HPEPTl

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. 

Ekins S, Johnston JS, Bahadduri P, D Souza VM, Ray A, Chang C, et al. In vitro and pharmacophore-based discovery of novel hPEPTl inhibitors. Pharm Res 2005 22 512-7. 

Brodin, S. Frokjaer, M. Taub, and B. Steffansen. Dipeptide model prodrugs for the intestinal oligopeptide transporter. Affinity for and transport via hPepTl in the human intestinal Caco-2 cell line.,... 

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,... 

Covitz, K. M., G. L. Amidon, and W. Sadee. Human dipeptide transporter, hPEPTl, stably transfected into Chinese hamster ovary cells. Pharm. Res. 1996, 13, 1631-1634. 

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. 

Han, H.-K., D.-M. Oh, and G. L. Amidon. Cellular uptake mechanism of amino acid ester prodrugs in Caco-2/hPEPTl cells overexpressing a human peptide transporter. Pharm. 

Surendran, N., et al. Evidence for overlapping substrate specificity between large neutral amino acid (LNAA) and dipeptide (hPEPTl) transporters for PD 158473, an NMDA antagonist. Pharm. Res. 1999, 16, 391-395. 

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

The affinity of the various stabilized dipeptidyl prodrugs to hPepTl in Caco-2 cells was also investigated [42, 43, 50]. In the case of the D-Glu-Ala ester-linked benzyl alcohols, an improved hPepTl affinity with increasing drug lipophilicity was observed [50], Furthermore, these model prodrugs are transported trans-epithelially across Caco-2 cells by virtue of a hPepTl-mediated process [50]. Preliminary hPepTl affinity studies made on Asp-Sar- and Glu-Sar-based (model)-... 

In other studies, bisphosphonate-pamidronate or alendronate were linked to the terminal carboxylic acid of the stabilized dipeptide Pro-Phe to improve the bioavailability of bisphosphonates by hPepTl-mediated absorption. In-situ single-pass perfused rat intestine studies revealed competitive inhibition of transport by Pro-Phe, suggesting carrier-mediated transport. Oral administration of the dipeptidyl prodrugs resulted in a 3-fold increase in drug absorption following oral administration to rats. The authors suggested that oral bioavailability of bisphosphonates may be improved by PepTl-mediated absorption when administered as peptidyl prodrugs [53]. Future mechanistic studies may prove if hPepTl is involved in the absorption process. 

Carrier-mediated prodrug absorption has especially focused upon the use of PepTl, and a variety of strategies using stabilized dipeptides and amino acid-based prodrugs with affinity to hPepTl appear promising. In retrospect, it has been shown that the commercially available prodrugs valaciclovir and valganciclovir are both absorbed via hPepTl, which provides evidence for the value of the carrier-mediated concept. 

M. Sala-Rabanal, D. D. Loo, B. A. Hirayama, E. Turk, and E. M. Wright. Molecular interactions between dipeptides, drugs and the human intestinal H+-oligopeptide cotransporter hPEPTl. J Physiol 574 149-166 (2006). 

X. Song, P. L. Lorenzi, C. P. Landowski, B. S. Vig, J. M. Hilfinger, and G. L. Amidon. Amino acid ester prodrugs of the anticancer agent gemcitabine synthesis, bioconversion, metabolic bioevasion, and hPEPTl-mediated transport. Mol Pharm 2 157-167 (2005). 

There have been sustained efforts in recent years to use the carrier systems of the brush-border membrane of intestinal mucosa to increase absorption of orally administered drugs [29] [30]. One system of particular interest is the intestinal peptide carrier (hPEPTl) whose physiological function is the absorption of di- and tripeptides and whose xenobiotic substrates include /3-lactam antibiotics, renin inhibitors, and angiotensin-converting enzyme (ACE) inhibitors [31]. 

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... 

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