St. John's Wort is a popular dietary supplement that many patients-including those with
epilepsy or seizures-take in addition to their regular medicines to elevate mood or relieve
stress. Preliminary research indicates that this supplement can speed the metabolism of the
anti-seizure drug Tegretol, causing reduced blood levels of the drug. Patients who take
Tegretol to control their seizures may have more frequent seizures if the blood level of the
drug drops too low. A recent study shows that this effect is not seen when Tegretol is
taken for at least 3 weeks. The present study will examine whether there is a medically
important drug interaction between St. John's wort and Tegretol when Tegretol is taken for 1
Normal healthy volunteers between 21 and 65 years old who are not taking medicines that can
affect the metabolism of drugs in the liver and have not used St. John's wort for at least
30 days may be eligible for this 25-day study.
Participants will take a 400-mg dose of Tegretol after fasting overnight. Blood samples
will be drawn the next day during a 12-hour clinic stay at the following intervals: just
before the Tegretol dose and at 1, 2, 4, 6, 8, 10, 24, 34, 48 and 72 hours after the dose.
A catheter will be placed in the vein to prevent the need for multiple needle sticks until
after the 10-hour sample. After completing the blood sampling, participants will take 300
mg of St. John's wort 3 times a day with meals for 2 weeks. After 2 weeks, another fasting
dose of Tegretol will be given and the 72-hour blood study will be repeated.
This study may provide information important for the care of patients with epilepsy who take
both Tegretol and St. John's Wort.
Alternative or complementary therapies are widely used by patients with epilepsy. St.
John's Wort is one of the most popular herbal dietary supplements with a variety of claims
including mood elevation and stabilization, stress relief, anti-viral effects, and
enhancement of the immune system. We have previously demonstrated that treatment with St.
John's Wort for 14 days does not induce the clearance of carbamazepine under steady state
conditions of autoinduction of carbamazepine clearance. One proposed mechanism for this
lack of effect is that St. John's Wort is not sufficiently potent to further induce
previously induced CYP3A4 enzyme activity. The purpose of this study is to investigate the
effect of St. John's Wort on single dose carbamazepine pharmacokinetics under conditions of
uninduced CYP3A4. To evaluate this potential drug interaction, as well as the effect of St.
John's Wort on epoxide hydrolase activity, eight normal healthy subjects will be enrolled
into this pharmacokinetic study. Subjects will take a single 400 mg dose of carbamazepine
followed by serial blood sampling over 72 hours for carbamazepine and carbamazepine epoxide
plasma concentrations. Subjects will then begin taking a standardized formulation of St.
John's Wort three times daily with meals for two weeks. Following 2 weeks of St. John's
Wort subjects will then again take a single 400 mg dose of carbamazepine and have serial
blood samples collected for carbamazepine and carbamazepine epoxide plasma concentrations.
The total carbamazepine and carbamazepine epoxide exposure (AUC), oral clearance (CL/F), and
maximal concentrations (Cmax) will be compared between treatment phases to characterize the
potential drug interaction.
Male or female.
Healthy by medical history and physical exam.
Age between 21 and 65 years old.
Non-smoker for a minimum of 6 months.
AST/SGOT less than or equal to 2 x upper limit of normal.
Serum creatinine less than or equal to upper limit of normal.
Hemoglobin greater than or equal to 10 g/dl.
Females of childbearing potential must be using a reliable form of birth control other
than hormonal contraceptives.
No concomitant therapy with other inhibitors or inducers of cytochrome P-450 mediated drug
metabolism within 30 days of study.
No inability to remain free of chronic medications and alcohol for at least 2 weeks prior
to and during the study.
No previous use of St. John's Wort. Subjects with prior history of St. John's Wort use
must abstain from use for 30 days prior to study participation.
No presence of renal, hepatic, cardiovascular, hematologic, neurologic, psychiatric, or
respiratory disease or any other condition that may interfere with the interpretation of
the study results or not be in the best interests of the subject in the opinion of the
No positive urine pregnancy test.
No presence of persistent diarrhea or malabsorption that would interfere with the
patients ability to adequately absorb drugs.