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Download PDFPlanta Med 2012; 78(13): 1458-1477
DOI: 10.1055/s-0032-1315117
DOI: 10.1055/s-0032-1315117
Mechanism of Herb-Drug Interactions
Reviews
Clinical Evidence of Herbal Drugs As Perpetrators of Pharmacokinetic Drug Interactions
Authors
Robert Hermann
1 Clinical Research Appliance, Radolfzell, GermanyOliver von Richter
2 Merck Serono, Darmstadt, Germany
Further Information
Publication History
received28 February 2012
revised22 June 2012
accepted02 July 2012
Publication Date:
01 August 2012 (online)
Abstract
The use of herbal/botanical products, also referred to as complementary and alternative medicines (CAM), worldwide enjoys increasing popularity. It appears in particular highly prevalent in patient populations already exposed to complex treatment algorithms and polypharmacotherapy, frequently involving narrow therapeutic index drugs. Accordingly, the potential clinical dimension and relevance of herb-drug interactions has received considerable attention over the last years. However, review of pertinent literature indicates that the available clinical evidence in this regard is still limited and sometimes inconclusive. Also, communication of herb-drug interaction data in the biopharmaceutical/medical literature is often complex and confusing, not always unbiased, and in many cases appears not to strive for clear-cut and useful guidance in terms of the clinical relevance of such findings.
This systematic review summarizes and interprets the published evidence on clinical herb-drug interaction studies which examined the potential of six popular herbal drugs (Echinacea, garlic, gingko, ginseng, goldenseal, and milk thistle) as perpetrators of pharmacokinetic (PK) drug interactions. Reported effect sizes were systematically categorized according to FDA drug interaction guideline criteria. A total of 66 clinical PK interaction studies, meeting the scope of the present review, were identified. The clinical evidence was found to be most robust and informative forGingko biloba (GB; 21 studies) and milk thistle/silymarin (MT; 13), and appears still limited for ginseng (9), goldenseal/berberine (GS; 8), garlic (8), andEchinacea (7). Collectively, the available evidence indicates that, at commonly recommended doses, none of these herbs act as potent or moderate inhibitors or inducers of cytochrome P450 (CYP) enzymes or P-glycoprotein (ABCB1). Weak effects in terms of either induction or inhibition were found for GB (presystemic/hepatic CYP3A4 induction/inhibition, CYP2C19 induction at high doses), milk thistle/silymarin (CYP2C9 inhibition), GS/berberine (CYP3A4 and CYP2D6 inhibition),Echinacea (presystemic/hepatic CYP3A4 inhibition/induction, CYP1A2 and CYP2C9 inhibition at high doses). Information was found not always complete for the major drug metabolizing CYP enzymes in the less well-studied herbs and is largely limited to P-glycoprotein (ABCB1) when effects on drug transporters have been investigated.
References
- 1 Bent S, Ko R. Commonly used herbal medicines in the United States: a review. Am J Med 2004; 116: 478-485
- 2 Tindle HA, Davis RB, Phillips RS, Eisenberg DM. Trends in use of complementary and alternative medicine by US adults: 1997–2002. Altern Ther Health Med 2005; 11: 42-49
- 3 Singh SR, Levine MAH. Natural health product use in Canada: analysis of the National Population Health Survey. Can J Clin Pharmacol 2006; 13: e240-e250
