No Relevant Interaction with Alprazolam, Caffeine, Tolbutamide, and Digoxin by Treatment with a Low-Hyperforin St John’s Wort Extract

Abstract

We evaluated the pharmacokinetic interaction between a low-hyperforin St John’s wort (SJW) extract and alprazolam, caffeine, tolbutamide, and digoxin. Previous reports on other SJW products had shown remarkably decreased plasma concentrations of certain co-medicated drugs, which was attributed to an inducing effect of SJW on cytochrome P-450 (CYP) and p-glycoprotein (p-gp) activity. Two randomised, placebo-controlled studies were performed with 28 healthy volunteers (age 18 - 55 years) in each study. In study A, single doses of alprazolam (1 mg; substrate of CYP3A4) and caffeine (100 mg; CYP1A2) were given on days 1 and 11. In study B, single doses of tolbutamide (500 mg, days 1 and 11; CYP2C9) and multiple doses of digoxin (0.75 mg on days -2 and -1, 0.25 mg/die on days 1 to 11; p-gp) were given. The participants received SJW (Esbericum® capsules; 240 mg/die of extract, 3.5 mg hyperforin) or placebo on days 2 to 11. Blood for pharmacokinetic analysis was drawn on days 1 and 11. No statistically significant differences were found in the primary kinetic parameter, AUC_{0 - 24}, of alprazolam, caffeine (AUC_{0 - 12}), paraxanthine, tolbutamide, 4-hydroxytolbutamide, and digoxin between the placebo group and the SJW group at the end of the study. The SJW-induced change in AUCs was less than 12 % of the initial median AUC of the participants in studies A and B, thus clinically irrelevant. On day 11, trough concentrations were 2.0 (range 0.6 - 4.1) μg/L and 1.0 (0.2 - 3.9) μg/L for hypericin and pseudohypericin, respectively, whereas hyperforin concentrations were below the quantification limit (< 1 μg/L). Kinetics of investigated probe drugs were only marginally influenced by concomitant treatment with Esbericum® capsules. This may be due in particular to the low hyperforin plasma concentration as this SJW component has been shown to activate the PXR receptor which regulates expression of CYP3A4 and p-gp. Our findings corroborate the view that reports about interactions of other SJW extracts seem not to be predictive for the product we studied.

Key words

St. John’s wort - Hypericum perforatum - Clusiaceae - interaction - clinical trial - drug safety

References

• 1 Linde K, Mulrow C D. St John’s wort for depression.  Cochraine Database Syst Rev. 2000;  2 CD000448
• 2 Johne A, Brockmöller J, Bauer S, Maurer A, Langheinrich M, Roots I. Pharmacokinetic interaction of digoxin with an herbal extract from St John’s wort (Hypericum perforatum).  Clin Pharmacol Ther. 1999;  66 338-45
• 3 Perloff M D, von Moltke L L, Störmer E, Shader R I, Greenblatt D J. Saint John’s wort: An in vitro analysis of P-glycoprotein induction due to extended exposure.  Br J Pharmacol. 2001;  134 1601-8
• 4 Mai I, Krüger H, Budde K, Johne A, Brockmöller J, Neumayer H H. et al . Hazardous pharmacokinetic interaction of Saint John’s wort (Hypericum perforatum) with the immunosuppressant cyclosporin.  Int J Clin Pharm Ther. 2000;  38 500-2
• 5 Bolley R, Zulke C, Kammerl M, Fischereder M, Kramer B K. Tacrolimus-induced nephrotoxicity unmasked by induction of the CYP3A4 system with St John’s wort.  Transplantation. 2002;  73 1009
• 6 Johne A, Schmider J, Brockmöller J, Stadelmann A M, Störmer E, Bauer S. et al . Decreased plasma levels of amitriptyline and its metabolites on comedication with an extract from St. John’s wort (Hypericum perforatum).  J Clin Psychopharmacol. 2002;  22 46-54
• 7 Piscitelli S C, Burstein A H, Chaitt D, Alfaro R M, Lalloon J. Indinavir concentrations and St. John’s wort.  Lancet. 2000;  355 547-8
• 8 Wang Z, Hamman M A, Huang S M, Lesko L J, Hall S D. Effect of St John’s wort on the pharmacokinetics of fexofenadine.  Clin Pharmacol Ther. 2002;  71 411-3
• 9 Meier B. Comparing phytopharmaceuticals: the example of St John’s wort.  Adv Ther. 2001;  18 35-46
• 10 Bundesanzeiger . Bekanntmachung über die Zulassung und Registrierung von Arzneimitteln: Aufbereitungsmonographie der Kommission E, Hyperici herba (Johanniskraut). BAnz Nr. 43, 02.03.1989
• 11 Bauer S, Störmer E, Graubaum H J, Roots I. Determination of hyperforin, hypericin, and pseudohypericin in human plasma using high-performance liquid chromatography analysis with fluorescence and ultraviolet detection.  Chromatogr B Biomed Sci Appl. 2001;  765 29-35
• 12 Kirchheiner J, Bauer S, Meineke I, Rohde W, Prang V, Meisel C. et al . Impact of CYP2C9 and CYP2C19 polymorphisms on tolbutamide kinetics and the insulin and glucose response in healthy volunteers.  Pharmacogenetics. 2002;  12 101-9
• 13 Friede M, Liske E, Wüstenberg P. Therapeutic effects of Hypericum perforatum in the treatment of depressive disorders.  J Cereb Blood Flow Metab. 1999;  19 (suppl. 1) 116
• 14 Bernhardt M, Liske E. Antidepressive Therapie mit Johanniskraut-Extrakt unter besonderer Berücksichtigung von zwei unterschiedlichen Dosierungsschemata.  Jatros Neurologie. 1996;  12 43-8
• 15 Zhou S, Chan E, Pan S Q, Huang M, Lee E J. Pharmacokinetic interactions of drugs with St. John’s wort.  Psychopharmacol. 2004;  18 262-76
• 16 Wang Z, Gorski J C, Hamman M A, Huang S M, Lesko L J, Hall S D. The effects of St John’s wort (Hypericum perforatum) on human cytochrome P450 activity.  Clin Pharmacol Ther. 2001;  70 317-26
• 17 Uehleke B, Mueller S C, Woehling H, Petzsch M, Riethling A -K. et al . Interaction of St. John’s wort with digoxin in relation to dosage and formulation.  Phytomedicine. 2000;  7 (suppl. II) 20
• 18 Loyda R, Gruber K. Safety and tolerability of different Hypericum extracts.  Phytomedicine. 2000;  7 (suppl. II) 20
• 19 Obach R S. Inhibition of human cytochrome P450 enzymes by constituents of St. John’s wort, an herbal preparation used in the treatment of depression.  J Pharmacol Exp Ther. 2000;  294 88-95
• 20 Wentworth J M, Agostini M, Love J, Schwabe J W, Chatterjee V K. St. John’s wort, a herbal antidepressant, activates the steroid X receptor.  J Endocrinol. 2000;  166 R11-6