Drug Interaction Study of Tegretol (Carbamazepine) and St. John's Wort in Normal Volunteers

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.