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Drug-herb interactions: Mechanisms involved and clinical implications of five commonly and traditionally used herbs
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  • Journal title : TANG [HUMANITAS MEDICINE]
  • Volume 4, Issue 3,  2014, pp.17.1-17.8
  • Publisher : Association of Humanitas Medicine
  • DOI : 10.5667/tang.2014.0008
 Title & Authors
Drug-herb interactions: Mechanisms involved and clinical implications of five commonly and traditionally used herbs
Ong, Chin Eng; Pan, Yan;
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Herbal remedies are commonly used by patients worldwide. Because these herbal preparations share the same metabolic and transport proteins with prescribed medicines, the potential for a drug-herb interaction is substantial and is an issue of significant concern. This review paper summarizes drug-herb interactions involving inhibition or induction of cytochrome P450 enzymes, drug transporters as well as modulation of drug pharmacodynamics. An increasing number of in vitro and animal studies, case reports and clinical trials evaluating such interactions have been reported, and implications of these studies are discussed in this review. The most commonly implicated drugs in the interaction include anticoagulants, antiplatelets, immunosuppressants, anti-neoplastics, protease inhibitors, and some antidepressants. Pharmacokinetic and/or pharmacodynamic interactions of five commonly used herbal remedies (danshen, garlic, Ginkgo biloba, ginseng, and St John`s wort) with these drugs are presented, with focus of discussion being the potentials for interaction, their mechanisms and clinical implications. There is a necessity for adequate pharmacovigilance to be carried out in minimizing unanticipated but often preventable drug-herb interactions.
cytochrome P450;drug-herb interaction;P-glycoprotein;pharmacodynamics;pharmacokinetics;
 Cited by
Aruna D, Maidu MU. Pharmacodynamic interaction studies of Ginkgo biloba with cilostazol and clopidogrel in healthy human subjects. Br J Clin Pharmacol. 2006;63:333-338.

Attele AS, Wu JA, Yuan CS. Ginseng pharmacology: multiple constituents and multiple actions. Biochem Pharmacol. 1999;58:1685-1693. crossref(new window)

Bauer S, Stormer E, Johne A, Kruger H, Budde K, Neumayer HH, Roots I, Mai I. Alterations in cyclosporinA pharmacokinetics and metabolism during treatment with St John's wort in renal transplant patients. Br J Clin Pharmacol. 2003;55:203-211. crossref(new window)

Becker BN, Greene J, Evanson J, Chidsey G, Stone WJ. Ginseng-induced diuretic resistance. JAMA. 1996;276:606-607.

Beckert BW, Concannon MJ, Henry SL, Smith DS, Puckett CL. The effect of herbal medicines on platelet function: an in vivo experiment and review of the literature. Plast Reconstr Surg. 2007;120:2044-2050. crossref(new window)

Black DJ, Kunze KL, Wienkers LC, Gidal BE, Seaton TL, McDonnell ND, Evans JS, Bauwens JE, TragerWF. Warfarinfluconazole. II. A metabolically based drug interaction: in vivo studies. Drug Metab Dispos.1996;24:422-428.

Block E. The chemistry of garlic and onions. Sci Am. 1985;252:114-119.

Bone KM. Potential interaction of Ginkgo biloba leaf with antiplatelet or anticoagulant drugs: what is the evidence? Mol Nutr Food Res. 2008;52:764-771. crossref(new window)

Bonetto N, Santelli L, Battistin L, Cagnin A. Serotonin syndrome and rhabdomyolysis induced by concomitant use of triptans, fluoxetine and Hypericum. Cephalalgia. 2007;27:1421-1423. crossref(new window)

Borrelli F, Capasso R, Izzo AA. Garlic (Allium sativum L.): adverse effects and drug interactions in humans. Mol Nutr Food Res. 2007;51:1386-1397. crossref(new window)

Boruban MC, Yasar U, Babaoglu MO, Sencan O, Bozkurt A. Tamoxifen inhibits cytochrome P450 2C9 activity in breastcancer patients. J Chemother. 2006;18:421-424. crossref(new window)

Butterweck V, Schmidt M. St John's wort: role of active compounds for its mechanism of action and efficacy. Wien Med Wochenschr. 2007;157:356-361. crossref(new window)

Chan K, Lo AC, Yeung JH, Woo KS. The effects of Danshen (Salvia miltiorrhiza) on warfarin pharmacodynamics and pharmacokinetics of warfarin enantiomers in rats. J Pharm Pharmacol. 1995;47:402-406. crossref(new window)

