St John's wort decreases the bioavailability of R- and S-verapamil through induction of the first-pass metabolism

• OBJECTIVE:Our objective was to investigate the inducing effect of repeated oral administration of St John's wort on the jejunal transport and presystemic extraction of R- and S-verapamil in humans.METHODS:Jejunal single-pass perfusion experiments with 120-mg/L (244 micromol/L) R-/S-verapamil were performed in 8 healthy male volunteers for 100 minutes before and after 14 days of oral treatment with St John's wort (300 mg 3 times a day). The enantiomers of verapamil and the cytochrome P450 (CYP) 3A4-formed metabolite norverapamil in perfusate and plasma were quantified by chiral HPLC with fluorescence and tandem mass spectrometry detection, respectively.RESULTS:St John's wort did not affect the jejunal permeability or the fraction absorbed of either R- or S-verapamil. The values for area under the plasma concentration-time curve (AUC) for R- and S-verapamil decreased by 78% and 80%, respectively (P <.0001). The corresponding decreases in the maximum concentration were 76% and 78%, respectively (P <.0001), whereas the terminal half-life did not change significantly for any of the enantiomers. The AUC for R-verapamil was 6 times higher than that for S-verapamil in the control phase, and St John's wort did not change this ratio. The AUC values for R- and S-norverapamil decreased by 51% (P <.01) and 63% (P <.0001), respectively.CONCLUSIONS:Repeated administration of St John's wort significantly decreased the bioavailability of R- and S-verapamil. This effect is caused by induction of first-pass CYP3A4 metabolism, most likely in the gut, because the jejunal permeability and the terminal half-life were unchanged for both enantiomers.

Nyckelord

Administration; Oral

Adult

Analysis of Variance

Area Under Curve

Biological Availability

Dose-Response Relationship; Drug

Drug Administration Schedule

Drug Interactions

Half-Life

Human

Hypericum

Intestinal Absorption/*drug effects

Jejunum/drug effects/physiology

Male

Perfusion

Phytotherapy

Plant Preparations/*administration & dosage

Sensitivity and Specificity

Support; Non-U.S. Gov't

Verapamil/administration & dosage/*pharmacokinetics

Publikations- och innehållstyp

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