St John's wort decreases the bioavailability of R- and S-verapamil through induction of the first-pass metabolism
2004 (English)In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6519, Vol. 75, no 4, 298-309 p.Article in journal (Refereed) Published
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.
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.
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.
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.
Place, publisher, year, edition, pages
2004. Vol. 75, no 4, 298-309 p.
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
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-91290DOI: 10.1016/j.clpt.2003.12.012PubMedID: 15060508OAI: oai:DiVA.org:uu-91290DiVA: diva2:163974