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St John's Wort induces intestinal P‐glycoprotein/MDR1 and intestinal and hepatic CYP3A4
Author(s) -
Dürr Donat,
Stieger Bruno,
KullakUblick Gerd A.,
Rentsch Katharina M.,
Steinert Hans C.,
Meier Peter J.,
Fattinger Karin
Publication year - 2000
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1067/mcp.2000.112240
Subject(s) - p glycoprotein , digoxin , hypericum perforatum , pharmacology , cyp3a4 , pharmacokinetics , medicine , pharmacokinetic interaction , organic anion transporting polypeptide , chemistry , drug interaction , metabolism , antibiotics , biochemistry , cytochrome p450 , transporter , heart failure , multiple drug resistance , gene
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/Mdr1 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 ( 14 C‐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. (Clin Pharmacol Ther 2000;68:598–604.) Clinical Pharmacology & Therapeutics (2000) 68 , 598–604; doi: 10.1067/mcp.2000.112240