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St Johns wort and herb-drug interactions Introduction St Johns Wort (SJW) is thought to be metabolised via the same systems that metabolise many pharmaceutical drugs. Much of the research on SJW demonstrates the increased clearance of concomitant drugs through the enzyme systems of the liver and small intestines. The only piece of new research that might be relevant to the Herb-drug interaction chart refers to opioid drugs like methadone and may need to be included so practitioners and pharmacists do not recommend SJW for depression during methadone treatment. Normal Drug Metabolism Drug metabolism is affected by Phase 1 and Phase 2 reactions. Phase 1 reactions are oxidation, reduction, hydrolysis – involving the CYP450 system. Phase 2 reactions are conjugation. A drug may be metabolised via different pathways at the one time. They may also have a secondary metabolism after these initial phases. The endoplasmic reticulum is the site where many transformations occur, forming microsomes. (Rowland & Tozer, 1995:156-157) Certain drugs can induce the metabolism of others by increasing the rate of synthesis of enzymes. Some drugs may clear slower in a person depending on the clearance rate of these drugs in its target organ. (Rowland & Tozer, 1995:186-188) Normal Drug metabolism assumes that the one compartment model is operating normally. Abnormal drug metabolism may be an example of the two-compartment model. (Rowland & Tozer, 1995:317) Factors to be considered in the individual may include age, genetics, diseases, and other drugs being taken. Another factor is diet. Many drugs require protein or lipids to be correctly assimilated or metabolised. Excessive protein may cause enzyme induction to occur. (Rowland & Tozer, 1995:208-209) Diseases, which may affect drug-drug interactions, could be Hepatic, Circulatory, and Renal dysfunction (Rowland & Tozer, 1995:250-258) Other discussions may be the receptor-effector theories in which drugs bind with one or more receptors to invoke an action or a secondary action such as secondary messengers. The types of receptors vary from Lipoproteins or glycoproteins, lipids, pure proteins and Nucleic Acids. (Nogrady, 1988:56-60) Herb-drug interaction mechanisms In this section, the mechanisms of interactions are examined. In the article, Topics in Xenobiochemistry the discussion on herb drug interaction demonstrates that the metabolism of concomitant pharmaceuticals and St John’s wort has led to issues in a small number of people. The herb SJW and specifically the photochemical hyperforin affected the pregnane X receptor, which regulates the expression of CYP3A4 (Ioannides, 2002:451-471)
‘Understanding Drug-Herb interactions’ states (SJW) reduces concomitant drug levels by inducing the CYP3A4 enzyme and the ATP dependant efflux pump, P-glycoprotein (P-gl) and that most of this information comes from the analysis of the Cyclosporin interaction. P-glycoprotein pumps drugs out of the cell membrane, decreasing drug levels thus limiting the absorption of drugs in the gut. Many interactions are Pharmacokinetic (PK), which reduce drug levels while Pharmacodynamic (PD) interaction antagonise or give an additive effect. Many anti-depressant interactions have been classified as PD interactions. In assessing a patient, we need to be aware of individuals who might be at an increased risk due to the use of multiple pharmaceuticals, transplant patients or those prior to surgery. (Brazier, Mitchell, Levine, 2003:427-430) P-glycoprotein (P-gl) is a transmembrane transport protein. P-gl seems to have broad substrate specificity. Chronic dosage is discussed in this paper and suggests that the chronic dosage reduces the bioavailability of a number of drugs. (Wang, 2004123-127) A recently described member of the steroid/thyroid hormone receptor family, the pregnane X receptor serves as a regulator of CYP3A4 in human hepatocytes. It is suggested that hyperforin is a ligand that stimulates the pregnane X receptor. The paper goes on to say that patients taking drugs metabolised by the CYP3A4 pathway should use SJW with caution. It also suggests that hypericum extract increases the metabolism of various drugs. (Moore, 2000:7500-7502) SJW influences neurotransmitters including serotonin, noradrenaline and dopamine (Bone, 2006:45) Another relevant article compares the long and short-term use of SJW stating that long-term use of SJW with voriconazole an anti-fungal agent, showed a reduction in the drugs bioavailability and short-term use displayed an increase in drug levels. (Xie & Kim:19-24) Recent publications involving SJW and possible herb-drug interactions. In the publication on Methadone Maintenance Treatment and St John’s Wort, four patients where