PepTl

PEPTl (Influx) ASBT (Influx) HT (Influx) P-gp (Efflux) 5CRP (Efflux) MRP (Efflux)... 

True zwitterionic compounds are rare among drugs. The oral absorption of truly zwitterionic compounds is poor unless the compound is a substrate for an absorptive biological transporter as in an a-amino acid which is a substrate for the PepTl nutrient transporter. The aqueous solubility of a true zwitterionic compound will be at a minimum at the isoelectric point which unfortunately for many compounds happens close to the neutral pH at which oral absorphon occurs. Species extrapolation predicting oral absorphon and pk/pD from preclinical animal tests to man are difficult for zwitterions. 

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... 

In cell lines, the organic anion transporters (OAT and OATP) have been identified and cloned into cells of kidney origin such as LLC-PK1, MDCK, HK-2, and Caco-2 [129]. The most well-known uptake transporters, which transport the substrate over the membrane into the organism are the amino acid- [35, 42, 139] and oligopeptide-carriers (PepTl and PepT2) [139-142]. These two transporter families are abundantly expressed in the small intestine of most animals, and can therefore be involved in the absorption process of pharmaceutical drugs. The PepTl is expressed in the cell lines Caco-2 and HT-29 [140-142]. 

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. 

E. E., Tukker, J. J., Mapping the binding site of the small intestinal peptide carrier (PepTl) using comparative molecular field analysis, Receptors Channels 1998, 6, 189-200. 

Lee, V. H., et al. Biopharmaceutics of transmucosal peptide and protein drug administration role of transport mechanisms with a focus on the involvement of PepTl. J. Control. Release 1999, 62, 129-140. 

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

Tamai, I., et al. The predominant contribution of oligopeptide transporter PepTl to intestinal absorption of beta-lactam antibiotics in the rat small intestine. J. Pharm. Pharmacol. 

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. 

Balimane, P. V., et al. Direct evidence for peptide transporter (PepTl)-mediated uptake of a nonpeptide prodrug, valacyclovir. Biochem. 

Ihara, T., et al. Regulation of PepTl peptide transporter expression in the rat small intestine under malnour-... 

Some drugs with low intrinsic permeability achieve acceptable oral bioavailability because they are substrates for uptake transporters, which normally function in nutrient uptake. The most prominent example is the peptide transporter, PepTl, which is active toward peptidomimetic antibiotics such as cephalexin, the antiviral agent valacyclovir [24] and other drugs. PepTl is natively expressed in Caco-2 cells, and adenovirus transduction has been used to increase PepTl expression levels [25]. However, the expression of PepTl was not polarized in this system and this expressed system appears to be of limited value as an improved screening model. PepTl has also been expressed in Chinese hamster ovary cells and a variety of other mammalian systems [26, 27]. 

In addition to PepTl, there is a related renal transporter, PepT2. There are also a series of other uptake transporters (organic anion transporting polypeptides, organic anion transporters, organic cation transporters), which are expressed primarily in the liver and other tissues but are not known to affect oral bioavailability. 

Cefadroxyl and cefaclor are beta-lactam antibiotics which show high affinity for the PepTl carrier system, whereas the other two beta-lactams, cephalotin and cef-metazole, are not recognized by PepTl protein and are not actively transported in the intestine. However, as the VolSurf Caco-2 model predicts that all the beta-lactams are nonpenetrating compounds, it is very probable that, as they rely only the diffusion mechanism, cefadroxyl and cefaclor will not cross the cell monolayer. 

PepTl gene by selective amino acids and dipeptides in the diet [81]. It has also been reported that the integrated response to certain stimuli may increase PepTl activity by translocation from a preformed cytoplasm pool [52]. 

Cellular and molecular mechanisms of dietary regulation on rat intestinal H+/Peptide transporter PepTl, Gastroenterology 1999, 116, 354-362. 

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. 

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