Peptide Derivation of Poorly Absorbable Drug Allows Intestinal Absorption Via Peptide Transporter
| Autor: | Kayoko Kanamitsu, Hiroyuki Sasabe, Tomoji Maeda, Ikumi Tamai, Akihiro Kikuchi, Michinori Tanaka, Masaaki Odomi, Tomoyasu Takahiro |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Patch-Clamp Techniques
Taurine Glutamine Xenopus Biological Availability Pharmaceutical Science Peptide In Vitro Techniques Quinolones Peptide Transporter 1 Intestinal absorption HeLa chemistry.chemical_compound medicine Animals Humans Enzyme Inhibitors Intestinal Mucosa Chromatography High Pressure Liquid chemistry.chemical_classification Alanine Dipeptide Symporters biology Chemistry Sodium Dodecyl Sulfate Transporter Dipeptides Prodrug biology.organism_classification Rats Intestines Intestinal Absorption Biochemistry Regional Blood Flow Drug delivery Oocytes Rebamipide Indicators and Reagents Caco-2 Cells Peptides HeLa Cells medicine.drug |
| Zdroj: | Journal of Pharmaceutical Sciences. 98:1775-1787 |
| ISSN: | 0022-3549 |
| DOI: | 10.1002/jps.21551 |
| Popis: | 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 [3H]Gly-Sar by PEPT1-expressing HeLa cells. Some of the peptide derivatives inhibited PEPT1-mediated uptake of [3H]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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text