given SJW for treatment of depression. The result was an overall reduction in plasma methadone concentrations by forty seven percent. Two patients reported withdrawal symptoms that could lead to resumptions of illicit drug use or discontinuation of either methadone or antidepressant treatments. (Eich-Hochli, 2003: ) Use of Opioid such as Methadone and loperamide with SJW would need to be monitored. A clinical study by Eich-Hochli et al in 2003 demonstrated that SJW reduced methadone plasma levels in four addict patients leading to withdrawal symptoms and the possible re-use of illicit drugs. A brief acute delirium was suspected to be caused from concomitant use of SJW, Valerian and loperamide. This writer concludes that the potential herb-drug interaction for drugs metabolised via the CYP3A4 enzymes and the P-glycoprotein transporter system are of concern. (Izzo, 2004:143) In Conclusion Individuals with abnormal drug metabolism should be monitored during the use of concomitant SJW and pharmaceutical medications. Another consideration would be individuals with malnutrition, disease or poor function of the liver, kidneys, circulatory system should be monitored during the use of concomitant SJW and pharmaceutical drugs. If the enzyme pathways in an individual are disturbed or abnormal, which may be determined by assessing the state of drug metabolism in the individual, we might see a possible risk of using high dose or prolonged use of SJW. If a person states that their medication is not controlling the condition as would be expected, then we could assume that there is either a problem in the enzyme or transporter systems of the small intestine or the liver. It would be wise at this point to recognize the risk and the necessity to avoid using herbs which might need these systems to be functioning normally. An example of this might be someone using warfarin not having a stable INR. Recent studies could show that the degree of enzyme induction by SJW correlates strongly with the amount of hyperforin found in the product. Many drugs have a narrow window of effective drug levels. Herbs, which increase or reduce the clearance of drugs are of concern. In these cases drug levels would need to be carefully monitored or the herb discontinued. Many of the reports of adverse herb-drug interactions were either self prescribed or given in a trial, usually in large doses. Relatively few people had side effects. All were reversed after cessation of concomitant use of SJW and pharmaceutical drugs. It should be considered that palliative patients taking opioid painkillers avoid the use of SJW. Further research is needed to ascertain if this is the case. In the study of Traditional Naturopathy, Traditional Chinese Medicine or the many other traditional medicines from all the different cultures, training on the design of herbal formula for an individual was and is currently included. Not often would an herb be given in large doses, used for prolonged time or given as a single herb.
Reference: Bone K, 2006, ‘HS432 Advanced Herbal Therapeutics’ UNE Handbook, Armadale Rowland M & Tozer T, 1995. ‘Clinical pharmacokinetics – concepts and applications 3rd ed.’ Williama & Wilkins USA.
Nogrady, Thomas. 1988 ‘Medicinal Chemistry, a biochemical approach. 2nd ed.’ Oxford University Press, New York
Ioannides C, 2002, ‘Topics in Xenobiochemistry Pharmacokinetic interactions between herbal remedies and medicinal drugs’ Molecular Toxicology Group, School of Biomedical and Life Sciences, University of Surrey, Guildford, UK
Izzo A, 2004, ‘Drug interactions with St John’s Wort (Hypericum perforatum): a review of the clinical evidence, International Journal of Clinical Pharmacology and Therapeutics, Vol 42-No 3/2004:139-148, Italy
Brazier N, Mitchell A, Levine H, 2003, ‘Understanding drug-herb interactions’, Pharmacoepidemiology and Drug Safety Vol 12:427-430 online
Wang E, Barecki-Roach M and Johnson W, 2004 ‘Quantitative characterization of direct P-glycoprotein inhibition by St John’s wort constituents hypericin and hyperforin’, Journal of Pharmacy and Pharmacology, USA
Eich-Höchli D, Oppliger R, Powell Golay K, Baumann P, Eap C. 2003, ‘Methadone Maintenance Treatment and St. John’s Wort’, University Clinic of Zurich, Switzerland & Unit of Biochemistry and Clinical psychopharmacology, Hospital of Cery, Prilly-Lausanne, Switzerland
Xie H, Kim R, 2005, ‘St John’s wort-associated drug interactions: Short-term inhibition and long term induction?’, Clinical Pharmacology & Therapeutics, Vol 78
Moore L, Goodwin B, Jones S, Wisely B, Serabjit-Sing C, Willson T, 2000, ‘St John’s wort induces hepatic drug metabolism through activation of the pregnane X receptor.’ National Academy of Sciences, Vol. 97, NC
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