Oral Drug Delivery by Activation of Peptide Transporter PEPT1

Since membrane transporters efficiently facillitate intestinal absorption of nutrients, it should be possible to utilyze those transporters to improve permeability of drugs/drug candidates. In the present study, oligopeptide transporter PEPT1, which accepts various di- and tri-peptides as substrates and transports them using proton gradient as the driving force, was examined as the tools for oral drug delivery of peptide-mimetic compounds. Since substrates of PEPT1 exhibits varible optimal pH depending on substrates, acidic polymer Eudragit L100-55 (EL) was employed to control intestinal luminal pH to be optimal for low permerble PEPT1 substrate, β-lactam antibiotic cefiximie which exhibits optimal transport by PEPT1 at pH 5 or lower, as model compound. Intestinal absorption of cefixime was studied in rats by in situ ileal closed loops and by in vivo oral administration of the drugs concomitantly with EL. EL decreased the pH in the intestinal lumen, and increased the absorption in both the in situ closed loop and in vivo oral administration studies. Furthermore, the increased absorption of cefixime caused by EL was reduced by simultaneous administration of cefadroxil, a PEPT1 substrate/inhibitor, in a dose-dependent manner. Accordingly, an improvement of intestinal absorption of peptide-mimetics via PEPT1 is possible by optimizing the transporter activity through coadministration of a proton-releasing polymer which supplies the driving force for the transporter.