EBM Consult


  • St. John's wort (Hypericum perforatum) is known to significantly decrease the blood concentrations of cyclosporine thereby increasing the risk for rejection in patients who have undergone kidney transplantation.        
  • Cyclosporine's metabolism is dependent on the presence and function of the cytochrome P450 (CYP) 3A4 enzyme, which means cyclosporine is a substrate CYP3A4.
  • Cyclosporine's elimination from the cell and ultimately from the body is partially mediated by P-glycoprotein (Pgp), thereby making it a substrate of Pgp.
  • St. John's wort interacts with cyclosporine by increasing the gene expression for the drug metabolizing enzyme CYP3A4 and the cell membrane efflux pump, P-glycoprotein (Pgp), which is known to be used by cyclosporine for its metabolism and elimination from the body.

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA

Last Reviewed: February 2018


  • St. John's wort (Hypericum perforatum) is known to significantly decrease the blood concentrations of the calcineurin inhibitor cyclosporine, thereby increasing the risk for rejection in patients who have undergone kidney transplantation.(1-4) As a quick review, several pharmacokinetic studies have shown that the coadministration of St. John's wort along with cyclosporine in patients with renal transplantation can result in a reduction in the concentrations of cyclosporine by 46-52% as compared to baseline.(3,4)  More importantly, this reduction in cyclosporine concentrations required about a 60-65% increase in the daily dose of cyclosporine to compensate for the increased elimination by St. John's wort.(3,4)  To complicate things further, it appears that the dosage formulation of St. John's wort also has an impact on the degree of change in cyclosporine concentrations.  What is known is that the increase in cyclosporine elimination appears to be directly related to the dose or concentration of St. John's wort extract being used.(4,5)

    What is St. John's wort doing to cause a reduction in the concentrations of cyclosporine?

    • In order to understand this, a basic review of the metabolic and elimination pathways for cyclosporine are needed. 
    • Cyclosporine's metabolism is dependent on the presence and function of the cytochrome P450 (CYP) 3A4 enzyme, which means cyclosporine is a substrate CYP3A4.(6,7) 
    • Furthermore, cyclosporine's elimination from cells and ultimately from the body is partially mediated by P-glycoprotein (Pgp), which makes it also a substrate for Pgp.(8,9) 
    • These two pathways of clearance are important to understanding why St. John's wort causes cyclosporine concentrations to decrease. 
    • For purposes of being complete, cyclosporine is a also a potent inhibitor of several influx cell membrane transporters (OATP1B1, OATP1B3, OATP2B1) as well as the efflux cell membrane transporters (MRP2 and P-gp).(8,10)  As such, it is evident why drug-drug interactions between cyclosporine and other medications are not only complex, but cannot be easily or fully explained by the a simple comparison of the CYP450 enzyme pathways between two or more medications. 

    How does St. John's wort influence CYP3A4 and Pgp activity which is known to reduce cyclosporine concentrations?

    • St. John's wort is a substrate for the activation of the pregnane X receptor (PXR), which is a well known nuclear receptor found in the cytoplasm of various cells, including liver and gastrointestinal cells.(11,12) 
    • The PXR is important because it is one of the transcription factors known to influence gene expression of both CYP3A4 and Pgp within the nucleus of hepatic and intestinal cells.(12,13) 
    • Therefore, any substrate that activates PXR will also increase the gene expression of CYP3A4, which will make more CYP3A4 enzyme available to metabolize more cyclosporine and increase the expression of Pgp, which will increase the presence of Pgp mediated efflux of cyclosporine.   

    How does St. John's wort actually increase the gene transcription of both CYP3A4 and Pgp inside the cell?

