St John's Wort induces intestinal P-glycoprotein/MDR1 and intestinal and hepatic CYP3A4

Clin Pharmacol Ther. 2000 Dec;68(6):598-604. doi: 10.1067/mcp.2000.112240.


Background: St John's Wort (hypericum perforatum) is an herbal medicine that is frequently used for therapy of mild depression. Recently, St John's Wort was reported to substantially decrease blood/plasma concentrations and efficacy of cyclosporine (INN, ciclosporin), indinavir, and digoxin. In this study we investigated the mechanisms of these St John's Wort-induced drug interactions.

Methods and results: In a preclinical study, the administration of St John's Wort extract to rats during 14 days resulted in a 3.8-fold increase of intestinal P-glycoprotein/Mdrl expression and in a 2.5-fold increase in hepatic CYP3A2 expression (Western blot analyses). In a clinical study, the administration of St John's Wort extract to 8 healthy male volunteers during 14 days resulted in an 18% decrease of digoxin exposure after a single digoxin dose (0.5 mg), in 1.4- and 1.5-fold increased expressions of duodenal P-glycoprotein/MDR1 and CYP3A4, respectively, and in a 1.4-fold increase in the functional activity of hepatic CYP3A4 (14C-erythromycin breath test).

Conclusions: These results indicate direct inducing effects of St John's Wort on intestinal P-glycoprotein/MDR1 (in rats and humans), hepatic CYP3A2 (in rats), and intestinal and hepatic CYP3A4 (in humans). Therefore the results provide a mechanistic explanation for the previously observed drug interactions in patients and support the importance of intestinal P-glycoprotein/MDR1 in addition to intestinal and hepatic CYP3A4 for overall drug absorption and disposition in humans.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / biosynthesis*
  • Adult
  • Animals
  • Biological Availability
  • Cardiotonic Agents / pharmacokinetics
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / biosynthesis*
  • Digoxin / pharmacokinetics
  • Drug Interactions
  • Duodenum / drug effects
  • Duodenum / enzymology
  • Duodenum / metabolism
  • Enzyme Induction / drug effects
  • Humans
  • Hypericum / adverse effects*
  • Intestine, Small / drug effects*
  • Intestine, Small / enzymology
  • Intestine, Small / metabolism
  • Liver / drug effects*
  • Liver / enzymology
  • Male
  • Mixed Function Oxygenases / biosynthesis*
  • Plant Extracts / adverse effects
  • Plant Extracts / pharmacology
  • Plants, Medicinal*
  • Rats
  • Rats, Sprague-Dawley


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Cardiotonic Agents
  • Plant Extracts
  • Digoxin
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human