Herb drug interaction

Herb- drug interactions.

Sardar Hussain

Asst.Prof of Biotechnology,

G.Sc, Chitradurga.

[email protected]

• HERB:

• DRUG:

• What are Herb-drug interactions???

• How????????

• Whether they are diagnoised??????

• Are they neglected????

• Any reports?????

• What is the significance????

Need for the study

• Early humans recognized their dependence on nature in both health and illness.

• The World Health Organization (WHO) estimates that 80 percent of the world population use herbal medicine for some aspect of primary health care[1].

• More than 60% Asians resort to herbal products to treat a variety of recalcitrant chronic disorders such as anxiety, depression, dementia and memory impairment, headache, weight loss, etc.[2].

• FDA Recent research estimates 50% of adult Americans use at least one prescription medication and with that, 16% also take herbal supplements[3].

• Herbal medicines (HMs) are readily available in the market from health food stores without prescriptions and are widely used in India, China, USA and all over the world.

• According to recent survey the majority of people who use HMs do not inform their physicians about their consumptions that can cause abnormal test results and confusion in proper diagnosis.

• The medical and scientific literature is abundant with reports suggesting that the concomitant oral administration of natural products and prescription drugs or over- the counter products may affect human drug metabolism and significantly increase the risk for serious clinical adverse reactions[4].

Nature of Herb Drug interaction:

• The nature of herb-drug interactions is not a chemical interaction between a drug and an herb component to produce something toxic.

• Instead, the interaction may involve having an herb component, causing either an increase or decrease in the amount of drug in the blood stream.

• Herbs and drugs may interact either pharmacokinetically or pharmacodynamically.

• Many drug interactions are due to alterations in drug metabolismand drug absorption, thereby altering the bioavailability of the drug.

• One notable system involved in metabolic drug interactions is the enzyme system comprising the cytochrome P450 oxidases[8].

• Another major player in herb-drug interaction is the P-glycoprotein transporter.

Herbal remedies Interacting drug comments

St. John’s Wort Theophyline,

Indinavir

Lower concentration may

cause treatment failure

Garlic Warfarin Increases effectiveness of drug,

bleeding

Garlic

Saqinavir Decreases drug effect

Kava Kava Additive effects with CNS

depressants, alcohol

Ephedra Cyclosporine,

theophyline, indinavir

Decreases drug effect

Ginkgo biloba aspirin, warfarin Bleeding, Hemorrhage,

Increases Drug toxicity

Licorice Spironolactone Decreases drug effect

Common herb –drug interactions

Some of the important documented herbs causing interaction

The Cytochrome P450 enzymes:

• Cytochrome P450 is a superfamily of heme-containing mono-oxygenase enzymes, crucial for the oxidative, peroxidative, and reductive metabolism of a diverse group of substances[12]. The basic reaction catalysed by CYPs is the addition of one oxygen atom to the substrate, while the other oxygen atom is further reduced to water with reducing equivalents derived from NADPH.

• They are responsible for most of the oxidative metabolism of both xenobiotics and endogenous substrates.

•

Role of cytochrome P450 in drug metabolism

• Most drugs are lipophilic and can not be easily eliminated from the body unless they are metabolised to more hydrophilic derivatives [9].

• A large number of enzymes exist which metabolise foreign compounds. They have been classified as belonging to phase I or phase II pathways of metabolism.

• Phase I enzymes include oxidases, hydrolases and reductases, while the phase II enzymes are all transferases .

• Among the large number of Phase I enzymes, the CYPs (cytochrome P450s) are the most important superfamily of enzymes which account for the majority of oxidative biotransformations of xenobiotics and endogenous biochemicals .

• The phase II transferases serve to transfer various water-soluble molecules such as glucuronic acid, sulfonic acid and glutathione to other chemicals [10].

• Often, drugs undergo both phase I and phase II reactions sequentially, but excretion after only one metabolic reaction is also possible.

• Quantitatively, the smooth endoplasmic reticulum of the liver cell is the principal organ of drug metabolism, although every biological tissue has some ability to metabolize drugs.