- 4 Singh SR, Levine MAH. Potential interactions between pharmaceuticals and natural health products in Canada. J Clin Pharmacol 2007; 47: 249-258
- 5 Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell A. Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA 2002; 287: 337-344
- 6 European medicines Agency (EMA). Guideline on the Investigation of Drug Interactions. CPMP/EWP/560/95/Rev. 1 – Corr.; 22 April 2010. Available athttp://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/05/WC500090112.pdf Accessed June 06, 2012
- 7 Chatterjee P, Franklin MR. Human cytochrome P450 inhibition and metabolic-intermediate complex formation by goldenseal extract and its methylendioxyphenyl components. Drug Metab Dispos 2003; 31: 1391-1397
- 8 Gurley BJ, Gardner SF, Hubbard MA, Williams DK, Gentry WB, Khan IA, Shah A.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: 415-426
- 9 Gurley BJ, Swain A, Hubbard MA, Hartsfield F, Thaden J, Williams DK, Gentry WB, Tony Y. Supplementation with goldenseal (Hydrastis canadensis), but not kava kava (Piper methysticum), inhibits human CYP3A activityin vivo . Clin Pharmacol Ther 2008; 83: 61-69
- 10 Guo Y, Chen Y, Tan ZR, Klaassen CD, Zhou HH. Repeated administration of berberine inhibits cytochromes P450 in humans. Eur J Clin Pharmacol 2012; 68: 213-217
- 11 Izzo AA, Ernst E. Interactions between herbal medicines and prescribed drugs: an updated systematic review. Drugs 2009; 69: 1777-1798
- 12 Johne A, Roots I. Clinical drug interactions with medicinal herbs. Evid Based Integr Med 2005; 2: 207-228
- 13 Ulbricht C, Chao W, Costa D, Rusie-Seamon E, Weissner W, Woods J. Clinical evidence of herb-drug interactions: a systematic review by the natural standard research collaboration. Curr Drug Metab 2008; 9: 1063-1120
- 14 University of Washington. Metabolism & Transport Drug Interaction Database (DIDB). Available athttp://www.druginteractioninfo.org/ Accessed June 06, 2012
- 15 DeFeudis FV, Drieu K.Ginkgo biloba extract (EGb 761) and CNS functions: basic studies and clinical applications. Curr Drug Targets 2000; 1: 25-58
- 16 Kressmann S, Müller WE, Blume HH. Pharmaceutical quality of differentGinkgo biloba brands. J Pharm Pharmacol 2002; 54: 661-669
- 17 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
- 18 Gurley B, Gardner S, Hubbard M. Clinical assessment of botanical supplementation on cytochrome P450 phenotypes in the elderly: St. Johnʼs wort, garlic oil,Panax ginseng, andGinkgo biloba . Drugs Aging 2005; 22: 525-539
- 19 Markowitz JS, Donovan JL, Lindsay DeVane C, Sipkes L, Chavin KD. Multiple-dose administration ofGinkgo biloba did not affect cytochrome P-450 2D6 or 3A4 activity in normal volunteers. J Clin Psychopharmacol 2003; 23: 576-581
- 20 Yasui-Furukori N, Furukori H, Kaneda A, Kaneko S, Tateishi T. The effects ofGinkgo biloba extracts on the pharmacokinetics and pharmacodynamics of donepezil. J Clin Pharmacol 2004; 44: 538-542
- 21 Robertson SM, Davey RT, Voel J, Formentini E, Alfaro RM, Penzak SR. Effect ofGinkgo biloba extract on lopinavir, midazolam and fexofenadine pharmacokinetics in healthy subjects. Curr Med Res Opin 2008; 24: 591-599
- 22 Niemi M, Kivistö KT, Hofmann U, Schwab M, Eichelbaum M, Fromm MF. Fexofenadine pharmacokinetics are associated with a polymorphism of the SLCO1B1 gene (encoding OATP1B1). Br J Clin Pharmacol 2005; 59: 602-604
- 23 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 ofGinkgo biloba leaf extract on the pharmacokinetics and pharmacodynamics of nifedipine in healthy volunteers. Biol Pharm Bull 2004; 27: 2006-2009
