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European Journal of Clinical Pharmacology

, Volume 62, Issue 3, pp 225–233 | Cite as

Hyperforin in St. John’s wort drug interactions

  • Rajanikanth Madabushi
  • Bruno Frank
  • Bernd Drewelow
  • Hartmut Derendorf
  • Veronika Butterweck
Pharmacokinetics and Disposition

Abstract

Recently, interactions of herbal medicines with synthetic drugs came into focus of particular interest. In the past 3 years, more than 50 papers were published regarding interactions between St. John’s wort (Hypericum perforatum L.; SJW) and prescription drugs. Co-medication with SJW resulted in decreased plasma concentrations of a number of drugs including amitriptyline, cyclosporine, digoxin, indinavir, irinotecan, warfarin, phenprocoumon, alprazolam, dextrometorphane, simvastatin, and oral contraceptives. Sufficient evidence from interaction studies and case reports indicate that SJW is a potent inducer of cytochrome P450 enzymes (particularly CYP3A4) and/or P-glycoprotein. Recent studies could show that the degree of enzyme induction by SJW correlates strongly with the amount of hyperforin found in the product. Products that do not contain substantial amounts of hyperforin (<1%) have not been shown to produce clinically relevant enzyme induction. On the other hand, some evidence suggests that hyperforin may also contribute to the antidepressant activity of SJW. However, clinical studies using SJW preparations with a low hyperforin amount (<1%) clearly demonstrated the superiority of this plant extract over placebo and its equivalence to imipramine and fluoxetine in the treatment of mild to moderate forms of depression. In the present paper clinical significant SJW interactions are critically evaluated against the background of hyperforin.

