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 tha t is frequently used for therapy of mild depression. Recently, St John's Wo rt was reported to substantially decrease blood/plasma concentrations and e fficacy 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 in testinal P-glycoprotein/Mdr1 expression and in a 2.5-fold increase in hepat ic CYP3A2 expression (Western blot analyses). In a clinical study, the admi nistration 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 digoxi n dose (0.5 mg), in 1.4- and 1.5-fold increased expressions of duodenal P-g lycoprotein/MDR1 and CYP3A4, respectively, and in a 1.4-fold increase in th e functional activity of hepatic CYP3A4 (C-14-erythromycin breath test). Conclusions: These results indicate direct inducing effects of St John's Wo rt on intestinal P-glycoprotein/MDR1 (in rats and humans), hepatic CYP3A2 ( in rats), and intestinal and hepatic CYP3A4 (in humans). Therefore the resu lts provide a mechanistic explanation for the previously observed drug inte ractions in patients and support the importance of intestinal P-glycoprotei n/MDR1 in addition to intestinal and hepatic CYP3A4 for overall drug absorp tion and disposition in humans.