title: Peptide derivation of poorly absorbable drug allows intestinal absorption via peptide transporter.
abstract: The purpose of the present study was to examine whether the intestinal absorption of low-permeability drugs could be improved by utilization of the intestinal influx transporter PEPT1. We investigated whether peptide derivatives of poorly absorbable nonamino acid-like drugs might be substrates of PEPT1, using rebamipide (Reb) as a model drug. We synthesized several peptide derivatives of rebamipide and examined their inhibitory effect on the uptake of [(3)H]Gly-Sar by PEPT1-expressing HeLa cells. Some of the peptide derivatives inhibited PEPT1-mediated uptake of [(3)H]Gly-Sar. Next, uptake of the inhibitory peptide derivatives was evaluated in PEPT1-expressing Xenopus oocytes and HeLa cells. Ser(Reb)-Gly exhibited significantly increased uptake by PEPT1-expressing cells in comparison with that by mock cells. The permeability of Ser(Reb)-Gly across a Caco-2 cell monolayer was significantly higher than that of rebamipide itself, and the transport was decreased in the presence of PEPT1 substrates. Further, a rat intestinal perfusion study revealed increased absorption of Ser(Reb)-Gly compared with rebamipide. These results demonstrate that the addition of a dipeptide moiety to a poorly absorbable nonpeptide/nonamino acid-like drug can result in absorption via the intestinal transporter PEPT1, though there is some selectivity as regards the structure of the added peptide moiety.
authors.affiliation: Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kikuchi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Tomoyasu
authors.forename: Michinori
authors.initials: M
authors.lastname: Tanaka
authors.forename: Kayoko
authors.initials: K
authors.lastname: Kanamitsu
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sasabe
authors.forename: Tomoji
authors.initials: T
authors.lastname: Maeda
authors.forename: Masaaki
authors.initials: M
authors.lastname: Odomi
authors.forename: Ikumi
authors.initials: I
authors.lastname: Tamai
mesh_terms: D000409:Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000818:Animals; D001682:Biological Availability; D018938:Caco-2 Cells; D002851:Chromatography, High Pressure Liquid; D004151:Dipeptides / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D005973:Glutamine / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007408:Intestinal Absorption / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000098:blood supply; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D000074011:Peptide Transporter 1; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D015363:Quinolones / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D051381:Rats; D012039:Regional Blood Flow; D012967:Sodium Dodecyl Sulfate; D027981:Symporters / Q000378:metabolism*; D013654:Taurine; D014981:Xenopus
chemical_list: D004151:Dipeptides; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D000074011:Peptide Transporter 1; D010455:Peptides; D015363:Quinolones; C082186:SLC15A1 protein, human; D027981:Symporters; D005973:Glutamine; D013654:Taurine; D012967:Sodium Dodecyl Sulfate; C052785:rebamipide; D000409:Alanine