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Annual for Hospital Pharmacy

Interactions Between Herbs And Drugs At The Level Of Сytochrome P450

Iliana Yaneva, Tatyana Karanesheva, Valentin Balabanski, Valentina Belcheva


Taking drugs simultaneously with plant products, nikotin, alcohol, insecticides can lead to  different drug interaction between them.

A literature review of potential adverse clinical interaction at pharmacokinetic level (cytochrome P450 enzyme superfamily) between plant products and medical products taken concomitantly has been performed. Necessary importance to plant products to cause side effects when taken in a combination with medical products is not given often. They seem to be underestimated by physicians and patients. Leading mechanism of drug interaction at pharmacokinetic level is Cytochrome P450 system (CYP450). CYP450 is one of the most important systems for biotransformation of the drugs. CYP 450 enzymes are responsible for the metabolism of more than 50 percent of the drugs. Among people are found more than 50 isoenzymes which are classified in different classes and families. Isoenzymes which are with most valuable role for metabolism of drugs are CYP 1А2, CYP 2А6, CYP 2В6, CYP 2С9, CYP 2D6, CYP 2Е1, CYP 3А4. Plant ingredients can affect the activity of  the cytochrome P450 enzyme superfamily by ty two mechanisms – induction and inhibition of isoenzymes. The use of in vitro and in vivo approaches in studying the mechanism of action of plants products and of bioactive substances isolated from plants has led to their identification as substrates, inhibitors and/ or inducers of various CYP isoenzymes.

Conclusion. Plant products which are inhibitors or inductors of cytochrome P450 enzymes can modulate the effectiveness of drugs substrates of this system at the pharmacokinetics level in their concomitant use. To avoid such situations in patients taking plant products and drugs is recommended this not to happen concomitantly but at 1.5-2 hours interval.



plant products, medical products, нerbdrug interactions, сytochrome p450

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Кукес ВГ, Сычев А, Раменская ГВ, Ших ЕВ, Колхир ПВ. Взаимодействие фитопрепаратов и синтетических лекарственных средств на уровне системы биотрансформации и транспортеров: клиническое значение. Биомедицина, 2007;6:29-47.

Симеонова Р. Клинична значимост на цитохром Р450-зависимите взаимодействия. Профилактика, диагностика, терапия. Актуални проблеми, 202-206.

Сычев ГВ, Кукес ВГ, Ших ЕВ, Булаев ВМ, Раменская ДА, Колхир ПВ. Клиническое значение фармакокинетического взаимодействия лекарственных средств и фитопрепаратов. Експериментальная и клиническая, фармакология, 2006;69(2):75-79.

Тарловская ЕИ, Козиолова НА, Чесникова АИ. Влияние образа жизни на эффективность и безопасность лекарственных препаратов в кардиологической практике:что должен учитывать врач? Российский кардиологический журнал, 2016;129(1):51-59.

Йотова М, Калоянов К, Григоров Е. Гинко билоба: фармакологични и токсикологични ефекти. Българско списание за обществено здраве, 2018;10(2):60-66.

Bailey DG, Dresser GK, Bend JR. Bergamottin, lime juice, and red wine as inhibitors of cytochrome P450 3A4 activity: comparison with grapefruit juice. Clin Pharmacol Ther, 2003;73(6):529-37.

Barone GW, Gurley BJ, Ketel BL, Lightfoot ML, Abul-Ezz SR. Drug interaction between St John’s wort and cyclosporine. Ann Pharmacother, 2000;34(9):1013–16.

Bhowmik S, Lu W, Rosenthal DS. Effects of Chinese herbal medicine on cytochrome P450, a systematic review. Journal of Clinical Oncology, 2010;28:15:suppl,e13150-e13150

Boullata J. Natural health product Interactions with medication, Invited Review

Bourian M, Runkel M, Krisp A et al. Naringenin and interindividual variability in interaction of coumarin with grapefruit juice. Exp Toxicol Pathol, 1999;51(4-5):289-93.

Breidenbach T, Kliem V, Burg M et al. Profound drop of cyclosporin A whole blood trough levels caused by St. John's wort (Hypericum perforatum). Transplantation, 1999;69(10):2229-30.

Budzinski J, Foster B, Vandenhoek S. An in vitro evaluation of human cytochrome P450 3A4, inhibition by selected commercial herbal axtracts and tinctures. Phytomedicine, 2000;7(4):273-82.

Burstein AH, Horton RL, Dunn T, Alfaro RM, Piscitelli SC, Theodore W. Lack of effect of St John's wort on carbamazepine pharmacokinetics in healthy volunteers. Clin Pharmacol Ther, 2000;68:605-12.