    • St. John's wort is an herb that is derived from the tops of the flowering parts of Hypericum perforatum L. and is known to have several active ingredients which include cyclopseudohypericin, hypericin, hyperforin, isohypericin, protohypericin, pseudohypericin and several other flavonoids.(14)  As it relates to these ingredients, hyperforin specially is a substrate, or activator, of PXR.(11) 
    • As mentioned before, PXR is a nuclear receptor found in the cytoplasm of cells.  It has 3 major domains that influence its function and level of activity on gene expression.  The first domain, (activation function 1 (AF-1) domain) located at the amino terminus, is where recognition of other transcription factors and/or co-activators cause ligand-independent activation.  The second domain (DNA-binding domain) is the part that directly binds to DNA to modulate gene transcription.  The third domain (ligand-binding domain) on PXR is where substrates, like drugs, bind to "activate" the transcription of more genes. 
    • Therefore, as St John's wort passes through the cell membrane, by diffusion or transport, it will bind to the ligand-binding domain of PXR in the cytoplasm. This causes a dissociation of the histone deacetylase-containing complex (transcriptions co-repressors) so that PXR can then enter the nucleus.  Once in the nucleus of the cell, the ligand-receptor complex either recruits co-activators to form a homodimer or heterodimer with the retinoid X receptor (RXR), where it can now bind to response elements in the promoter and enhancer regions of the target gene.  Once this occurs, gene transcription for CYP3A4 is turned on as well as activation of the ABCB1gene, which is needed to make Pgp. 
    • The more CYP3A4 and Pgp transcribed, the greater the ability to metabolize medications known to be a substrate for CYP3A4 and eliminate substrates of Pgp from inside the cell, thereby accelerating their clearance from the body.


    1. Mai I, Kruger H, Budde K et al.  Hazardous pharmacokinetic interaction of Saint John's wort (Hypericum perforatum) with the immunosuppressant cyclosporine.  Int J Clin Pharmacol Ther  2000;38:500-2.
    2. Barone GW, Gurley BJ, Ketel BL et al.  Herbal supplements: a potential for drug interactions in transplant recipients.  Transplantation  2001;71:239-41. 
    3. Bauer S, Stormer E, Johne A et al.  Alterations in cyclosporin A pharmacokinetics and metabolism during treatment with St. John's wort in renal transplant patients.  Br J Clin Pharmacol  2003;55:203-11.
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    5. Mueller SC, Majcher-Peszynska J, Uehleke B et al.  The extent of induction of CYP3A by St. John's wort varies among products and is linked to hyperforin dose.  Eur J Clin Pharmacol  2006;62:29-36.  
    6. Cyclosporine (Gengraf) product package insert.  Abbott Laboratories.  Abbott Park, Ill.  June 2004.
    7. Cyclosporine (Neoral) product package insert.  Novartis Pharmaceuticals Corp.  East Hanover, NJ.  August 2005.
    8. Rao US, Scarborough GA.  Direct demonstration of high affinity interactions of immunosuppressant drugs with the drug binding site of the human P-glycoprotein.  Mol Pharmacol  1994;45:773-6.
    9. Anglicheau D, Pallet N, Rabant M et al.  Role of P-glycoprotein in cyclosporine cytotoxicity in the cyclosporine-sirolimus interaction.  Kidney Int  2006;70:1019-25.
    10. Neuvonen PJ, Niemi M, Backman JT.  Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance.  Clin Pharmacol Ther  2006;80:565-81.
    11. Moore LB, Goodwin B, Jones SA et al.  St. John's wort induces hepatic drug metabolism through activation of the pregnane X receptor.  Proc Natl Acad Sci USA  2000;97:7500-2.
    12. Urquhart BL, Tirona RG, Kim RB.  Nuclear receptors and the regulation of drug-metabolizing enzymes and drug transporters: implications for interindividual variability in response to drugs.  J Clin Pharmacol  2007;47:566-78.
    13. Zhou S, Lim LY, Chowbay B. Herbal modulation of P-glycoprotein. Drug Metab Rev  2004;36:57-104.
    14. Ebadi M.  Pharmacodynamic basis of herbal medicine. 2nd Ed.  Taylor & Francis Group.  Boca Raton, FL. 2007.


  • St Johns wort, Hypericum perforatum, Cyclosporine, Gengraf, Neoral, Sandimmune, Renal Transplantation