European Journal of Clinical Pharmacology

, Volume 62, Issue 1, pp 29–36 | Cite as

The extent of induction of CYP3A by St. John’s wort varies among products and is linked to hyperforin dose

  • Silke C. Mueller
  • Jolanta Majcher-Peszynska
  • Bernhard Uehleke
  • Sebastian Klammt
  • Ralf G. Mundkowski
  • Wolfram Miekisch
  • Hartwig Sievers
  • Steffen Bauer
  • Bruno Frank
  • Guenther Kundt
  • Bernd Drewelow
Pharmacokinetics and Disposition

Abstract

Objective

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.

Methods

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.

Results

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).

Conclusion

The extent of induction of CYP3A varies among St. John’s wort products and depends on hyperforin dose.

Keywords

St. John’s wort Hyperforin Hypericins CYP3A Midazolam 

References

  1. 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
  2. 2.
    Butterweck V, Nahrstedt A, Evans J, Hufeisen S, Rauser L, Savage J, Popadak B, Ernsberger P, Roth BL (2002) In vitro receptor screening of pure constituents of St. John’s wort reveals novel interactions with a number of GPCRs. Psychopharmacology 162:193–202PubMedCrossRefGoogle Scholar
  3. 3.
    Butterweck V (2003) Mechanism of action of St. John’s wort in depression—What is known? CNS Drugs 17:539–562PubMedCrossRefGoogle Scholar
  4. 4.
    De los Reyes GC, Koda RT (2002) Determining hyperforin and hypericin content in eight brands of St. John’s wort. Am J Health Syst Pharm 59:545–547PubMedGoogle Scholar
  5. 5.
    De Vries JX, Rudi J, Walter-Sack I, Conradi R (1990) The determination of total and unbound midazolam in human plasma. A comparison of high performance liquid chromatography, gas chromatography and gas chromatography/mass spectrometry. Biomed Chromatogr. 4:28–33PubMedCrossRefGoogle Scholar
  6. 6.
    De Wildt SN, Kearns GL, Hop WC, Murry DJ, Abdel-Rahman SM, van den Anker JN (2002) Pharmacokinetics and metabolism of oral midazolam in preterm infants. Br J Clin Pharmacol. 53:390–392PubMedCrossRefGoogle Scholar
  7. 7.
    Draves AH, Walker SE (2003) Analysis of the hypericin and pseudohypericin content of commercially available St. John’s wort preparations. Can J Clin Pharmacol 10:114–118PubMedGoogle Scholar
  8. 8.
    Dresser GK, Schwarz UI, Wilkinson GR, Kim RB (2003) Coordinate induction of both cytochrome P4503A and MDR1 by St. John’s wort in healthy subjects. Clin Pharmacol Ther 73:41–50PubMedCrossRefGoogle Scholar
  9. 9.
    Dürr D, Stieger B, Kullak-Ublick GA, Rentsch KM, Steinert HC, Meier PJ, Fattinger K (2000) St. John’s wort induces intestinal p-glycoprotein/MDR1 and intestinal and hepatic CYP3A4. Clin Pharmacol Ther 68:598–604PubMedCrossRefGoogle Scholar
  10. 10.
    Gaedcke F (1997) Johanniskraut und dessen Zubereitungen. Dtsch Apoth Ztg 137:3753–3757Google Scholar
  11. 11.
    Henderson L, Yue QY, Bergquist C, Gerden B, Arlett P (2002) St. John’s wort (Hypericum perforatum): drug interactions and clinical outcomes. Br J Clin Pharmacol 54:349–356PubMedCrossRefGoogle Scholar
  12. 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
  13. 13.
    Komoroski BJ, Zhang S, Cai H, Hutzler JM, Frye R, Tracy TS, Strom SC, Lehmann T, Ang CYW, Cui YY, Venkataramanan R (2004) Induction and inhibition of cytochromes P450 by the St. John’s wort constituent hyperforin in human hepatocyte cultures. Drug Metab Dis 32:512–518CrossRefGoogle Scholar
