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

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