Mechanism of drug metabolism by liver

Relative levels and importance of cytochrome p450 isozymes

Herb-drug interactions involving CYP enzymes

• During the past few years a revolution has

taken place in our understanding of drug

interactions, mostly as a result of

advances in the molecular biology of the

CYP enzyme system. Several factors

directly or indirectly influence the CYP

activity. Many drug interactions are a result

of induction or inhibition of CYP enzymes.

Enzyme inhibition:

• Many herbal constituents have been reported to inhibit various CYPs [21]. The nature of inhibition may be competitive, noncompetitive, or mechanism based. The later is characterized by NADPH, time and concentration dependent enzyme activation, occurring when some herbal constituents are converted by CYPs to reactive metabolites that are capable of irreversibly binding to CYPs [22]. Mechanism based inhibitors require atleast one cycle of the CYP catalytic process to form reactive metabolites. The resultant metabolites lead to CYP inactivation by chemical modification of the heme, the apoprotein, or both as a result of covalent binding of modified heme to the apoprotein. An in vitro study indicated that Licorice, which is used as anti-allergic and anti-inflammatory agents inactivated CYP3A4 and 2B6 in a time and concentration dependent manner, but 2C9 is competitively inhibited[23]. Similarly, Clinical studies have shown that Kava, which is an effective herbal medicine for the therapy of anxiety and insomnia, inhibited CYP1A2, 2C9, 2C19, 2D6, 3A4 and 4A9[24].

Enzyme induction:

• Herb-drug interactions involving enzyme induction are not as common as inhibition based drug interactions but equally profound and clinically important. The most common mechanism is transcriptional activation leading to increased synthesis of more CYP enzyme proteins[25]. Increased metabolism of the affected drug leads to decreased intensity and duration of drug effects. If the drug is a prodrug or it is metabolized to an active or toxic metabolite then the effect or toxicity is increased. It is somewhat difficult to predict the time course of enzyme induction because several factors including the half-life of drug and enzyme turnover determine the time course of induction[26]. Several recent reports provide evidence that St. John,s wort, an ancient herbal remedy for antidepressants, promotes the metabolism of coadministrated drugs, including the HIV protease inhibitor indinavir, the immunodepressant cyclosporine, and oral contraceptives[27 ]. Because each of these drugs is metabolised by CYP3A4, these findings suggested that St.John wort induces CYP 3A4 expression[28].

References:

• Farnsworth, N.R., Akerele, O., Bingel, A. S., Soejarta, D. D. & Eno, Z. (1985), Medicinal plants in therapy. Bull. World Health Organ. 63::965-981

• 2. Shiew, M. H., Stephen, D. H., Paul, Watkins, J., B., Shaw, T C., Gregory, L K. & Michael, D. M. (2003), Drug interactions with herbal products and grapefruit juice: a conference report. Clinical Pharmacology Therapeutics, 75: 1-12.

• 3. Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA. Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. (JAMA.)2002;287(3):(337-344.)

• 4. Foster, B.C., Vandenhoek, S., Hana, J., Krantis, A., Akhtar, M.H., Bryan, M., Budzinski, J.W., Ramputh, A. and Arnason, J.T.(2003). In vitro inhibition of marker substrates by natural products. Phytomedicine. 10:334-342.

• 5. Angelo,A., Izzo Herb–drug interactions: an overview of the clinical evidence. (2005). Fundamental & Clinical Pharmacology.19(1):1-16.

• Boullata J. (2005). Natural Health Product Interactions with Medication. Nutr. Clin. Pract. 20(1): 33-51.

• Parmar,V. (2005). Herbal medicines: its toxic effects and drug interactions. The Indian Anesthetist’s forum. ISSN 0973-0311:1-9

References:

• Guengerich, F.P. (2006), Cytochrome P450s and Other Enzymes in Drug Metabolism and Toxicity. AAPS Journal, 8:101-111.

• 9.Nelson DR, Koymans L, Kamataki T, Stegeman JJ, Feyereisen R, Waxman DJ, Waterman MR, Gotoh O, Coon MJ, Estabrook RW, Gunsalus IC, Nebert DW. P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics 1996;6:1-42.

