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St John's wort decreases the bioavailability of R- and S-verapamil through induction of the first-pass metabolism
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
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2004 (English)In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 75, no 4, 298-309 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2004. Vol. 75, no 4, 298-309 p.
Keyword [en]
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
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-91290DOI: 10.1016/j.clpt.2003.12.012PubMedID: 15060508OAI: oai:DiVA.org:uu-91290DiVA: diva2:163974
Available from: 2004-02-04 Created: 2004-02-04 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Intestinal Permeability and Presystemic Extraction of Fexofenadine and R/S-verapamil
Open this publication in new window or tab >>Intestinal Permeability and Presystemic Extraction of Fexofenadine and R/S-verapamil
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The main objective of this thesis was to investigate the in vivo relevance of membrane transporters and cytochrome P450 (CYP) 3A4-mediated metabolism in the intestine and liver for the bioavailability of drugs in humans after oral administration.

In the first part of the thesis, the main transport mechanisms involved in the intestinal absorption and bioavailability were investigated for fexofenadine, a minimally metabolized drug, which is a substrate for P-glycoprotein (P-gp) and members of organic anion transporting polypeptide (OATP) family. Jejunal perfusion studies revealed that co-perfusion with verapamil increased the bioavailability of fexofenadine by decreasing the first-pass liver extraction as the low intestinal permeability was unchanged by the transport inhibitors studied. The mechanism behind the interaction probably involves inhibition of OATP-mediated sinusoidal uptake and/or P-gp-mediated canalicular secretion of fexofenadine. Results from the Caco-2 model supported that the intestinal absorption of fexofenadine is mainly determined by the low passive permeability of the drug, even though fexofenadine clearly is a P-gp substrate.

In the second part of the thesis, the effect of repeated oral administration of the P-gp and CYP3A4 inducer St. John’s wort on the in vivo intestinal permeability and presystemic metabolism of the dual P-gp and CYP3A4 substrate verapamil was investigated in a jejunal perfusion study. St. John’s wort decreased the bioavailability of the enantiomers of verapamil by inducing the CYP3A4-mediated presystemic metabolism, probably mainly in the gut. It was also concluded that induction of efflux transporters, such as P-gp, does not affect the intestinal transport or the gut wall extraction of high permeability substrates like verapamil. Data from Caco-2 cells with induced CYP3A4-activity supported these findings. The plasma levels of the enantiomers of norverapamil also decreased despite an increased formation, which was attributed to induction of CYP3A4 and/or other metabolic routes.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2004. 53 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 0282-7484 ; 306
Keyword
Biopharmacy, Bioavailability, Fexofenadine, Verapamil, P-glycoprotein, CYP3A4, OATP, Enantioselective, Permeability, Caco-2, Intestinal perfusion, Biofarmaci
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-3971 (URN)91-554-5856-4 (ISBN)
Public defence
2004-02-27, B21, Uppsala Biomedicinska centrum, Uppsala, 10:15
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Available from: 2004-02-04 Created: 2004-02-04 Last updated: 2014-01-27Bibliographically approved

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Knutson, LarsHedeland, MikaelBondesson, UlfLennernäs, Hans

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