Chen MF, Shimada F, Kato H, Yano S, Kanaoka M. Effect oforal administration of glycyrrhizin on the pharmacokinetics of prednisolone. Endocrinol Jpn, 1991;38(2):167–74.

Cordell GA. Sustainable medicines and global health care. Planta Med, 2011;77(11):1129-38.

Correia MA. Drug Biotransformation. Basic & Clinical Pharmacology, Fourteenth Edition 2018, McGraw-Hill Education. ISBN 978-1-259-64115-2

Dharmananda S. The Interactions of herbs and drugs. Portland, OR: Institute for Traditional Medicine

Dürr D, Stieger B, Kullak-Ublick GA, Rentsch KM et al. St John's wort induces intestinal P-glycoprotein/MDR1 and intestinal and hepatic CYP3A4. Clin Pharmacol Ther, 2000;68:598-604.

Foster BC, Foster MS, Vandenhoek S et al. An in vitro evaluation of human cytochrome P450 3A4 and P-glycoprotein inhibition by garlic. J Pharm Pharm Sci. 2001;4(2):176-84.

Gary NA, Corvett AH, Hawke RL. Common Herbal Dietary Supplement–Drug Interactions. Am Fam Physician, 2017, 96 (2):101-107

Ganzera M, Schneider Р, Stuppner Н. Inhibitory effects of the essential oil of chamomile (Matricaria recutita L.) and its major constituents on human cytochrome P450 enzymes. Life Sci, 2006;78(8):856-861.

Georgiev KD. Study of Herbal-Drug Interactions (HDIs) Using in Silico Methods – Mission (Im)Possible. Arch Phar & Pharmacol Res, 2019;2(3):APPR.MS.ID.000540.

Georgiev KD, Radeva-Ilieva M. In vitro inhibitions of CYP2C9 and CYP3A4 by fractions isolated from Goji berry (Lycium barbarum) fruits. Scripta Scientifica Pharmaceutica, 2019;6(1):17-21.

Georgiev KD, Radeva-Ilieva M, Stoeva S, Zhelev I. Isolation, analysis and in vitro assessment of CYP3A4 inhibition by methylxanthines extracted from Pu-erh and Bancha tea leaves. Sci Rep, 2019;9(1):13941.

Gorski JC, Hamman MA, Wang Z et al. The effect of St. John’s wort on the efficacy of oral contraceptives. Clin Pharmacol Ther, 2001;71:P.25

Gorski JC, Huang S-M, Pinto A, Hamman MA et al. The Effect of Echinacea (Echinacea Purpurea Root) on Cytochrome P450 activity in vivo. Clin Pharmacol Ther, 2004;75(1):89-100.

Guo LQ, Taniguchi M, Chen QY et al. Inhibitory Potential of Herbal Medicines on Human Cytochrome P450-mediated Oxidation: Properties of Umbelliferous or Citrus Crude Drugs and Their Relative Prescriptions. Jpn J Pharmacol, 2001;85(4):399-408.

Gurley BJ, Gardner SF, Hubbard MA et al. Clinical assessment of effects of botanical supplementation on cytochrome P450 phenotypes in the elderly: St John's wort, garlic oil, Panax ginseng and Ginkgo biloba. Drugs Aging, 2005;22(6):525-39.

Gurley BJ, Gardner SF, Hubbard MA et al. In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes. Clin Pharmacol Ther, 2005;77(5):415-26.

Guttman Y, Nudel A, Kerem Z. Polymorphism in Cytochrome P450 3A4 is ethnicity Rrelated. Front Genet, 2019;10:224

Guyonnet D, Belloir C, Suschetet M, Siess MH, Le Bon AM. Liver subcellular fractions from rats treated by organosulfur compounds from Allium modulate mutagen activation. Mutat Res, 2000;466:17

He N, Edeki TI. Effects of ginseng and ginkgo biloba components on CYP 3A4 mediated testosterone 6 –Hydroxilation in human livers microsomes. Clin Pharmacol Ther, 2003;73:P50–P50

Henderson G, Harkey MR, Gershwinet ME et al. Effects of ginseng components on c-DNA-expressed cytochrome P450 enzyme catalytic activity. Life Science, 1999;65:209

Highleyman L. Drug interactions and Anti-HIV Therapy. BETA, 2005;17(4):20-9.

Iwata H, Tezuka Y, Kadota S et al. Identification and characterization of potent CYP3A4 inhibitors in schisandra fruit extract. Drug Metab Dispos, 2004;32(12):1351-8.

