The extent of induction of CYP3A by St. John’s wort varies among products and is linked to hyperforin dose
- First Online:
Induction of CYP3A by St. John’s wort (SJW) extracts with high hyperforin (HYF) content is well described. Since SJW products vary in the amount of HYF and other main constituents, the aim of the study was to evaluate the effect on CYP3A function of SJW preparations with a range from very low to high HYF content.
Forty-two male, healthy volunteers were randomized into six parallel SJW medication groups with varying composition especially with regard to HYF content. Midazolam plasma concentration profiles were characterized after a single oral dose of 7.5 mg midazolam on the day before and on the 14th day of SJW medication.
All SJW preparations tested resulted in a decrease in midazolam AUC, although the extent of the effect differed. The extract LI 160 (HYF 41 mg/day) decreased midazolam AUC0–12h by 79.4% (95% CI −88.6; −70.1), which was significantly greater than the effect by any other medication (p<0.05). SJW powder tablets 2.7 g/day (HYF 12 mg/day) resulted in a midazolam AUC0–12h decrease of 47.9% (95% CI −59.7;−36.2), while 2.7 g/day SJW powder tablets that were almost devoid of HYF (0.13 mg/day) reduced midazolam AUC0–12h by only 21.1% (95% CI −33.9; −8.3). Considering all six SJW medications tested, the extent of midazolam AUC decrease correlated significantly with increasing HYF dose (r=−0.765, p<0.001), but not with hypericin dose (r=−0.067; p=0.673).
The extent of induction of CYP3A varies among St. John’s wort products and depends on hyperforin dose.
KeywordsSt. John’s wort Hyperforin Hypericins CYP3A Midazolam
- 1.Bjornsson TD, Callaghan JT, Einolf HJ, Fischer V, Gan L, Grimm S, Kao J, King SP, Miwa G, Ni L, Kumar G, McLeod J, Obach SR, Roberts S, Roe A, Shah A, Snikeris F, Sullivan JT, Tweedie D, Vega JM, Walsh J, Wrighton SA (2003) The conduct of in vitro and in vivo drug drug interaction studies: a PhRMA perspective. J Clin Pharmacol 43:443–469PubMedGoogle Scholar
- 10.Gaedcke F (1997) Johanniskraut und dessen Zubereitungen. Dtsch Apoth Ztg 137:3753–3757Google Scholar
- 12.Hölzl J, Ostrowski E (1987) Johanniskraut (Hypericum perforatum): HPLC-Analyse der wichtigen Inhaltsstoffe und deren Variabilität in einer Population. Dtsch Apoth Ztg 127:1227–1230Google Scholar
- 16.Melzer M, Fuhrken D, Kolkmann R (1998) Hyperforin im Johanniskraut—Hauptwirkstoff oder nur Leitsubstanz? Dtsch Apoth Ztg 138:56–62Google Scholar
- 17.Miekisch W, Fuchs P, Berg A, Nöldge-Schomburg G, Drewelow B, Mundkowski R (2003) An improved GC/MS method for the determination of midazolam in human plasma. [abstract] Int J Clin Pharmacol Ther 4:560Google Scholar
- 20.Ring BJ, Patterson BE, Mitchell MI, Vandenbranden M, Gillespie J, Bedding AW, Jewell H, Payne CD, Forgue ST, Ecksetin J, Wrighton SA, Phillips DL (2005) Effect of tadalafil on cytochrome P450 3A4-mediated clearance:studies in vitro and in vivo. Clin Pharmacol Ther 77:63–75PubMedCrossRefGoogle Scholar
- 21.Rosenberger WF, Lachin JM (2002) Randomization in clinical trials. Wiley, New YorkGoogle Scholar
- 25.Wurglics M, Westerhoff K, Kaunzinger A, Wilke A, Baumeister A, Dressman J, Schubert-Zsilavecz M (2001) Comparison of German St. John’s wort products according to hyperforin and total hypericin content. J Am Pharm Assoc 41:560–566Google Scholar