Intestinal peptide transporter

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... 

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. 

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. 

Chen, H., et al. Molecular cloning and functional expression of a chicken intestinal peptide transporter (cPepTl) in Xenopus oocytes and Chinese hamster ovary cells. J. Nutr. 2002, 132, 387-393. 

Doring, F., S. Theis, and H. Daniel. Expression and functional characterization of the mammalian intestinal peptide transporter PepTl in the methylotropic yeast Pichia pastoris. Biochem. Biophys. Res. Commun. 1997, 232, 656-662. 

Wenzel, U., D. T. Thwaites, and H. Daniel. Stereoselective uptake of beta-lactam antibiotics by the intestinal peptide transporter. Br. ]. Pharmacol. 1995, 116, 3021-3027. 

Temple, C. S., et al. Peptide mimics as substrates for the intestinal peptide transporter. J. Biol. Chem. 1998, 273, 20-22. 

Walker, D., et al. Substrate upregula-tion of the human small intestinal peptide transporter, hPepTl. J. Physiol. 1998, 507, 697-706. 

Danzig, A. H., Oral absorption of (S-lactams by intestinal peptide transport proteins, Adv. Drug Ddiv. Rev. 1997,... 

Friedrichsen, G. M., Nielsen, C. U., Steffansen, B., Begtrup, M., Model prodrugs designed for the intestinal peptide transporter. A synthetic approach for coupling of hydroxy-containing compounds to dipeptides, Eur. J. Pharm. Sci. 2001, 14, 13-19. 

Bai, J. P. F., pGlu-L-Dopa-Pro a tripeptider prodrug targeting the intestinal peptide transporter for absorption and tissue enzymes for conversation, Pharm. Res. 1995, 12, 1101-1104. 

H. Daniel. Molecular and integrative physiology of intestinal peptide transport. Annu Rev Physiol 66 361-384 (2004). 

F. Doring, J. Will, S. Amasheh, W. Clauss, H. Ahlbrecht, and H. Daniel. Minimal molecular determinants of substrates for recognition by the intestinal peptide transporter. J Biol Chem 273 23211-23218 (1998). 

Groneberg DA, Doring F, Eynott PR, et al. Intestinal peptide transport ex vivo uptake studies and localization of peptide carrier PEPT1. Am J Physiol Gastrointest Liver Physiol 2001 28LG697-G704. 

Canapathy, V. and Leibach, F.H. 1985. Is intestinal peptide transport energized by a proton gradient Am. J. Physiol. 249, 153-160. 

Balimane P, Sinko P (2000), Effect of ionization on the variable uptake of valacyclovir via the human intestinal peptide transporter (hPepTl) in CHO cells. Biopharm Drug Dispos 21 165-174... 

A lot of structure-activity information has been accumulated over the last two decades for various intestinal transporters. However, the two most studied transporters in terms of quantitative structure-activity relationship (QSAR) are SLC15A1 [74—80] and ABCB1 (for references see Ref. [81]), which will be the topic of Chapter 18. In the following section, the focus will be on strategies for increasing intestinal absorption of dmg candidates by targeting intestinal peptide transporters. 

Dantzig, A.H. (1998) Oral absorption of beta-lactams by intestinal peptide transport proteins. Advanced Drug Delivery Reviews, 23, 63-76. 

Meredith, D., Temple, C.S., Guha, N., Sword, C.J., Boyd, C.A., Collier, I.D., Morgan, K.M. and Bailey, P.D. (2000) Modified amino acids and peptides as substrates for the intestinal peptide transporter PepTl. European Journal of Biochemistry, 267 (12), 3723-3728. 

Thorn, K., Andersen, R., Christensen, J., Jakobsen, P., Nielsen, C.U., Steffansen, B. and Begtrup, M. (2007) Design, synthesis, and evaluation of tripeptidic promoieties targeting the intestinal peptide transporter hPEPTl. ChemMedChem,... 

Yang, C.Y., Dantzig, A.H. and Pidgeon, C. (1999) Intestinal peptide transport systems... 

Figure 9.7 Intestinal peptide transport. Peptides are taken upinto enterocytes together with H+ ions. The proton gradient is maintained via an Na + /H+ antiport system in the apical cell membrane. The Na+ gradient is guaranteed by the Na + /I<+-ATPase in the basolateral cell membrane.

Perkins EJ, Abraham T (2007) Pharmacokinetics, metabolism, and excretion of the intestinal peptide transporter 1 (SLC15Al)-targeted prodrug (IS, 2S, 5R, 6S)-2-[(2 S)-(2-amino)propionyl]aminobicyclo[3.1.0.]hexen-2, 6-di carboxylic acid (LY544344) in rats and dogs assessment of first-pass bioactivation and dose linearity. Drug Metab Dispos 35 1903-1909... 

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