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St John's Wort Decreases the Bioavailability of R ‐ and S ‐verapamil Through Induction of the First‐pass Metabolism
Author(s) -
Tannergren Christer,
Engman Helena,
Knutson Lars,
Hedeland Mikael,
Bondesson Ulf,
Lennernäs Hans
Publication year - 2004
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2003.12.012
Subject(s) - verapamil , bioavailability , chemistry , pharmacokinetics , pharmacology , oral administration , first pass effect , metabolite , cyp3a4 , metabolism , intestinal permeability , area under the curve , cytochrome p450 , medicine , biochemistry , calcium , organic chemistry
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 μmol/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. Clinical Pharmacology & Therapeutics (2004) 75 , 298–309; doi: 10.1016/j.clpt.2003.12.012