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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Influence of P-Glycoprotein on the Transport and Metabolism of Indinavir in Caco-2 Cells Expressing Cytochrome P-450 3A4

Jerome H. Hochman, Masato Chiba, Joy Nishime, Masayo Yamazaki and Jiunn H. Lin
Journal of Pharmacology and Experimental Therapeutics January 2000, 292 (1) 310-318;
Jerome H. Hochman
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Masato Chiba
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Joy Nishime
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Masayo Yamazaki
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Jiunn H. Lin
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Abstract

Caco-2 cells grown in the presence of 1α,25-di-OH vitamin D3 (di-OH vit D3) were used as a model to evaluate the effects of P-glycoprotein (Pgp) efflux on CYP3A4-mediated metabolism of indinavir during intestinal absorption. Caco-2 cells grown under these conditions demonstrated significant CYP3A4 activity and maintained Pgp-mediated directional transport of indinavir. Metabolism of indinavir in the di-OH vit D3-treated cells correlated with the level of CYP3A activity and generated metabolites consistent with CYP3A4-mediated metabolism. During transport experiments, indinavir metabolites are selectively secreted into the apical compartment, consistent with Pgp-mediated efflux. Using formation of the most abundant metabolite, M6, as a marker for indinavir metabolism, we observed that the extent of indinavir metabolism is not significantly affected by the direction of indinavir transport or by inhibition of Pgp with cyclosporin A. However, because Pgp efflux results in higher indinavir transport in the basolateral-to-apical direction than in the apical-to-basolateral direction, the ratio of M6 produced normalized to the amount of drug transported across the monolayer was higher for apical-to-basolateral transport. Thus, Pgp efflux in a direction opposite to absorptive transport results in more metabolite produced per mole of drug that is absorbed. In summary, the results support a role of Pgp in increasing intestinal presystemic metabolism and in removal of CYP3A4-generated metabolites from the intracellular compartment.

Footnotes

  • Send reprint requests to: Dr. Jerome H. Hochman, Department of Drug Metabolism, WP 75-200, Merck and Co., Inc., West Point, PA 19486. E-mail: jerome_hochman{at}merck.com

  • Abbreviations:
    Pgp
    P-glycoprotein
    EHS
    Engelbreth-Holme-Swarm
    LC/MS
    liquid chromatography/mass spectrometry
    CYP3A4
    cytochrome P-450 3A4
    di-OH vit D3
    1α,25-di-OH vitamin D3
    CsA
    cyclosporin A
    HBSS
    Hanks' balanced salt solution
    • Received June 11, 1999.
    • Accepted September 29, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 292 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 292, Issue 1
1 Jan 2000
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Influence of P-Glycoprotein on the Transport and Metabolism of Indinavir in Caco-2 Cells Expressing Cytochrome P-450 3A4

Jerome H. Hochman, Masato Chiba, Joy Nishime, Masayo Yamazaki and Jiunn H. Lin
Journal of Pharmacology and Experimental Therapeutics January 1, 2000, 292 (1) 310-318;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Influence of P-Glycoprotein on the Transport and Metabolism of Indinavir in Caco-2 Cells Expressing Cytochrome P-450 3A4

Jerome H. Hochman, Masato Chiba, Joy Nishime, Masayo Yamazaki and Jiunn H. Lin
Journal of Pharmacology and Experimental Therapeutics January 1, 2000, 292 (1) 310-318;
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