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.