The Predominant Contribution of Oligopeptide Transporter PepT1 to Intestinal Absorption of β-Lactam Antibiotics in the Rat Small Intestine

Abstract

Although recent evidence suggests that certain beta-lactam antibiotics are absorbed via a specific transport mechanism, its nature is unclear. To confirm whether peptide transport in the rat can be largely ascribed to the intestinal oligopeptide transporter PepT1, the transporter has been functionally characterized and its significance in the intestinal absorption of beta-lactam antibiotics was evaluated. For evaluation of transport activity complementary RNA (cRNA) of rat PepT1 was synthesized in-vitro and expressed in Xenopus laevis oocytes. cRNA induced uptake of several beta-lactam antibiotics and the dipeptide [14C]glycylsarcosine; this was specifically inhibited by various dipeptides and tripeptides but not by their constituent amino acids or by tetra- or pentapeptides. The transport activity of PepT1 for beta-lactam antibiotics correlated well with their in-vivo intestinal transport and absorption. Furthermore, mutual inhibitory effects on uptake were observed between glyclsarcosine and beta-lactam antibiotics. Hybrid depletion of the functional expression of rat PepT1 in oocytes injected with rat intestinal epithelial total mRNA was studied using an antisense oligonucleotide corresponding to the 5'-coding region of PepT1. In oocytes injected with rat mRNA pre-hybridized with the antisense oligonucleotide against rat PepT1, the uptake of [14C]glycylsarcosine was almost completely abolished, whereas its uptake was not influenced by a sense oligonucleotide for the same region of PepT1. Similarly, the uptake of beta-lactam antibiotics was also reduced by the antisense oligonucleotide against rat PepT1. These results demonstrate that the intestinal proton-coupled oligopeptide transporter PepT1 plays a predominant role in the carrier-mediated intestinal absorption of beta-lactam antibiotics and native oligopeptides in the rat.

PDZK1 Regulates Two Intestinal Solute Carriers (Slc15a1 and Slc22a5) in Mice

“…The H ϩ /oligopeptide transporter PEPT1 (SLC15A1) is localized on apical membranes of small intestinal epithelial cells and recognizes not only dipeptides and tripeptides but also peptide-like drugs, including oral ␤-lactam antibiotics, angiotensin-converting enzyme inhibitor, rennin inhibitor, and bestatin (Hu and Amidon, 1988;Frieman and Amidon, 1990;Kramer et al, 1990;Saito et al, 1993;Nakanishi et al, 1997;Tamai et al, 1997). Moreover, intestinal uptake and permeability of some ␤-lactam antibiotics are well correlated with the expression level of PEPT1 in the small intestine (Chu et al, 2001;Naruhashi et al, 2002).…”

Involvement of Multidrug Resistance-Associated Protein 1 in Intestinal Toxicity of Methotrexate

“…play a key role in drug absorption (7,8,(13)(14)(15)(16), little is known about the pharmacological and/or toxicological effects of transporter(s) expressed in undifferentiated cells in the small intestine. The aim of the present study is to clarify whether Mrp1, which was reported to be expressed in proliferative cells of crypts in mice, is involved in the intestinal toxicity provoked by MTX in vivo.…”

“…Among them, oligopeptide transporter (PEPT1/SLC15A1) has been proposed to be involved not only in gastrointestinal absorption of di-and tripeptides, but also in that of various therapeutic agents, including ß-lactam antibiotics (7,8). Similarly, both reduced folate carrier (RFC/SLC19A1) and SLC46A1, originally identified as a heme carrier protein (HCP1), were reported to be expressed in small intestine, and both recognize folate and MTX (9,10).…”

Investigation of the Role of Oligopeptide Transporter PEPT1 and Sodium/Glucose Cotransporter SGLT1 in Intestinal Absorption of Their Substrates Using Small GTP-Binding Protein Rab8-Null Mice

“…In contrast, cefixime has no amino group, but it exhibits high membrane perme-ability despite its hydrophilic character, probably because it shares the same transport systems as dipeptide and ␣-amino ␤-lactam antibiotics in small intestine (Tsuji et al, 1987a,b). PEPT1 was cloned as a possible candidate for the oligopeptide transport system (Fei et al, 1994;Miyamoto et al, 1996) and recognizes various ␤-lactam antibiotics, including cefixime and cephalexin Wenzel et al, 1996;Tamai et al, 1997). However, most of the studies that have supported a fundamental role of PEPT1 were in vitro studies, and no direct in vivo evidence has been available up to now.…”