  14. 14.
    Mai I, Bauer S, Perloff ES, Johne A, Uehleke B, Frank B, Budde K, Roots I (2004) Hyperforin content determines the magnitude of the St. John’s wort–cyclosporine drug interaction. Clin Pharmacol Ther 76:330–340PubMedCrossRefGoogle Scholar
  15. 15.
    Mannel M (2004) Drug interactions with St. John’s wort—mechanisms and clinical implications. Drug Safety 27:773–797PubMedCrossRefGoogle Scholar
  16. 16.
    Melzer M, Fuhrken D, Kolkmann R (1998) Hyperforin im Johanniskraut—Hauptwirkstoff oder nur Leitsubstanz? Dtsch Apoth Ztg 138:56–62Google Scholar
  17. 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
  18. 18.
    Moore LB, Goodwin B, Jones SA, Wisely GB, Serabjit-Singh CJ, Willson TM, Collins JL, Kliewer SA (2000) St John’s wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc Natl Acad Sci USA 97:7500–7502PubMedCrossRefGoogle Scholar
  19. 19.
    Mueller SC, Uehleke B, Woehling H, Petzsch M, Majcher-Peszynska J, Hehl E-M, Sievers H, Frank B, Rithling A-K, Drewelow B (2004) Effect of St. John’s wort dose and preparations on the pharmacokinetics of digoxin. Clin Pharmacol Ther 75:546–557PubMedCrossRefGoogle Scholar
  20. 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. 21.
    Rosenberger WF, Lachin JM (2002) Randomization in clinical trials. Wiley, New YorkGoogle Scholar
  22. 22.
    Streetman DS, Bertino Jr JS, Nafziger AN (2000) Phenotyping of drug-metabolizing enzymes in adults: a review of in-vivo cytochrome P450 phenotyping probes. Pharmacogenetics 10:187–216PubMedCrossRefGoogle Scholar
  23. 23.
    Wang Z, Gorski C, Hamman MA, Huang S-M, Lesko LJ, Hall SD (2001) The effects of St. John’s wort (Hypericum perforatum) on human cytochrome P450 activity. Clin Pharmacol Ther 70:317–326PubMedGoogle Scholar
  24. 24.
    Wentworth JM, Agostini M, Love J, Schwabe JW, Chatterjee VKK (2000) St. John’s wort, a herbal antidepressant, activates the steroid X receptor. J Endocrinol 166:R11–R16PubMedCrossRefGoogle Scholar
  25. 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
  26. 26.
    Zanoli P (2004) Role of hyperforin in the pharmacological activities of St. John’s wort. CNS Drug Rev 10:203–218PubMedCrossRefGoogle Scholar
  27. 27.
    Zhou S, Chan E, Pan S-Q, Huang M, Lee EJD (2004) Pharmacokinetic interactions of drugs with St John’s wort. J Psychopharmacol 18:262–276PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Silke C. Mueller
    • 1
  • Jolanta Majcher-Peszynska
    • 1
  • Bernhard Uehleke
    • 4
  • Sebastian Klammt
    • 1
  • Ralf G. Mundkowski
    • 1
  • Wolfram Miekisch
    • 2
  • Hartwig Sievers
    • 7
  • Steffen Bauer
    • 5
  • Bruno Frank
    • 6
  • Guenther Kundt
    • 3
  • Bernd Drewelow
    • 1
  1. 1.Center of Pharmacology and Toxicology, Institute of Clinical PharmacologyUniversity of RostockRostockGermany
  2. 2.Clinic and Polyclinic of Anaesthesiology and Intensive Care MedicineUniversity of RostockRostockGermany
  3. 3.Institute for Medical Informatics and BiometryUniversity of RostockRostockGermany
  4. 4.Clinic for NaturopathyCharité-Universitätsmedizin BerlinBerlinGermany
  5. 5.Institute of Clinical PharmacologyCharité- Universitätsmedizin BerlinBerlinGermany
  6. 6.Kneipp-WerkeWürzburgGermany
  7. 7.PhytoLab GmbH & Co KGVestenbergsgreuthGermany

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