Chang TK, Chen J, Benetton SA. In vitro effect of standardized ginseng extracts and individual ginsenosides on the catalytic activity of human CYP1A1, CYP1A2, and CYP1B1. Drug Metab Dispos. 2002;30:378-384. crossref(new window)

Cheng TO. Cardiovascular effects of Danshen. Int J Cardiol. 2007;121:9-22. crossref(new window)

Cox MC, Low J, Lee J, Walshe J, Denduluri N, Berman A, Permenter MG, Petros WP, Price DK, Figg WD, Sparreboom A, Swain SM. Influence of garlic (Allium sativum) on the pharmacokinetics of docetaxel. Clin Cancer Res. 2006;12:4636-4640. crossref(new window)

Dannawi M. Possible serotonin syndrome after combination of buspirone and St John's wort. J Psychopharmacol. 2002;16:401.

DeFeudis FV, Drieu K. Ginkgo biloba extract (EGb 761) and CNS functions: basic studies and clinical applications. Curr Drug Targets. 2000;1:25-58. crossref(new window)

deMaat MM, Hoetelmans RM, Math t RA, van Gorp EC, Meenhorst PL, Mulder JW, Beijnen JH. Drug interaction between St John's wort and nevirapine. AIDS. 2001;15:420-421. crossref(new window)

Deng JF. Clinical and laboratory investigations in herbal poisonings. Toxicology. 2002;181-182:571-576. crossref(new window)

Dresser GK, Spence JD, Bailey DG. Pharmacokineticpharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin Pharmacokinet. 2000;38:41-57. crossref(new window)

Foster BC, Vandenhoek S, Tang R, Budzinski JW, Krantis A, Li KY. Effect of several Chinese natural health products of human cytochrome P450 metabolism. J Pharm Pharm Sci. 2002;5:185-189.

Gallicano K, Foster B, Choudhri S. Effect of short-term administration of garlic supplements on single-dose ritonavir pharmacokinetics in healthy volunteers. Br J Clin Pharmacol. 2003;55:199-202. crossref(new window)

Gao S, Liu Z, Li H, Little PJ, Liu P, Xu S. Cardiovascular actions and therapeutic potential of tanshinone IIA. Atherosclerosis. 2012;220:3-10. crossref(new window)

Greenblatt DJ, von Moltke LL, Luo Y, Perloff ES, Horan KA, Bruce A, Reynolds RC, Harmatz JS, Avula B, Khan IA, Goldman P. Ginkgo biloba does not alter clearance of flurbiprofen, a cytochrome P450-2C9 substrate. J Clin Pharmacol. 2006;46:214-221. crossref(new window)

Gurley BJ, Gardner SF, Hubbard MA, Williams DK, Gentry WB, Cui Y, Ang CY. Cytochrome P450 phenotypic ratios for predicting herb-drug interactions in humans. Clin Pharmacol Ther. 2002;72:276-287. crossref(new window)

Gurley BJ, Gardner SF, Hubbard MA, Williams DK, Gentry WB, Cui Y, Ang CY. 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;22:525-539. crossref(new window)

Hafner V, Jager M, Matthee AK, Ding R, Burhenne J, Haefeli WE, Mikus G. Effect of simultaneous induction andinhibition of CYP3A by St John's wort and ritonavir on CYP3A activity. Clin Pharmacol Ther. 2010;87:191-196. crossref(new window)

He N, Xie HG, Collins X, Edeki T, Yan Z. Effects of individual ginsenosides, ginkgolides and flavonoids on CYP2C19 and CYP2D6 activity in human liver microsomes. Clin Exp Pharmacol Physiol. 2006;33:813-815. crossref(new window)

Hebert MF, Park JM, Chen YL, Akhtar S, Larson AM. Effects of St. John's wort (Hypericum perforatum) on tacrolimus pharmacokinetics in healthy volunteers. J Clin Pharmacol. 2004;44:89-94. crossref(new window)

Izzat MB, Yim AP, El-Zufari MH. A taste of Chinese medicine!. Ann Thorac Surg. 1998;66:941-942. crossref(new window)

Izzo AA, Borrelli F, Capasso R. Herbal medicine: the dangers of drug interaction. Trends Pharmacol Sci. 2002;23:358-391. crossref(new window)

Janetzky K, Morreale AP. Probable interaction between warfarin and ginseng. Am J Heath Syst Pharm. 1997;54:692-693.

