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Research ArticleArticle

Transport of Rhodamine 123, a P-Glycoprotein Substrate, across Rat Intestine and Caco-2 Cell Monolayers in the Presence of Cytochrome P-450 3A-Related Compounds

Ryoko Yumoto, Teruo Murakami, Yuko Nakamoto, Risa Hasegawa, Junya Nagai and Mikihisa Takano
Journal of Pharmacology and Experimental Therapeutics April 1999, 289 (1) 149-155;
Ryoko Yumoto
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Teruo Murakami
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Yuko Nakamoto
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Risa Hasegawa
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Junya Nagai
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Mikihisa Takano
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Abstract

Effects of cytochrome P-450 3A- and P-glycoprotein (P-gp)-related compounds, erythromycin, midazolam, ketoconazole, verapamil, and quinidine, on transport of rhodamine 123 (Rho-123), a P-gp substrate, were studied in rat intestine and in Caco-2 cells. Ileum was mainly used in rat studies because this segment showed greater P-gp-mediated Rho-123 transport. In an in vitro everted rat ileum, all the compounds examined significantly inhibited the transport of Rho-123 from serosal to mucosal surfaces across the intestine, with different inhibitory potencies among these compounds. In an in vivo rat study, the exsorption of Rho-123 from blood to the intestinal lumen, which was evaluated as exsorption clearance of Rho-123 under a steady-state plasma concentration of Rho-123, was also inhibited when these compounds were added to the intestinal lumen. Similarly, transepithelial transport of Rho-123 from the basolateral to apical side across Caco-2 cell monolayers was inhibited by these compounds. A linear relationship was observed in their inhibitory potencies on Rho-123 transport between in vitro and in vivo studies using rat ileum and between studies with rat ileum and Caco-2 cells. P-gp-mediated transport across the intestine was found to be inhibited not only by P-gp-related but also by all the cytochrome P-450 3A-related compounds examined. Within experimental error, the relative inhibitory potencies were the same between the studies with rat ileum (in vivo, in vitro) and those with Caco-2 cells. Thus, it is suggested that the function of P-gp and its sensitivity to these drugs may be similar in rat intestine and Caco-2 cells.

Footnotes

  • Send reprint requests to: Mikihisa Takano, Ph.D., Institute of Pharmaceutical Sciences, Hiroshima University School of Medicine, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan. E-mail:takanom{at}pharm.hiroshima-u.ac.jp

  • ↵1 This work was supported in part by a grant-in-aid from the Tokyo Biochemical Research Foundation.

  • Abbreviations:
    CYP
    cytochrome P-450
    P-gp
    P-glycoprotein
    Rho-123
    rhodamine 123
    TEER
    transepithelial electric resistance
    D-PBS
    Dulbecco’s PBS
    CLtotal
    total plasma clearance
    CLexp
    exsorption clearance
    CLurine
    urinary excretion clearance
    CLbile
    biliary excretion clearance
    • Received July 22, 1998.
    • Accepted November 2, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 289 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 289, Issue 1
1 Apr 1999
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Research ArticleArticle

Transport of Rhodamine 123, a P-Glycoprotein Substrate, across Rat Intestine and Caco-2 Cell Monolayers in the Presence of Cytochrome P-450 3A-Related Compounds

Ryoko Yumoto, Teruo Murakami, Yuko Nakamoto, Risa Hasegawa, Junya Nagai and Mikihisa Takano
Journal of Pharmacology and Experimental Therapeutics April 1, 1999, 289 (1) 149-155;

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Research ArticleArticle

Transport of Rhodamine 123, a P-Glycoprotein Substrate, across Rat Intestine and Caco-2 Cell Monolayers in the Presence of Cytochrome P-450 3A-Related Compounds

Ryoko Yumoto, Teruo Murakami, Yuko Nakamoto, Risa Hasegawa, Junya Nagai and Mikihisa Takano
Journal of Pharmacology and Experimental Therapeutics April 1, 1999, 289 (1) 149-155;
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