Jin K, Shi S, Teng L et al. Mechanism of herb-herb Interaction between Ginseng and Trogopterus based on CYPs in rat livers. Journal of US-China Medical Science, 2008;5(8):46-51.

Ketter TA, Flockhart DA, Post RM et al. The emerging role of cytochrome P450 3A in psychopharmacology. J Clin Psychopharmacol, 1995;15(6):387-98.

Klotz U, Ammon, E. Clinical and toxicological consequences of the inductive potential of ethanol. Eur J Clin Pharmacol, 1998;54(1):7-12.

Lefebvre T, Foster BC, Drouin CE et al. In vitro activity of commercial valerian root extracts against human cytochrome P450 3A4. J Pharm Pharmaceut Sci, 2004;7(2):265-73.

Li CG, Yang L, Zhou SF. Interactions between Chinese Herbal Medicines and Drugs. Australian Journal of Acupuncture and Chinese Medicine, 2007;2(1):17-24.

Lown KS, Mayo RR, Leichtman AB et al. Role of intestinal P-glycoprotein (mdr1) in interpatient variation in the oral bioavailability of cyclosporine. Clin Pharmacol Ther, 1997;62(3):248-60.

Lown KS, Bailey DG, Fontana RJ et al. Grapefruit juice increasesfelodipine oral availability in humans by decreasing intestinal CYP3A expression. J Clin Invest, 1997;99:2545–2553.

Marechal J-D, Kemp CA, Roberts GC et al. Insights into drug metabolism by cytochromes P450 from modelling studies of CYP2D6-drug interactions. British Journal of Pharmacology, 2008;153:S82-S89.

Mathews JM, Etheridge AS, Black SR. Inhibition of human cytochrome P450 activities by kava extract and kava lactones. Drug Metab Dispos, 2002;30:1153-57.

Markowitz JS, Donovan JL, DeVane CL et al. Effect of St John's wort on drug metabolism by induction of cytochrome P450 3A4 enzyme. JAMA, 2003;290(11):1500-4.

Michalets EL. Update: clinically significant cytochrome P-450 drug interactions. Pharmacotherapy, 1998;18(1):84-112.

Miller LG. Herbal medicines: selected clinical considerataions focusing on known or potential drug-herb interactions. Arch Intern Med, 1998; 158:2200-2211.

Moltke LL, Weemhoff JL, Bedir E et al. Inhibition of human cytochromes P450 by components of Ginkgo biloba. J Pharm Pharmacol, 2004;56:1039-44.

Modi S, Paine MJ, Sutclive MJ et al. A model for human cytochrome P450 2D6 based on homology modeling and NMR studies of substrate binding. Biochemistry, 1996;35:4540-50.

Nebel A, Schneider BJ, Baker RK, Kroll DJ. Potential metabolic interaction between St. John’s wort and theophylline. Ann Pharmacother, 1999;33(4):502.

Nishikawa M, Ariyoshi N, Kotani A et al. Effects of continuous ingestion of green tea or grape seed extracts on the pharmacokinetics of midazolam. Drug Metab Pharmacokin, 2004;19(4):280-289.

Ohnishi N, Kusuhara M, Yoshioka M et al. Studies on interactions between functional foods or dietary supplements and medicines. I. Effects of Ginkgo biloba leaf extracton the pharmacokinetics of diltiazem in rats. Biol Pharm Bull, 2003;26:1315-20.

Picking D, Chambers B, Barker J et al. Inhibition of Cytochrome P450 Activities by Extracts of Hyptis verticillata Jacq.: Assessment for Potential HERB-Drug Interactions. Molecules, 2018;23(2):430.

Piscitelli S., Burstein AH, Chaitt D et al. Indinavir concentrations and St John's wort. Lancet, 2000;355 (9203):547-8.

Piscitelli SC, Burstein AH, Welden N et al. The effect of garlic supplements on the pharmacokinetics of saquinavir. Clin Infect Dis, 2002;34:234–238.

Raucy JL. Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products. Drug Metab Disp, 2003;31:533–539.

Riley RJ. The potential pharmacological and toxicological impact of P450 screening. Curr Opin Drug Discov Devel, 2002;4:45

Rodrigues AD, Wong S. Scientific and Regulatory Perspectives. London: 1997;65:101.

Rodrigues AD. Use of in vitro human metabolism studies in drug development: An industrial perspective. Biochem Pharmacol, 1994;48:2147-56.

Sarfaraj H. Patient Counselling about herbal–drug Interactions. Afr J Tradit Complement Altern Med, 2011;8(S):152-163.

