Potential Drug-Drug Interactions

There is a potential for drug-drug interactions between St John's wort and certain prescribed medicines

caduceus resizedAs the popularity of St. John’s wort has increased, there has been an increasing number of case reports of drug-herb interactions (Ernst, 1999; Johne et al., 1999; Nebel et al., 1999; Ruschitzka et al., 2000; Yue et al., 2000; de Maat et al., 2001). 

Recent reports indicate that St. John’s wort extracts may potentiate certain sub-enzymes of the cytochrome P450 enzyme system, decreasing the serum concentration of a number of concomitant drugs, including warfarin, digoxin, theophylline, cyclosporin and oral contraceptives (Biffignandi et al., 2000), as well as the HIV protease inhibitor indinavir (Piscitelli et al., 2000) and nevirapine, a non-nucleoside reverse transcriptase inhibitor (de Maat et al., 2001).  

In vitro experiments have shown that P-glycoprotein expression was strongly induced by SJW (400% increase) and more so by hypericin (700% increase) in a dose-dependent fashion (Greenblatt et al., 2001; and Perloff et al., 2001).  

In vitro experiments have also shown that hyperforin is a potent ligand (Ki = 27 nM) for the pregnane X receptor, an orphan nuclear receptor that regulates expression of the cytochrome P450 (CYP) 3A4 monooxygenase (Kliewer et. al, 2000).  

Chronic administration of St. John’s wort extracts was shown to increase expression of P-glycoprotein in healthy volunteers and enhance cellular efflux of rhodamine (Hennessy et al., 2000).  

It recently has been hypothesized that Hypericum extract may interfere with anesthetic drugs (Koupparis, 2000). However, this hypothesis is based on the assumption that hypericin exhibits clinically significant MAOI activity, an effect which is not supported by the current scientific literature.

It is clear that St. John’s wort extracts alter the pharmacokinetics of a wide variety of therapeutic agents such that significant adverse clinical consequences can occur.  The exact contributions of St. John’s wort constituents such as hyperforin, hypericin, I3 and II8-biapigenin, a potent competitive inhibitor of CYP1A2, CYP2C9 and CYP3A4, to cytochrome P450 induction/inhibition are unclear.   

Thus, there are issues of efficacy (bioactive antidepressant ingredients), safety (drug-drug interactions) and stability that are very relevant to the standardization of this popular herb.

References

  • Biffignandi P and Bilia A. (2000). The Growing Knowledge of St. John’s Wort (Hypericum perforatum) Drug Interactions and Their Clinical Significance. Current Therapeutic Research, 61(7), 389-394.
  • de Maat M, Hoetelmans R, Math R, et al. (2001). Drug interaction between St. John’s wort and nevirapine. AIDS 15(3):420-421.
  • de Maat M, Huitema A, Mulder J, et al., (2002). Population pharmacokinetics of nevirapine in an unselected cohort of HIV-1-infected individuals. Br. J. Clin. Pharmacol. 54(4):378-385.
  • Ernst E. (1999). Second thoughts about safety of St John's Wort. Lancet 354:2014-2016.
  • Greenblatt D, von Moltke L, Perloff M, Shader R and Stormer E. (2001). St. John’s Wort: An In  Vitro Analysis of P-glycoprotein Induction Due to Extended Exposure. British Journal of Pharmacology, 134(8), 1601-1608.
  • Hennessy M, Feely J, Kelleher D, Mulcahy F and Barry M. (2000). St. John’s Wort Modulates Both Expression and Function of P Glycoprotein in Peripheral Blood Lymphocytes. AIDS, 14, S95.
  • Johne A, Brockmoller J, Bauer S, Maurer A, Langheinrich M and Roots I. (1999). Pharmacokinetic interaction of digoxin with an herbal extract from St John's Wort (Hypericum perforatum. Clin.Pharmacol.Ther. 66:338-345.
  • Kliewer S, Collins J, Goodwin B, Jones S and Moore L, Serabjit-Singh C, Willson T and Wisely G. (2000). St. John’s Wort Induces Hepatic Drug Metabolism Through Activation of the Pregnane X Receptor. Proceedings of the National Academy of Sciences of the United States of America, 97(13), 7500-7502.
  • Koupparis L. (2000). Harmless herbs: a cause for concern? J Pharmacol Exp Ther 251: 207–215.
  • Nebel A, Schneider B, Baker R and Kroll D. (1999). Potential metabolic interaction between St. John's Wort and theophylline. Ann.Pharmacother. 33:502.
  • Perloff M, Greenblatt D and von Moltke L. (2001). The Saint John’s Wort Drug Interaction: An In Vitro Analysis of P-Glycoprotein (MDRI) Induction Due to Chronic Exposure. FASEB Journal, 15(4), A548.
  • Piscitelli S, Burstein A, Chaitt D, Alfaro R and Falloon J. (2000). Indinavir concentrations and St. John's wort. Lancet, 355(9203):547-8.
  • Ruschitzka F, Meier P, Turina M, Luscher T and Noll G. (2000). Acute heart transplant rejection due to Saint John's Wort. Lancet 355:548-549.
  • Yue Q, Bergquist C and Gerden B. (2000). Safety of St John's Wort (Hypericum perforatum). Lancet 355:576-577.