• 10.Gonzalez FJ, Idle JR. Pharmacogenetic phenotyping and genotyping. Present status and future potential. Clin Pharmacokinet 1994;26:59-70.

• Krishna,D.R., Klotz,U. (1994). Extrahepatic metabolism of drugs in humans. Clin Pharmacokinet. 26:144-160.

• Wrighton, S.A., Stevens, J.C. (1992). The human hepatic cytochromes P450 involved in drug metabolism. Crit Rev Toxicol .22:1-21.

• Guengerich, F.P.(2001). Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity. Chem Res Toxicol. 14:611-50.

• Parkinson, A. (2001). Biotransformation of xenobiotics. In: Klaassen CD (ed) Casarett & Doull’s Toxicology, The Basic Science of Poisons. 6th edition, McGraw-Hill, USA.

References:

• Nelson D.R. (1999).Cytochrome P450 and the individuality of species. Arch Biochem Biophys .369:1-10

• Meyer U.A. (1996). Overview of enzymes of drug metabolism. J Pharmacokinet Biopharm. 24:449-459.

• Dresser,G.K.,Spence,J.D.,Bailey,D.,G. (2000). Pharmacokinetic pharmacodynami consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin Pharmacokinet. 38:41-57.

• Lin, J.H., Lu A.Y. (1998). Inhibition and induction of cytochrome P450 and the clinical implications. Clin Pharmacokinet. 35:361-390.

• Nelson, D.R., Koymans, L., Kamataki, T., Stegeman, J.J., Feyereisen, R., Waxman, D.J., Waterman, M.R., Estabrook R.W., Gunsalus, I.C., Nebert, D.W. (1996) P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics. 6:1-42

• Wrighton,S.A., Branden,M., Ring,B.J.(1996).The human drug metabolizing cytochromes P450. J Pharmacokinet Biopharm . 24:461-473

• Zhou, S.F., Gao, Y.H., Wen, Q.J., Huang, M. (2003). Interaction of herbs with cytochrome P450. Drug metabolism reviews. 35(1): 35-98.

References:

• Ortiz, M., Correia, M.A. (1995). Inhibition of Cytochrome P450. In: Ortiz de Montellano, P.R. (Ed.), Cytochrome P450: structure, mechanism and biochemistry. 305-366.

• Kent, U.M., Aviram, M., Rosenblat, M., Hollenberg, P.F. (2002). The licorice root derived isoflavin glabdrin inhibits the activites of human cytochrome P450s 3A4, 2B6 and 2C9. Drug Metabolism and Disposition. 30(6): 709-715.

• Mathews, J.M., Etheridge, A.S., Black, S.R. (2002). Inhibition of human Cytochrome P450 activities by kava extract and kavalactones. Drug Metabolism and Disposition. 30(22): 1153-1157.

• Shimada,T.,Yamazaki,H.,Mimura,M.,Guengerich, F.P., Dossing,M., Pilsgaard,H., Rasmussen,B.,Poulssen,H.E. (1983). Time course of phenobarbital and cimetidine mediated changes in hepatic drug metabolism. Eur J Clin Pharmacol .25:215-222.

• Wilkins PB, Wrighton SA, Schuetz EG, Molona DT, Guzelian PS. Identification of glucocorticoid inducible cytochromeP450 in the intestinal mucosa of rats and man. J Clin Inves 1987;80:1029-36.

• Moore, L.B., Goodwin, B., Jones, S.A., Wisley, G.B., Singh, C.J.S., Willson, T.M.Kiliewer, S.A. (2000). St. John,s wort induces hepatic drug metabolism through activation of the pregane X receptor. PNAS. 97(13):7500-7502.

• Markowitz, J.S., Donovan, J.L., Taylor, R.M., Wang, J.S., Chavin, K.D. (2003). Effect of St. John;s wort on drug metabolism by induction of cytochrome P450 3A4 enzyme. JAMA. 290(11):1500-1504.