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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Interaction of Cytochrome P450 3A Inhibitors with P-Glycoprotein

Kazuto Yasuda, Lu-bin Lan, Dominique Sanglard, Katryn Furuya, John D. Schuetz and Erin G. Schuetz
Journal of Pharmacology and Experimental Therapeutics October 2002, 303 (1) 323-332; DOI: https://doi.org/10.1124/jpet.102.037549
Kazuto Yasuda
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Lu-bin Lan
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Dominique Sanglard
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Katryn Furuya
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John D. Schuetz
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Erin G. Schuetz
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Abstract

Many clinically important drug interactions occur due to inhibition of human liver cytochrome P450 3A (CYP3A) metabolism. The drug efflux pump P-glycoprotein (Pgp) can be an additional locus contributing to these drug interactions because there is overlap in drugs that are substrates for both proteins. We screened a number of CYP3A inhibitors (macrolide antibiotics, azole antifungals, and ergotpeptides) for their ability to interact with Pgp, compared with prototypical Pgp inhibitors. We used cell lines expressing human, mouse, and rat mdr1 genes. Pgp antagonism was defined by interactions of the drugs with four cell lines (LLC-PK1, L-MDR1, L-mdr1a, and L-mdr1b) using a microfluorometric calcein-AM assay and characterized for their inhibitor constant (Ki) toward calcein-AM. The compounds were further defined for their ability to inhibit MDR1 by their effect on vinblastine accumulation into L-MDR1 cells. Representative compounds from each class of drugs were further tested as Pgp substrates, defined by the ability of human Pgp or mouse mdr1a/Pgp to transport them across a polarized kidney epithelial cell in vitro. These same compounds were administered radiolabeled in vivo to mdr1a (+/+) and (−/−) mice and the distribution of radioactivity compared. The results are summarized as follows: 1) Some drug interactions with Pgp were substrate- and/or assay-dependent. 2) Ergot alkaloids were identified as a class of MDR1/Pgp chemosensitizers. 3) The Ergot alkaloids revealed species differences in the structure-activity relationships for inhibition of Pgp. Simultaneous inhibition of Pgp by many CYP3A inhibitors contributes to human variation in the extent of drug-drug interactions.

Footnotes

  • This study was supported by National Institutes of Health Grants ES08658 and P30 CA21745 and a Cancer center support grant, and the American Lebanese Syrian Associated Charities.

  • DOI: 10.1124/jpet.102.037549

  • Abbreviations:
    Pgp
    p-glycoprotein
    MDR/mdr
    multidrug resistance
    AM
    acetoxymethyl ester
    DMSO
    dimethyl sulfoxide
    TAO
    triacetyloleandomycin
    VBL
    vinblastine
    KCZ
    ketoconazole
    FCZ
    fluconazole
    CsA
    cyclosporin A
    ITZ
    itraconazole
    • Received April 15, 2002.
    • Accepted June 4, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 303 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 303, Issue 1
1 Oct 2002
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Interaction of Cytochrome P450 3A Inhibitors with P-Glycoprotein

Kazuto Yasuda, Lu-bin Lan, Dominique Sanglard, Katryn Furuya, John D. Schuetz and Erin G. Schuetz
Journal of Pharmacology and Experimental Therapeutics October 1, 2002, 303 (1) 323-332; DOI: https://doi.org/10.1124/jpet.102.037549

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Interaction of Cytochrome P450 3A Inhibitors with P-Glycoprotein

Kazuto Yasuda, Lu-bin Lan, Dominique Sanglard, Katryn Furuya, John D. Schuetz and Erin G. Schuetz
Journal of Pharmacology and Experimental Therapeutics October 1, 2002, 303 (1) 323-332; DOI: https://doi.org/10.1124/jpet.102.037549
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