Keywords

Drug interactions Hypericum perforatum Herbal medicine St. John’s wort 

References

  1. 1.
    Behnke K, Jensen GS, Graubaum HJ, Gruenwald J (2002) Hypericum perforatum versus fluoxetine in the treatment of mild to moderate depression. Adv Ther 19(1):43–52PubMedGoogle Scholar
  2. 2.
    Bjerkenstedt L, Edman GV, Alken RG, Mannel M (2005) Hypericum extract LI 160 and fluoxetine in mild to moderate depression: a randomized, placebo-controlled multi-center study in outpatients. Eur Arch Psychiatry Clin Neurosci 255(1):40–47CrossRefPubMedGoogle Scholar
  3. 3.
    Schrader E (2000) Equivalence of St John’s wort extract (Ze 117) and fluoxetine: a randomized, controlled study in mild-moderate depression. Int Clin Psychopharmacol 15(2):61–68PubMedGoogle Scholar
  4. 4.
    Brenner R, Azbel V, Madhusoodanan S, Pawlowska M (2000) Comparison of an extract of hypericum (LI 160) and sertraline in the treatment of depression: a double-blind, randomized pilot study. Clin Ther 22(4):411–419CrossRefPubMedGoogle Scholar
  5. 5.
    Gastpar M, Singer A, Zeller K (2005) Efficacy and tolerability of hypericum extract STW3 in long-term treatment with a once-daily dosage in comparison with sertraline. Pharmacopsychiatry 38(2):78–86CrossRefPubMedGoogle Scholar
  6. 6.
    Philipp M, Kohnen R, Hiller KO (1999) Hypericum extract versus imipramine or placebo in patients with moderate depression: randomised multicentre study of treatment for eight weeks. BMJ 319(7224):1534–1538PubMedGoogle Scholar
  7. 7.
    Woelk H (2000) Comparison of St John’s wort and imipramine for treating depression: randomised controlled trial. BMJ 321(7260):536–539CrossRefPubMedGoogle Scholar
  8. 8.
    Schulz V (2002) Clinical trials with hypericum extracts in patients with depression–results, comparisons, conclusions for therapy with antidepressant drugs. Phytomedicine 9(5):468–474CrossRefPubMedGoogle Scholar
  9. 9.
    Butterweck V (2003) Mechanism of action of St John’s wort in depression: what is known? CNS Drugs 17(8):539–562CrossRefPubMedGoogle Scholar
  10. 10.
    Melzer M, Fuhrken D, Kolkmann R (1998) Hyperforin im Johanniskraut. Dt Apoth Ztg 138(49):56–62Google Scholar
  11. 11.
    Brattstroem A (2002) Der Johanniskrautextrakt ZE 117: Wirksamkeit und Sicherheit. DAZ 30:97–99Google Scholar
  12. 12.
    Willmar Schwabe GC (1997) Stable extract of Hypericum perforatum L., process for preparing the same and pharmaceutical composition. International Patent, WO 97/13489Google Scholar
  13. 13.
    Willmar Schwabe GC (1998) Stable extract of Hypericum perforatum L., a method for producing the same, and corresponding pharmaceutical preparations. International Patent, WO 98/44936Google Scholar
  14. 14.
    Arold G, Donath F, Maurer A, Diefenbach K, Bauer S, Henneicke-von Zepelin HH, Friede M, Roots I (2005) No relevant interaction with alprazolam, caffeine, tolbutamide, and digoxin by treatment with a low-hyperforin St John’s wort extract. Planta Med 71(4):331–337CrossRefPubMedGoogle Scholar
  15. 15.
    Mai I, Bauer S, Perloff E, 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 in pressGoogle Scholar
  16. 16.
    Mannel M (2004) Drug interactions with St John’s wort: mechanisms and clinical implications. Drug Saf 27(11):773–797CrossRefPubMedGoogle Scholar
  17. 17.
    Zhou S, Chan E, Pan SQ, Huang M, Lee EJ (2004) Pharmacokinetic interactions of drugs with St John’s wort. J Psychopharmacol 18(2):262–276CrossRefPubMedGoogle Scholar
  18. 18.
    Landrum-Michalets E (1998) Update: clinically significant cytochrome P450 drug interactions. Pharmacotherapy 18:84–112PubMedGoogle Scholar
  19. 19.
