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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Piperine, a Major Constituent of Black Pepper, Inhibits Human P-glycoprotein and CYP3A4

Rajinder K. Bhardwaj, Hartmut Glaeser, Laurent Becquemont, Ulrich Klotz, Suresh K. Gupta and Martin F. Fromm
Journal of Pharmacology and Experimental Therapeutics August 2002, 302 (2) 645-650; DOI: https://doi.org/10.1124/jpet.102.034728
Rajinder K. Bhardwaj
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Hartmut Glaeser
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Laurent Becquemont
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Ulrich Klotz
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Suresh K. Gupta
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Martin F. Fromm
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Abstract

Dietary constituents (e.g., in grapefruit juice; NaCl) and phytochemicals (e.g., St. John's wort) are important agents modifying drug metabolism and transport and thereby contribute to interindividual variability in drug disposition. Most of these drug-food interactions are due to induction or inhibition of P-glycoprotein and/or CYP3A4. Preliminary data indicate that piperine, a major component of black pepper, inhibits drug-metabolizing enzymes in rodents and increases plasma concentrations of several drugs, including P-glycoprotein substrates (phenytoin and rifampin) in humans. However, there are no direct data whether piperine is an inhibitor of human P-glycoprotein and/or CYP3A4. We therefore investigated the influence of piperine on P-glycoprotein-mediated, polarized transport of digoxin and cyclosporine in monolayers of Caco-2 cells. Moreover, by using human liver microsomes we determined the effect of piperine on CYP3A4-mediated formation of the verapamil metabolites D-617 and norverapamil. Piperine inhibited digoxin and cyclosporine A transport in Caco-2 cells with IC50 values of 15.5 and 74.1 μM, respectively. CYP3A4-catalyzed formation of D-617 and norverapamil was inhibited in a mixed fashion, with Ki values of 36 ± 8 (liver 1)/49 ± 6 (liver 2) and 44 ± 10 (liver 1)/77 ± 10 μM (liver 2), respectively. In summary, we showed that piperine inhibits both the drug transporter P-glycoprotein and the major drug-metabolizing enzyme CYP3A4. Because both proteins are expressed in enterocytes and hepatocytes and contribute to a major extent to first-pass elimination of many drugs, our data indicate that dietary piperine could affect plasma concentrations of P-glycoprotein and CYP3A4 substrates in humans, in particular if these drugs are administered orally.

Footnotes

  • This work was supported by the Deutscher Akademischer Austauschdienst (to R.B.; Bonn, Germany), Council of Scientific and Industrial Research (New Delhi, India), the Association Francaise pour la Recherche Therapeutique (www.afrt.org, to L.B., France), the Deutsche Forschungsgemeinschaft (Fr1298/2-1; Bonn, Germany), and the Robert Bosch Foundation (Stuttgart, Germany).

  • DOI: 10.1124/jpet.102.034728

  • Abbreviations:
    HIV
    human immunodeficiency virus
    TEER
    transepithelial resistance
    • Received February 12, 2002.
    • Accepted March 26, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 302 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 302, Issue 2
1 Aug 2002
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Piperine, a Major Constituent of Black Pepper, Inhibits Human P-glycoprotein and CYP3A4

Rajinder K. Bhardwaj, Hartmut Glaeser, Laurent Becquemont, Ulrich Klotz, Suresh K. Gupta and Martin F. Fromm
Journal of Pharmacology and Experimental Therapeutics August 1, 2002, 302 (2) 645-650; DOI: https://doi.org/10.1124/jpet.102.034728

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Piperine, a Major Constituent of Black Pepper, Inhibits Human P-glycoprotein and CYP3A4

Rajinder K. Bhardwaj, Hartmut Glaeser, Laurent Becquemont, Ulrich Klotz, Suresh K. Gupta and Martin F. Fromm
Journal of Pharmacology and Experimental Therapeutics August 1, 2002, 302 (2) 645-650; DOI: https://doi.org/10.1124/jpet.102.034728
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