Abstracts

RATIONALE: We have previously described the lack of effect of St. John[ssquote]s wort (SJW) on the pharmacokinetics of chronically dosed carbamazepine. These findings were in contrast to previous reports describing significant interactions with CYP3A4 substrates. We proposed that autoinduction of carbamazepine clearance with chronic dosing may minimize the potential for further induction by SJW. The present study was conducted to determine the effect of SJW on single dose carbamazepine and carbamazepine-10,11-epoxide pharmacokinetics in the absence of carbamazepine autoinduction.
METHODS: Eight healthy volunteers (5 M, 24-43 yrs) participated in this two-treatment, two period, single sequence, longitudinal, open label study. Subjects initially received a single dose of carbamazepine 400mg orally. Blood samples were collected prior to and 1, 2, 4, 6, 8, 10, 12, 24, 32, 48 and 72 hours following dosing. SJW 300mg (0.3% hypericin standardized tablet) three times daily with meals was then taken for 17 days. On day 15 of SJW subjects again received a single dose of carbamazepine 400mg orally and blood sampling was repeated. Plasma samples were analyzed for carbamazepine and carbamazepine-10,11-epoxide by HPLC. Pharmacokinetic parameter values were determined using noncompartmental techniques. Statistical tests for concentration data were based on geometric means from logarithmic transformed values.
RESULTS: In the presence of SJW, mean carbamazepine area under the curve over the 72 hours sampling period (AUC0-72) decreased 21% from 267.7 to 210.3 mg*h/L (p=0.002). Mean maximum concentrations (Cmax) decreased 11% from 5.4 to 4.8 mg/L (p=0.017) while mean apparent oral clearance (CL/F) increased 43% from 1.08 to 1.52 L/h (p=0.0003). Carbamazepine-10,11-epoxide mean Cmax increased 29% from 0.40 to 0.51 mg/L (p=0.005 ) and mean AUC0-72 increased 26% from 20.2 to 25 mg*h/L (p=0.023). The ratio of carbamazepine-10,11-epoxide AUC to carbamazepine AUC increased 64% from 0.076 to 0.019 (p=0.0005). Geometric mean ratios (presence of SJW to absence of SJW) and 90% confidence intervals for all parameter values, except carbamazepine Cmax, were outside the limits (80% to 125%)indicative of no interaction.
CONCLUSIONS: The results suggest that treatment with SJW for 14 days is capable of inducing the clearance of single dose carbamazepine. The decrease in carbamazepine AUC with an associated increase in carbamazepine-10,11-epoxide AUC suggests the mechanism to be induced clearance rather than reduced bioavailability of carbamazepine. The lack of effect of SJW on carbamazepine seen in our earlier study is likely related to the chronic administration of carbamazepine.
Support: NIH Clinical Center Pharmacy Department and NINDS Intramural Funds