St John's wort is a popular herbal product used to treat depression
but it has been implicated in drug interactions.
To assess the potential of St John's wort administration to alter the
activity of the cytochrome P450 (CYP) enzymes extensively involved in drug
Design, Setting, and Participants
Open-label crossover study with fixed treatment order conducted March
2002 to February 2003 in a US general clinical research center involving 12
healthy volunteers (6 men and 6 women) aged 22 to 38 years before and after
14 days of administration of St John's wort.
Participants were given probe drugs (30 mg of dextromethorphan and 2
mg of alprazolam) to establish baseline CYP 3A4 and CYP 2D6 activity. After
a minimum 7-day washout period, participants began taking one 300-mg tablet
3 times per day. After 14 days of St John's wort administration, participants
were given the probe drugs along with 1 St John's wort tablet to establish
postadministration CYP activity; the St John's wort dosing regimen was continued
for 48 hours.
Main Outcome Measures
Changes in plasma pharmacokinetics of alprazolam as a probe for CYP
3A4 activity and the ratio of dextromethorphan to its metabolite, dextrorphan,
in urine as a probe for CYP 2D6 activity.
A 2-fold decrease in the area under the curve for alprazolam plasma
concentration vs time (P<.001) and a 2-fold increase
in alprazolam clearance (P<.001) were observed
following St John's wort administration. Alprazolam elimination half-life
was shortened from a mean (SD) of 12.4 (3.9) hours to 6.0 (2.4) hours (P<.001). The mean (SD) urinary ratio of dextromethorphan
to its metabolite was 0.006 (0.010) at baseline and 0.014 (0.025) after St
John's wort administration (P = .26).
A 14-day course of St John's wort administration significantly induced
the activity of CYP 3A4 as measured by changes in alprazolam pharmacokinetics.
This suggests that long-term administration of St John's wort may result in
diminished clinical effectiveness or increased dosage requirements for all
CYP 3A4 substrates, which represent at least 50% of all marketed medications.