Kauffman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA. Recent patterns of medication use in the ambulatory adult population of the United States. JAMA. 2002;287:337-344. crossref(new window)

Klotz U. Pharmacokinetics and drug metabolism in the elderly. Drug Metab Rev. 2009;41:67-76. crossref(new window)

Kremers P. In vitro tests for predicting drug-drug interactions: the need for validated procedures. Pharmacol Toxicol. 2002;91:209-217. crossref(new window)

Kuo SC, Teng CM, Leed JC, Ko FN, Chen SC, Wu TS. Antiplatelet components in Panax ginseng. Planta Med. 1990;56:164-167. crossref(new window)

Kuo YH, Lin YL, Don MJ, Chen RM, Ueng YF. Induction of cytochrome P450-dependent monooxygenase by extracts of the medicinal herb Salvia miltiorrhiza. J Pharm Pharmacol. 2006;58:521-527. crossref(new window)

Lam FF, Yeung JH, Cheung JH, Or PM. Pharmacological evidence for calcium channel inhibition by Danshen (Salvia miltiorrhiza) on rat isolated femoral artery. J Cardiovasc Pharmacol. 2006;47:139-145. crossref(new window)

Lei HP, Ji W, Lin J, Chen H, Tan ZR, Hu DL, Liu LJ, Zhou HH. Effects of Ginkgo biloba extract on the pharmacokinetics of bupropion in healthy volunteers. Br J Clin Pharmacol. 2009;68:201-206. crossref(new window)

Linde K, Berner MM, Kriston L. St. John's wort for major depression. Cochrane Database Syst Rev. 2008;CD000448.

Lo AC, Chan K, Yeung JH, Woo KS. The effects of Danshen (Salvia miltiorrhiza) on pharmacokinetics and pharmacodynamics of warfarin in rats. Eur J Drug Metab Pharmacokinet. 1992;17:257-262. crossref(new window)

Mai I, Bauer S, Perloff ES, Johne A, Uehleke B, Frank B, Budde K, Roots I. Hyperforin content determines the magnitude of the St John's wort-cyclosporine drug interaction. Clin Pharmacol Ther. 2004;76:330-340. crossref(new window)

Mai I, Stormer E, Bauer S, Kruger H, Budde K, Roots I. Impact of St John's wort treatment on the pharmacokinetics of tacrolimus and mycophenolic acid in renal transplant patients. Nephrol Dial Transplant. 2003;18:819-822. crossref(new window)

Markowitz JS, Donovan JL, Lindsay DeVane C, Sipkes L, Chavin KD. Multiple-dose administration of Ginkgo biloba did not affect cytochrome P-450 2D6 or 3A4 activity in normal volunteers. J Clin Psychopharmacol. 2003;23:576-581. crossref(new window)

Mathhews MK Jr. Association of ginkgo biloba with intracerebral haemorrhage. Neurology. 1998;50:1933-1934. crossref(new window)

Mohutsky MA, Anderson GD, Miller JW, Elmer GW. Ginkgo biloba: evaluation of CYP2C9 drug interactions in vitro and in vivo. Am J Ther. 2006;13:24-31. crossref(new window)

Morris J, Burke V, Mori TA, Vandongen R, Beilin LJ. Effects of garlic extract on platelet aggregation: a randomized placebo-controlled double-blind study. Clin Exp Pharmacol Physiol. 1995;22:414-417. crossref(new window)

Mullins ME, Horowitz BZ, Linden DH, Smith GW, Norton RL, Stump J. Life-threatening interaction of mibefradil and b-blockers with dihydropyridine calcium channel blockers. JAMA. 1998;280:157-158. crossref(new window)

Palmer ME, Haller C, McKinney PE, Klein-Schwartz W, Tschirgi A, Smolinske SC, Woolf A, Sprague BM, Ko R, Everson G, Nelson LS, Dodd-Butera T, Bartlett WD, Landzberg BR. Adverse events associated with dietary supplements: an observational study. Lancet. 2003;361:101-106. crossref(new window)

Pathak A, Leger P, Bagheri H, Senard JM, Boccalon H, Montastruc JL. Garlic interaction with fluindione: a case report. Therapie. 2003;58:380-381. crossref(new window)

Piscitelli SC, Burstein AH, Chaitt D, Alfaro RM, Falloon J. Indinavir concentrations and St John's wort. Lancet. 2000;355:547-548. crossref(new window)

Piscitelli SC, Burstein AH, Welden N, Gallicano KD, Falloon J. The effect of garlic supplements on the pharmacokinetics of saquinavir. Clin Infect Dis. 2002;34:234-238. crossref(new window)