- 24 Uchida S, Yamada H, Li XD, Maruyama S, Ohmori Y, Oki T, Watanabe H, Umegaki K, Ohashi K, Yamada S. Effects ofGinkgo biloba extract on pharmacokinetics and pharmacodynamics of tolbutamide and midazolam in healthy volunteers. J Clin Pharmacol 2006; 46: 1290-1298
- 25 Zuo XC, Zhang BK, Jia SJ, Liu SK, Zhou LY, Li J, Zhang J, Dai LL, Chen BM, Yang GP, Yuan H. Effects ofGinkgo biloba extracts on diazepam metabolism: a pharmacokinetic study in healthy Chinese male subjects. Eur J Clin Pharmacol 2010; 66: 503-509
- 26 Jiang X, Williams KM, Liauw WS, Ammit AJ, Roufogalis BD, Duke CC, Day RO, McLachlan AJ. Effect of ginkgo and ginger on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. Br J Clin Pharmacol 2005; 59: 425-432
- 27 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
- 28 Mohutsky MA, Anderson GD, Miller JW, Elmer GW.Ginkgo biloba: evaluation of CYP2C9 drug interactionsin vitro andin vivo . Am J Ther 2006; 13: 24-31
- 29 Yin OQP, Tomlinson B, Waye MMY, Chow AHL, Chow MSS. Pharmacogenetics and herb-drug interactions: experience withGinkgo biloba and omeprazole. Pharmacogenetics 2004; 14: 841-850
- 30 Lei HP, Wang G, Wang LS, Ou-yang DS, Chen H, Li Q, Zhang W, Tan ZR, Fan L, He YJ, Zhou HH. Lack of effect ofGinkgo biloba on voriconazole pharmacokinetics in Chinese volunteers identified as CYP2C19 poor and extensive metabolizers. Ann Pharmacother 2009; 43: 726-731
- 31 Lei HP, Ji W, Lin J, Chen H, Tan ZR, Hu DL, Liu LJ, Zhou HH. Effects ofGinkgo biloba extract on the pharmacokinetics of bupropion in healthy volunteers. Br J Clin Pharmacol 2009; 68: 201-206
- 32 Mauro VF, Mauro LS, Kleshinski JF, Khuder SA, Wang Y, Erhardt PW. Impact ofGinkgo biloba on the pharmacokinetics of digoxin. Am J Ther 2003; 10: 247-251
- 33 Fan L, Tao GY, Wang G, Chen Y, Zhang W, He YJ, Li Q, Lei HP, Jiang F, Hu DL, Huang YF, Zhou HH. Effects ofGinkgo biloba extract ingestion on the pharmacokinetics of talinolol in healthy Chinese volunteers. Ann Pharmacother 2009; 43: 944-949
- 34 Fan L, Mao XQ, Tao GY, Wang G, Jiang F, Chen Y, Li Q, Zhang W, Lei HP, Hu DL, Huang YF, Wang D, Zhou HH. Effect ofSchisandra chinensis extract andGinkgo biloba extract on the pharmacokinetics of talinolol in healthy volunteers. Xenobiotica 2009; 39: 249-254
- 35 Kudolo GB, Wang W, Javors M, Blodgett J. The effect of the ingestion ofGinkgo biloba extract (EGb 761) on the pharmacokinetics of metformin in non-diabetic and type 2 diabetic subjects–a double blind placebo-controlled, crossover study. Clin Nutr 2006; 25: 606-616
- 36 Zhou M, Xia L, Wang J. Metformin transport by a newly cloned proton-stimulated organic cation transporter (plasma membrane monoamine transporter) expressed in human intestine. Drug Metab Dispos 2007; 35: 1956-1962
- 37 Tzvetkov MV, Saadatmand AR, Lötsch J, Tegeder I, Stingl JC, Brockmöller J. The effects of genetic polymorphisms in the organic cation transporters OCT1, OCT2, and OCT3 on the renal clearance of metformin. Clin Pharmacol Ther 2009; 86: 299-306
- 38 Lu WJ, Huang JD, Lai ML. The effects of ergoloid mesylates andGinkgo biloba on the pharmacokinetics of ticlopidine. J Clin Pharmacol 2006; 46: 628-634
- 39 Kim BH, Kim KP, Lim KS, Kim JR, Yoon SH, Cho JY, Lee YO, Lee KH, Jang IJ, Shin SG, Yu KS. Influence ofGinkgo biloba extract on the pharmacodynamic effects and pharmacokinetic properties of ticlopidine: an open-label, randomized, two-period, two-treatment, two-sequence, single-dose crossover study in healthy Korean male volunteers. Clin Ther 2010; 32: 380-390