    Smith DA, Abel SM, Hyland R, Jones BC (1998) Human cytochrome P450’s: selectivity and measurment in vivo. Xenobiotica 28:1095–1128CrossRefPubMedGoogle Scholar
  20. 20.
    Smith S, Stubbins MJ, Harries LW, Wolf CR (1998) Molecular genetics of human cytochrome P450 monooxygenase superfamily. Xenobiotica 28:1129–1165CrossRefPubMedGoogle Scholar
  21. 21.
    Bienvenu T, Rey E, Pons G, d’Athis P, Olive G (1991) A simple non-invasive procedure for the investigation of cytochrome P-450 IIIA dependent enzymes in humans. Int J Clin Pharmacol Ther Toxicol 29(11):441–445PubMedGoogle Scholar
  22. 22.
    Dolara P, Lodovici M, Salvadori M, Zaccara G, Muscas GC (1987) Urinary 6-beta-OH-cortisol and paracetamol metabolites as a probe for assessing oxidation and conjugation of chemicals in humans. Pharmacol Res Commun 19(4):261–273CrossRefPubMedGoogle Scholar
  23. 23.
    Ged C, Rouillon JM, Pichard L, Combalbert J, Bressot N, Bories P, Michel H, Beaune P, Maurel P (1989) The increase in urinary excretion of 6 beta-hydroxycortisol as a marker of human hepatic cytochrome P450IIIA induction. Br J Clin Pharmacol 28(4):373–387PubMedGoogle Scholar
  24. 24.
    Roby CA, Anderson GD, Kantor E, Dryer DA, Burstein AH (2000) St John’s Wort: effect on CYP3A4 activity. Clin Pharmacol Ther 67(5):451–457CrossRefPubMedGoogle Scholar
  25. 25.
    Gatmaitan ZC, Arias IM (1993) Structure and function of P-glycoprotein in normal liver and small intestine. Adv Pharmacol 24:77–97PubMedGoogle Scholar
  26. 26.
    Lown KS, Mayo RR, Leichtman AB, Hsiao HL, Turgeon DK, Schmiedlin-Ren P, Brown MB, Guo W, Rossi SJ, Benet LZ, Watkins PB (1997) Role of intestinal P-glycoprotein(mdr1) in interpatient variation in the oral bioavailability of cyclosporine. Clin Pharmacol Ther 62:248–260CrossRefPubMedGoogle Scholar
  27. 27.
    Durr 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(6):598–604CrossRefPubMedGoogle Scholar
  28. 28.
    Wang Z, Gorski JC, Hamman MA, Huang SM, Lesko LJ, Hall SD (2001) The effects of St John’s wort (Hypericum perforatum) on human cytochrome P450 activity. Clin Pharmacol Ther 70(4):317–326CrossRefPubMedGoogle Scholar
  29. 29.
    Johne A, Brockmoller J, Bauer S, Maurer A, Langheinrich M, Roots I (1999) Pharmacokinetic interaction of digoxin with an herbal extract from St John’s wort (Hypericum perforatum). Clin Pharmacol Ther 66(4):338–345CrossRefPubMedGoogle Scholar
  30. 30.
    Piscitelli SC, Burstein AH, Chaitt D, Alfaro RM, Falloon J (2000) Indinavir concentrations and St John’s wort. Lancet 355(9203):547–548CrossRefPubMedGoogle Scholar
  31. 31.
    Ruschitzka F, Meier PJ, Turina M, Luscher TF, Noll G (2000) Acute heart transplant rejection due to Saint John’s wort [letter] [see comments]. Lancet 355(9203):548–549CrossRefPubMedGoogle Scholar
  32. 32.
    Obach RS (2000) 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 294(1):88–95PubMedGoogle Scholar
  33. 33.
    Hennessy M, Kelleher D, Spiers JP, Barry M, Kavanagh P, Back D, Mulcahy F, Feely J (2002) St John’s Wort increases expression of P-glycoprotein: Implications for drug interactions. Br J Clin Pharmacol 53:75–82CrossRefPubMedGoogle Scholar
  34. 34.
    Markowitz JS, DeVane CL, Boulton DW, Carson SW, Nahas Z, Risch SC (2000) Effect of St. John’s wort (Hypericum perforatum) on cytochrome P-450 2D6 and 3A4 activity in healthy volunteers. Life Sci 66(9):L133–L139CrossRefGoogle Scholar
  35. 35.
    Rengelshausen J, Banfield M, Riedel KD, Burhenne J, Weiss J, Thomsen T, Walter-Sack I, Haefeli WE, Mikus G (2005) Opposite effects of short-term and long-term St John’s wort intake on voriconazole pharmacokinetics. Clin Pharmacol Ther 78(1):25–33CrossRefPubMedGoogle Scholar
