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Enhanced intestinal absorption of drugs by activation of peptide transporter PEPT1 using proton-releasing polymer

Authors

  • Takashi Nozawa,

    1. Faculty of Pharmaceutical Sciences, Department of Molecular Biopharmaceutics, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan
    2. Faculty of Pharmaceutical Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-0934, Japan
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  • Hidekazu Toyobuku,

    1. Faculty of Pharmaceutical Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-0934, Japan
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  • Daisuke Kobayashi,

    1. Faculty of Pharmaceutical Sciences, Department of Molecular Biopharmaceutics, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan
    2. Faculty of Pharmaceutical Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-0934, Japan
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  • Keiko Kuruma,

    1. Faculty of Pharmaceutical Sciences, Department of Molecular Biopharmaceutics, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan
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  • Akira Tsuji,

    1. Faculty of Pharmaceutical Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-0934, Japan
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  • Ikumi Tamai

    Corresponding author
    1. Faculty of Pharmaceutical Sciences, Department of Molecular Biopharmaceutics, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan
    • Faculty of Pharmaceutical Sciences, Department of Molecular Biopharmaceutics, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan. Telephone: 81 47121 3615; Fax: 81 47121 3615
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Abstract

Utilization of carrier-mediated transport systems in the gastrointestinal tract to increase the bioavailability of drugs is of great interest. In the present study, an increased supply of the driving force for peptide transporter PEPT1 by utilizing a proton-releasing polymer, Eudragit L100-55, was employed to increase the intestinal transport activity. Intestinal absorption of zwitterionic cefadroxil and dianionic cefixime was studied in rats by using in situ ileal closed loops and by in vivo oral administration of the drugs concomitantly with Eudragit L100-55. The results showed that Eudragit L100-55 decreased the pH in the intestinal loops, and increased the disappearance of both cefadroxil and cefixime from the loops. In rats, the plasma concentration after oral administration was increased significantly by coadministration of Eudragit L100-55, whereas a proton-nonreleasing analogous polymer, Eudragit RSPO, did not have any effect. Furthermore, the increased absorption of cefixime caused by Eudragit L100-55 was blocked by simultaneous administration of cefadroxil, a PEPT1 substrate/inhibitor, in a concentration-dependent manner. These results demonstrate that improvement of intestinal absorption of peptide-mimetics via a peptide transporter is possible by optimizing the transporter activity through coadministration of a proton-releasing polymer that supplies the driving force for the transporter. © 2003 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:2208–2216, 2003

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