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Vol. 302, Issue 2, 645-650, August 2002

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

Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany (R.K.B., H.G., L.B., U.K., M.F.F.); and Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, India (R.K.B., S.K.G.)

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.

0022-3565/02/3022-0645$07.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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