Sunday, March 23, 2014

St. John's Wort Effect on Drug Efficacy

      One of the most studied herbs with regards to drug interactions is St. John’s Wort.   It can be effective in treating mild, moderate and major depression.   Considering many patients who undergo organ transplantation or suffer from HIV and cancer suffer from depression, they many feel inclined to try out St. John’s Wort to treat their mental affliction thinking it to be harmless.  Well, “natural” doesn’t always translate to harmless especially if you are undergoing medical therapy for a variety of medical conditions and there is a potential for an herb-drug interaction.  A decrease in drug efficacy is one of the many ways St. John’s Wort can interact with medications.   St. John’s Wort is comprised of many phytochemicals from flavonoids to napthodianthrones. More specifically there is a phloroglucinol derivative called hyperforin that negatively impacts the pharmacokinetics of certain medications causing a decrease of the drugs plasma concentration in the system thereby disrupting it’s therapeutic potential.  St. John’s Wort preparations with hyperforin concentrations of greater than 1% are often seen to exert negative effects on drug efficacy with certain medications. 

     The isoenzyme CYP3A4 is part of the family of enzymes (otherwise known as  cytochrome P450)  that are involved in drug metabolism.  CYP3A4 with or without the ATP transporter P-glycoprotein when present as  substrates of certain medications are involved in decreasing plasma concentration of these drugs.  These medications include anticoagulants, beta blockers, immunosuppresants, hormonal contraceptives, anti-retrovirals, anti- cancer, and HMG Co-A reductase inhibitors among others.  A cascade of events that effects the genome when hyperforin interacts with a medication causing CYP3A4 and/or P-glycoprotein to be induced  results in decreased drug efficacy. 

     One of the most studied of these interactions with St. John’s Wort involves the immunosuppressant drug cyclosporine.  This medication is given to organ transplant patients to help prevent rejection of the organ.  Cyclosporine is substrate of both CYP3A4 and P-Glycoprotein.  Additionally it has a narrow therapeutic range which also helps encourage the herb-drug interaction.  When St. John’s Wort is taken with cyclosporine it has been observed that plasma concentration of the medication is decreased and dosing adjustments were required.  This is shown to be reversed with discontinuation of St. John’s Wort supplementation. 

Mannel, Marcus. Drug Interactions with St John’s Wort. Drug Safety.  2004;
27(11): 773-797
Zeping H, Xiaoxia Y, Paul C, et al. Herb-Drug Interactions: A Literature Review. Drugs.2005; 65(9): 1239-1282.
 Izzo A, Edzard E.  Interactions Between Herbal Medicines and Prescribed Drugs: An
Updated Review.  Drugs.  2004; 69(13): 1777-1798. 
Borrelli F, Izzo A.  Herb-Drug Interactions with St John’s Wort (Hypericum
perforatum): an Update on Clinical Observations.  AAPS Journal. 2009; 11(4):
 Wang X, Li J, Su Q, et al.  Impact of the haplotypes the human pregnane X
Receptor gene on the basal and St John’s wort-induced activity of cytochrome
P4503A4 enzyme.  Br J Clin Pharmacol.  2009; (62) 2: 255-261.
 Hiromitsu I, Tsutomu K, Kimiko T.  The recovery time-course of CYP3A after
Induction by St John’s wort administration.  2008; (65) 5: 701-707.
Mueller S, 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.
Mai I, Bauer S, Perloff E, et al.  Hyperforin content determines the magnitude of
The St. John’s wort-cyclosporine drug interaction.  Clinical Pharmacology and
Therapeutics.  2004; (76) 4: 330-340.
Nowack, R.  Review Article: Cytochrome P450 enzyme, and transport protein
mediated herb-drug interactions in renal transplant patients: Grapefruit juice, St.
John’s Wort- and beyond! Nephrology.  2008; 13: 337-347.
Murakami Y, Tanaka T, Murakami H, et al.  Pharmacokinetic modelling of the
interaction between St. John’s wort and ciclosporin A.  Br J Clincal Pharmacol. 
2006; (61) 6: 671-676.