  36. 36.
    Izzo AA, Ernst E (2001) Interactions between herbal medicines and prescribed drugs: a systematic review. Drugs 61(15):2163–2175CrossRefPubMedGoogle Scholar
  37. 37.
    Mills E, Montori VM, Wu P, Gallicano K, Clarke M, Guyatt G (2004) Interaction of St John’s wort with conventional drugs: systematic review of clinical trials. BMJ 329(7456):27–30CrossRefPubMedGoogle Scholar
  38. 38.
    Ernst E (1999) Second thoughts about safety of St John’s wort. Lancet 354(9195):2014–2016CrossRefPubMedGoogle Scholar
  39. 39.
    Medical Products Agency, Sweden. St John’s Wort may influence other medications. In; 2002Google Scholar
  40. 40.
    Schwarz UI, Buschel B, Kirch W (2003) Unwanted pregnancy on self medication with St John’s Wort despite hormonal contraception. Br J Clin Pharmacol 55:112–113CrossRefPubMedGoogle Scholar
  41. 41.
    Hall SD, Wang Z, Huang SM, Hamman MA, Vasavada N, Adigun AQ, Hilligoss JK, Miller M, Gorski JC (2003) The interaction between St John’s wort and an oral contraceptive. Clin Pharmacol Ther 74(6):525–535CrossRefPubMedGoogle Scholar
  42. 42.
    Murphy PA, Kern SE, Stanczyk FZ, Westhoff CL (2005) Interaction of St. John’s Wort with oral contraceptives: effects on the pharmacokinetics of norethindrone and ethinyl estradiol, ovarian activity and breakthrough bleeding. Contraception 71(6):402–408CrossRefPubMedGoogle Scholar
  43. 43.
    Pfrunder A, Schiesser M, Gerber S, Haschke M, Bitzer J, Drewe J (2003) Interaction of St John’s wort with low-dose oral contraceptive therapy: a randomized controlled trial. Br J Clin Pharmacol 56(6):683–690CrossRefPubMedGoogle Scholar
  44. 44.
    Guengerich FP (1990) Metabolism of 17 alpha-ethinyl estradiol in humans. Life Sci 47:1981–1988CrossRefPubMedGoogle Scholar
  45. 45.
    Shader RI, Oesterheld JR (2000) Contraceptive effectiveness: cytochromes and induction. J Clin Psychopharmacol 20:119–121CrossRefPubMedGoogle Scholar
  46. 46.
    Shane-McWhorter L, Cerveny JD, MacFarlane LL, Osborn C (1998) Enhanced metabolism of levonorgestrel during phenobarbital treatment and resultant pregnancy. Pharmacotherapy 18(6):1360–1364PubMedGoogle Scholar
  47. 47.
    Haukkamaa M (1986) Contraception by Norplant subdermal capsules is not reliable in epileptic patients on anticonvulsant treatment. Contraception 33(6):559–565CrossRefPubMedGoogle Scholar
  48. 48.
    Odlind V, Olsson SE (1986) Enhanced metabolism of levonorgestrel during phenytoin treatment in a woman with Norplant implants. Contraception 33(3):257–261CrossRefPubMedGoogle Scholar
  49. 49.
    Gentile DM, Verhoeven CH, Shimada T, Back DJ (1998) The role of CYP2C in the in vitro bioactivation of the contraceptive steroid desogestrel. J Pharmacol Exp Ther 287(3):975–982PubMedGoogle Scholar
  50. 50.
    Burstein AH, Horton RL, Dunn T, Alfaro RM, Piscitelli SC, Theodore W (2000) Lack of effect of St John’s Wort on carbamazepine pharmacokinetics in healthy volunteers. Clin Pharmacol Ther 68(6):605–612CrossRefPubMedGoogle Scholar
  51. 51.
    Gu L, Gonzalez FJ, Kalow W, Tang BK (1992) Biotransformation of caffeine, paraxanthine, theobromine and theophylline by cDNA-expressed human CYP1A2 and CYP2E1. Pharmacogenetics 2(2):73–77PubMedCrossRefGoogle Scholar
  52. 52.
    Bilia AR, Gallori S, Vincieri FF (2002) St. John’s wort and depression: efficacy, safety and tolerability-an update. Life Sci 70(26):3077–3096CrossRefPubMedGoogle Scholar
  53. 53.
    Ernst E (1999) Herbal medications for common ailments in the elderly. Drugs Aging 15(6):423–428CrossRefPubMedGoogle Scholar
  54. 54.
