title: St John's Wort induces intestinal P-glycoprotein/MDR1 and intestinal and hepatic CYP3A4.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Medicine, Institute of Clinical  Chemistry, Zürich, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Dürr
authors.forename: B
authors.initials: B
authors.lastname: Stieger
authors.forename: G A
authors.initials: GA
authors.lastname: Kullak-Ublick
authors.forename: K M
authors.initials: KM
authors.lastname: Rentsch
authors.forename: H C
authors.initials: HC
authors.lastname: Steinert
authors.forename: P J
authors.initials: PJ
authors.lastname: Meier
authors.forename: K
authors.initials: K
authors.lastname: Fattinger
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D000328:Adult; D000818:Animals; D001682:Biological Availability; D002316:Cardiotonic Agents / Q000493:pharmacokinetics; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004077:Digoxin / Q000493:pharmacokinetics; D004347:Drug Interactions; D004386:Duodenum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D020902:Hypericum / Q000009:adverse effects*; D007421:Intestine, Small / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D006899:Mixed Function Oxygenases / Q000096:biosynthesis*; D010936:Plant Extracts / Q000009:adverse effects / Q000494:pharmacology; D010946:Plants, Medicinal; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002316:Cardiotonic Agents; D010936:Plant Extracts; D004077:Digoxin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human