Qi LW, Wang CZ, Yuan CS. Isolation and analysis of ginseng: advances and challenges. Nat Prod Rep. 2011;28:467-495. crossref(new window)

Qiu F, Wang G, Zhao Y, Sun H, Mao G, A J, Sun J. Effect of danshen extract on pharmacokinetics of theophylline in healthy volunteers. Br J Clin Pharmacol. 2008;65:270-274. crossref(new window)

Robertson SM, Davey RT, Voell J, Formentini E, Alfaro RM, Penzak SR. Effect of Ginkgo biloba extract on lopinavir, midazolam and fexofenadine pharmacokinetics in healthy subjects. Curr Med Res Opin. 2008;24:591-599. crossref(new window)

Rosado MF. Thrombosis of a prosthetic aortic valve disclosing a hazardous interaction between warfarin and a commercial ginseng product. Cardiology. 2003;99:111. crossref(new window)

Rossenblatt M, Mindel J. Spontaneous hyphema associated with ingestion of Ginkgo biloba extract. N Engl J Med. 1997;336:1108.

Shi S, Klotz U. Drug interactions with herbal medicines. Clin Pharmacokinet. 2012;51:77-104. crossref(new window)

Singh YP, Singh RA. In silico studies of organosulfurfunctional active compounds in garlic. Biofactors. 2010;36:297-311. crossref(new window)

Smith M, Lin KM, Zheng YP. An open trial of nifedipine-herb interactions: nifedipine with St John's wort, ginseng or ginkgo biloba. Clin Pharmacol Ther. 2001;69:P89. crossref(new window)

Solecki RS, Shanidar IV.A Neanderthal flower burial in northern Iraq. Science. 1975;190:880-881. crossref(new window)

Solomon D, Ford E, Adams J, Graves N. Potential of St John's wort for the treatment of depression: the economic perspective. Aust N Z J Psychiatry. 2011;45:123-130. crossref(new window)

Vaes LP, Chyka PA. Interactions of warfarin with garlic, ginger, ginkgo, or ginseng: nature of the evidence. Ann Pharmacother. 2000;34:1478-1482. crossref(new window)

Ueng YF, Kuo YH, Wang SY, Lin YL, Chen CF. Induction of CYP1A by a diterpene quinine tanshinone IIA isolated from a medicinal herb Salvia miltiorrhiza in C57BL/6J but not in DBA/2J mice. Life Sci. 2004;74:885-896. crossref(new window)

van Beek TA, Montoro P. Chemical analysis and quality control of Ginkgo biloba leaves, extracts, and phytopharmaceuticals. J Chromatogr A. 2009;1216:2002-2032. crossref(new window)

Vlachojannis J, Cameron M, Chrubasik S. Drug interactions with St John's wort products. Pharmacol Res. 2011;63:254-256. crossref(new window)

Weinmann S, Roll S, Schwarzbach C, Vauth C, Willich SN. Effects of Ginkgo biloba in dementia: systematic review and meta-analysis. BMC Geriatr. 2010;10:14. crossref(new window)

Yin OQ, Tomlinson B, Waye MM, Chow AH, Chow MS. Pharmacogenetics and herb-drug interactions: experience with Ginkgo biloba and omeprazole. Pharmacogenetics. 2004;14:841-850. crossref(new window)

Yoshioka M, Ohnishi N, Koishi T, Obata Y, Nakagawa M, Matsumoto T, Tagagi K, Takara K, Ohkuni T, Yokoyama T, Kuroda K. Studies on interactions between functional foods or dietary supplements and medicines: IV. Effects of Ginkgo biloba leaf extract on the pharmacokinetics and pharmacodynamics of nifedipine in healthy volunteers. Biol Pharm Bull. 2004;27:2006-2009. crossref(new window)

Yu CM, Chan JC, Sanderson JE. Chinese herbs and warfarin potentiation by 'danshen'. J Intern Med. 1997;241:337-339. crossref(new window)

Yu CT, Chen J, Teng XW, Tong V, Chang TK. Lack of evidence for induction of CYP2B1, CYP3A23, and CYP1A2 gene expression by Panax ginseng and Panax quinquefolius extracts in adult rats and primary cultures of rat hepatocytes. Drug Metab Dispos. 2005;33:19-22.

Zhou S, Koh HL, Gao Y, Gong ZY, Lee EJ. Herbal bioactivation: the good, the bad and the ugly. Life Sci. 2004;74:935-968. crossref(new window)