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

J Pharmacol Exp Ther. 2002 Aug;302(2):645-50. doi: 10.1124/jpet.102.034728.

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 IC(50) values of 15.5 and 74.1 microM, respectively. CYP3A4-catalyzed formation of D-617 and norverapamil was inhibited in a mixed fashion, with K(i) values of 36 +/- 8 (liver 1)/49 +/- 6 (liver 2) and 44 +/- 10 (liver 1)/77 +/- 10 microM (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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
  • Alkaloids*
  • Benzodioxoles
  • Biological Transport / drug effects
  • Colonic Neoplasms
  • Cyclosporine / pharmacokinetics
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors*
  • Digoxin / pharmacokinetics
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Kinetics
  • Mixed Function Oxygenases / antagonists & inhibitors*
  • Piperidines / pharmacology*
  • Polyunsaturated Alkamides
  • Tumor Cells, Cultured

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Alkaloids
  • Benzodioxoles
  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Piperidines
  • Polyunsaturated Alkamides
  • Digoxin
  • Cyclosporine
  • Mixed Function Oxygenases
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • piperine