Saxena A, Tripathi KP, Roy S et al. Pharmacovigilance: Effects of herbal components on human drugs interactions involving cytochrome P450. Bioinformation, 2008;3(5): 98-204

Schwarz UI. Unwanted pregnancy on self-medication with St John's wort despite hormonal contraception. Br J Clin Pharmacol, 2003; 55:112-113

Showande SJ, Fakeye TO, Kajula M et al. Potential inhibition of major human cytochrome P450 isoenzymes by selected tropical medicinal herbs-Implication for herb–drug interactions. Food Sci Nutr, 2019;7:44–55.

Smith M, Lin KM, Zheng YP. PIII-89 an open trial of nifedipine-herb interactions: nifedipine with St John's wort, ginseng or ginkgo biloba. Clin Pharmacol Ther, 2001;69:P86

Sridar С, Goosen T, Kent U et al. Silybin Inactivates Cytochromes P450 3A4 and 2C9 and Inhibits Major Hepatic Glucuronosyltransferases. Drug Metab Dispos, 2004;32(6):587-94.

Sugimoto K, Ohmori M, Tsuruoka S et al. Different effects of St John's wort on the pharmacokinetics of simvastatin and pravastatin. Clin Pharmacol Ther, 2001;70(6):518-24.

Teelucksingh S, Mackie AD, Burt D et al. Potentiation of hydrocortisone activity in skin by glycyrrhetinic acid. Lancet, 1990;335(8697):1060–3.

Treasure J. Herbal Pharmacokinetics: A Practitioner Update With Reference to St. John's Wort (Hypericum perforatum) Herb-Drug Interactions. 2000, 31p.

Vermani M, Milosevic I, Smith F. Herbs for mental illness: Effectiveness and interaction with conventional medicines. J Fam Pract, 2005;54(9):789-800.

Wan CK, Tse AK, Yu ZL et al. Inhibition of cytochrome P450 3A4 activity by schisandrol. A and gomisin A isolated from Fructus Schisandrae chinensis. Phytomedicine: International Journal of Phytotherapy and Phytopharmacology, 2010;17(8-9):702-705.

Wang Z, Gorski JC, Hamman MA et al. The Effects of St John's Wort (Hypericum Perforatum) on human cytochrome P450 activity. Clin Pharmacol Ther, 2001;70(4):317-26.

Wang LS, Zhou G, Zhu B et al. St John's wort induces both cytochrome P450 3A4-catalyzed sulfoxidation and 2C19-dependent hydroxylation of omeprazole. Clin Pharmacol Ther, 2004;75(3):191-7.

Wang Y, Gho WM, Chan FL et al. The red clover (Trifolium pratense) isoflavone biochanin A inhibits aromatase activity and expression. Br J Nutr, 2008;99(2):303-10.

Waxman DJ. Steroid Hormones and other Physiologic Regulators of Liver Cytochromes P450: Metabolic Reactions and Regulatory Pathways. Advances in Molecular and Cell Biology, 1996;14:341-74.

WHO Traditional Medicine Strategy 2002–2005.

Yang CS, Chhabra SK, Hong JY et al. Mechanisms of Inhibition of Chemical Toxicity and Carcinogenesis by Diallyl sulfide (DAS) and related compounds from Garlic. J Nutr, 2001;131(3s):1041S-5S.

Yin O Q, Tomlinson B, Chow MS. Prediction and mechanism of herb-drug interaction: effect of gingko biloba on omega zole in Chinese subjects. Paper presented at the annual meeting of the American Society of Clinical Pharmacology, Washington, DC, 2003. Abstract in Clin Pharmacol Ther, 2003; P94.

Yue QY, Bergquist C, Gerden B. Safety of St John's wort (Hypericum perforatum). Lancet, 2000;355:576.

Murakami Y, Tanaka T, Murakami H et al. Pharmacokinetic modelling of the interaction between St. John’s wort and ciclosporin A. Br J Clin Pharmacol, 2006;61(6):671–76.

Zhou S, Gao Y, Jiang W et al. Interactions of herbs with cytochrome P450. Drug Metab Rev, 2003;35(1):35-98.

Zhou S, Chan E, Pan SQ, Huang M, Lee EJ. Pharmacokinetic interactions of drugs with St John's wort. J Psychopharmacol, 2004;18(2):262-76. Review.

Zou L, Harkey MR, Henderson GL. Effects of herbal components on cDNA-expressed cytochrome P450 enzyme catalytic activity. Life Sci, 2002;71:1579-89.



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