    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(4):349–356CrossRefPubMedGoogle Scholar
  55. 55.
    Nebel A, Schneider BJ, Baker RK, Kroll DJ (1998) Potential metabolic interaction between St John’s Wort and theophylline. Ann Pharmacother 33:202Google Scholar
  56. 56.
    Morimoto T, Kotegawa T, Tsutsumi K, Ohtani Y, Imai H, Nakano S (2004) Effect of St. John’s wort on the pharmacokinetics of theophylline in healthy volunteers. J Clin Pharmacol 44(1):95–101CrossRefPubMedGoogle Scholar
  57. 57.
    Komoroski BJ, Zhang S, Cai H, Hutzler JM, Frye R, Tracy TS, Strom SC, Lehmann T, Ang CY, 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 Dispos 32(5):512–518CrossRefPubMedGoogle Scholar
  58. 58.
    Keech A, Collins R, MacMahon S, Armitage J, Lawson A, Wallendszus K, Fatemian M, Kearney E, Lyon V, Mindell J, et al (1994) Three-year follow-up of the Oxford Cholesterol Study: assessment of the efficacy and safety of simvastatin in preparation for a large mortality study. Eur Heart J 15(2):255–269PubMedGoogle Scholar
  59. 59.
    Christians U, Jacobsen W, Floren LC (1998) Metabolism and drug interactions of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in transplant patients: are the statins mechanistically similar? Pharmacol Ther 80(1):1–34CrossRefPubMedGoogle Scholar
  60. 60.
    Vickers S, Duncan CA, Vyas KP, Kari PH, Arison B, Prakash SR, Ramjit HG, Pitzenberger SM, Stokker G, Duggan DE (1990) In vitro and in vivo biotransformation of simvastatin, an inhibitor of HMG CoA reductase. Drug Metab Dispos 18(4):476–483PubMedGoogle Scholar
  61. 61.
    Sugimoto K, Ohmori M, Tsuruoka S, Nishiki K, Kawaguchi A, Harada K, Arakawa M, Sakamoto K, Masada M, Miyamori I, Fujimura A (2001) Different effects of St John’s wort on the pharmacokinetics of simvastatin and pravastatin. Clin Pharmacol Ther 70(6):518–524CrossRefPubMedGoogle Scholar
  62. 62.
    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(13):7500–7502PubMedCrossRefGoogle Scholar
  63. 63.
    Cantoni L, Rozio M, Mangolini A, Hauri L, Caccia S (2003) Hyperforin contributes to the hepatic CYP3A-inducing effect of Hypericum perforatum extract in the mouse. Toxicol Sci 75(1):25–30CrossRefPubMedGoogle Scholar
  64. 64.
    Butterweck V, Christoffel V, Nahrstedt A, Petereit F, Spengler B, Winterhoff H (2003) Step by step removal of hyperforin and hypericin: activity profile of different Hypericum preparations in behavioral models. Life Sci 73(5):627–639PubMedGoogle Scholar
  65. 65.
    Laakmann G, Schule C, Baghai T, Kieser M (1998) St. John’s wort in mild to moderate depression: the relevance of hyperforin for the clinical efficacy. Pharmacopsychiatry 31 Suppl 1:54–59PubMedGoogle Scholar
  66. 66.
    Schrader E, Meier B, Brattstrom A (1998) Hypericum treatment of mild-moderate depression in a placebo-controlled study. A prospective, double-blind, randomized, placebo-controlled, multicentre study. Human Psychopharmacol 13:163–169CrossRefGoogle Scholar
  67. 67.
    Mueller SC, Majcher-Peszynska J, Klammt S, Uehleke B, Miekisch B, Kundt G, Drewelow B (2005) Induction of CYP3A by St. Johns Wort (SJW) depends on hyperforin (HYF) dose ABSTRACT. Clin Pharmacol Ther 77(2):P36CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Rajanikanth Madabushi
    • 1
  • Bruno Frank
    • 2
  • Bernd Drewelow
    • 3
  • Hartmut Derendorf
    • 1
  • Veronika Butterweck
    • 1
  1. 1.Department of Pharmaceutics, College of PharmacyUniversity of FloridaGainesvilleUSA
  2. 2.Kneipp Werke WürzburgWürzburgGermany
  3. 3.Institute of Clinical PharmacologyUniversity of RostockRostockGermany

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