of expression range. PEPT1, di-, tri-peptide transporter HPT1 (Ll-cadherin) peptide transporter SLC3A1, cystine, dibasic and neutral amino acid transporter y+LATl, cationic amino acid transporter ATBq, neutral... 

Another type of intestinal peptide transporter, hPTl, which is significantly different in sequence from PEPT1, was identified using a functionally inhibitory monoclonal antibody [99]. This transporter is widely expressed in the human GI tract and facilitates the oral absorption of pdactam antibiotics and ACE inhibitors from the intestine [18, 99]. Interestingly, we recently reported that hPTl gene expression is approximately 4-fold higher than PEPT1 in the human duodenum [4] (Fig. 11.1). 

Yang, C. Y., A. H. Dantzig, and C. Pidgeon. Intestinal peptide transport systems and oral drug availability. Pharm. Res. 1999, 16, 1331-1343. 

Rubio-Aliaga, I. and H. Daniel. Mammalian peptide transporters as... 

Inui, K., et al. Physiological and pharmacological implications of peptide transporters, PEPT1 and PEPT2. Nephrol. Dial. Transplant. 

Meredith, D. and C. A. Boyd. Structure and function of eukaryotic peptide transporters. Cell. Mol. Life Sci. 2000, 57, 754-778. 

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Herrera-Ruiz, D., et al. Spatial expression patterns of peptide transporters in the human and rat gastrointestinal tracts, Caco-2 in vitro cell culture model, and multiple human tissues. AAPS PharmSci. 2001, 3, E9. 

Saito, H., et al. Molecular cloning and tissue distribution of rat peptide transporter PEPT2. Biochim. Biophys. Acta 1996, 1280, 173-177. 

Brodin, B., et al. Transport of peptidomimetic drugs by the intestinal Di/tri-peptide transporter, PepTl. Pharmacol. Toxicol. 2002, 90, 285-296. 

Pan, Y., et al. Expression of a cloned ovine gastrointestinal peptide transporter (oPepTl) in Xenopus oocytes induces uptake of oligopeptides in vitro. J. Nutr. 2001, 131, 1264-1270. 

Han, H. K., et al. CHO/hPEPTl cells overexpressing the human peptide transporter (hPEPTl) as an alternative in vitro model for peptidomimetic drugs. J. Pharm. Sci. 1999, 88, 347-350. 

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