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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Polarized Efflux of Mono- and Diacid Metabolites of ME3229, an Ester-Type Prodrug of a Glycoprotein IIb/IIIa Receptor Antagonist, in Rat Small Intestine

Noriko Okudaira, Izumi Komiya and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics November 2000, 295 (2) 717-723;
Noriko Okudaira
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Izumi Komiya
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Yuichi Sugiyama
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Abstract

ME3229 is an ester-type prodrug of a glycoprotein IIb/IIIa receptor antagonist ME3277. In our previous study, it was shown that only a small part of the drug taken up into the enterocytes reached the mesenteric vein, mainly due to transporter-mediated efflux of its hydrolyzed metabolites formed in the cells. To characterize the efflux transport system for the metabolites, the transport of the diacid metabolite ME3277 and the monoacid metabolites PM-10 and PM-11 were studied. ME3277 and PM-10 were preferentially transported in the serosal-to-mucosal direction across the rat small intestine in the presence of glucose. Permeability of ME3277 across monolayer of Caco-2 cells with P-glycoprotein (P-gp) and indomethacin-sensitive efflux pump expression did not show any directionality and verapamil, an inhibitor of P-gp, and indomethacin did not affect the permeability of ME3277 across rat intestinal tissue. Directional transport was not site specific and was observed in the Eisai hyperbilirubinemic rat whose canalicular multispecific organic anion transporter/multidrug resistance-associated protein (cMOAT/MRP2) is hereditarily defective as well as in normal rats. The efflux transport of ME3277 was inhibited by 1-naphthol, 1-choloro-2,4-dinitrobenzene, and sulfobromophthalein, and efflux of ME3277 and monoacid metabolites from intestinal tissue preloaded with ME3229 fell in the presence of 1-naphthol and sulfobromophthalein. These results demonstrate that mono- and diacid metabolites of ME3229 were pumped out into the gut lumen by an energy-dependent transport system located on the mucosal membrane of intestinal tissue and distinct from either P-gp, indomethacin-sensitive efflux pump or canalicular multispecific organic anion transporter/MRP2. An inhibition study suggested that this unknown transporter has a substrate specificity similar to that of MRP transporter families.

Footnotes

  • Send reprint requests to: Noriko Okudaira, Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan. E-mail:noriko_okudaira{at}meiji.co.jp

  • Abbreviations:
    GP IIb/IIIa antagonist
    glycoprotein IIb/IIIa receptor antagonist
    P-gp
    P-glycoprotein
    cMOAT/MRP2
    canalicular multispecific organic anion transporter/multidrug resistance-associated protein 2
    EHBR
    Eisai hyperbilirubinemic rat
    DNP-SG
    2,4-dinitrophenyl-S-glutathione
    SD rat
    Sprague-Dawley rat
    DIDS
    4,4′-diisothiocyanostilbene-2,2′-disulfonic acid
    BSP
    sulfobromophthalein
    CDNB
    1-choloro-2,4-dinitrobenzene
    2-DG
    2-deoxyglucose
    A
    apical
    S
    serosal
    M
    mucosal
    pe
    permeability
    1-NG
    1-naphthol glucuronide
    • Received May 15, 2000.
    • Accepted July 26, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 295 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 295, Issue 2
1 Nov 2000
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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Polarized Efflux of Mono- and Diacid Metabolites of ME3229, an Ester-Type Prodrug of a Glycoprotein IIb/IIIa Receptor Antagonist, in Rat Small Intestine

Noriko Okudaira, Izumi Komiya and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics November 1, 2000, 295 (2) 717-723;

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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Polarized Efflux of Mono- and Diacid Metabolites of ME3229, an Ester-Type Prodrug of a Glycoprotein IIb/IIIa Receptor Antagonist, in Rat Small Intestine

Noriko Okudaira, Izumi Komiya and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics November 1, 2000, 295 (2) 717-723;
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