- 40 Zadoyan G, Rokitta D, Klement S, Dienel A, Hoerr R, Gramatté T, Fuhr U. Effect ofGinkgo biloba special extract EGb 761® on human cytochrome P450 activity: a cocktail interaction study in healthy volunteers. Eur J Clin Pharmacol 2012; 68: 553-560
- 41 Niemi M, Kivistö KT, Hofmann U, Schwab M, Eichelbaum M, Fromm MF. Fexofenadine pharmacokinetics are associated with a polymorphism of the SLCO1B1 gene (encoding OATP1B1). Br J Clin Pharmacol 2005; 59: 602-604
- 42 Abenavoli L, Aviello G, Capasso R, Milic N, Capasso F. Milk thistle for treatment of nonalcoholic fatty liver disease. Hepat Mon 2011; 11: 173
- 43 Pradhan SC, Girish C. Hepatoprotective herbal drug, silymarin from experimental pharmacology to clinical medicine. Indian J Med Res 2006; 124: 491-504
- 44 Brantley SJ, Oberlies NH, Kroll DJ, Paine MF. Two flavonolignans from milk thistle (Silybum marianum) inhibit CYP2C9-mediated warfarin metabolism at clinically achievable concentrations. J Pharmacol Exp Ther 2010; 332: 1081-1087
- 45 Etheridge AS, Black SR, Patel PR, So J, Mathews JM. Anin vitro evaluation of cytochrome P450 inhibition and P-glycoprotein interaction with goldenseal,Ginkgo biloba, grape seed, milk thistle, and ginseng extracts and their constituents. Planta Med 2007; 73: 731-741
- 46 Sridar C, Goosen T, Kent U, Williams J. Silybin inactivates cytochromes P450 3A4 and 2C9 and inhibits major hepatic glucuronosyltransferases. Drug Metab Dispos 2004; 32: 587-594
- 47 Venkataramanan R, Ramachandran V, Komoroski BJ, Zhang S, Schiff PL, Strom SC. Milk thistle, a herbal supplement, decreases the activity of CYP3A4 and uridine diphosphoglucuronosyl transferase in human hepatocyte cultures. Drug Metab Dispos 2000; 28: 1270-1273
- 48 Budzinski JW, Trudeau VL, Drouin CE, Panahi M, Arnason JT, Foster BC. Modulation of human cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) in Caco-2 cell monolayers by selected commercial-source milk thistle and goldenseal products. Can J Physiol Pharmacol 2007; 85: 966-978
- 49 Leber HW, Knauff S. Influence of silymarin on drug metabolizing enzymes in rat and man. Arzneimittelforschung 1976; 26: 1603-1605
- 50 Gurley BJ, Gardner SF, Hubbard MA, Williams DK, Gentry WB, Carrier J, Khan IA, Edwards DJ, Shah A.In vivo assessment of botanical supplementation on human cytochrome P450 phenotypes:Citrus aurantium, Echinacea purpurea, milk thistle, and saw palmetto. Clin Pharmacol Ther 2004; 76: 428-440
- 51 Gurley B, Hubbard MA, Williams DK, Thaden J, Tong Y, Gentry WB, Breen P, Carrier DJ, Cheboyina S. Assessing the clinical significance of botanical supplementation on human cytochrome P450 3A activity: comparison of a milk thistle and black cohosh product to rifampin and clarithromycin. J Clin Pharmacol 2006; 46: 201-213
- 52 Fuhr U, Beckmann-Knopp S, Jetter A, Lück H, Mengs U. The effect of silymarin on oral nifedipine pharmacokinetics. Planta Med 2007; 73: 1429-1435
- 53 Gurley BJ, Swain A, Hubbard MA, Williams DK, Barone G, Hartsfield F, Tong Y, Carrier DJ, Cheboyina S, Battu SK. Clinical assessment of CYP2D6-mediated herb–drug interactions in humans: effects of milk thistle, black cohosh, goldenseal, kava kava, St. Johnʼs wort, and Echinacea. Mol Nutr Food Res 2008; 52: 755-763
- 54 DiCenzo R, Shelton M, Jordan K, Koval C, Forrest A, Reichman R, Morse G. Coadministration of milk thistle and indinavir in healthy subjects. Pharmacotherapy 2003; 23: 866-870
- 55 Piscitelli S, Formentini E. Effect of milk thistle on the pharmacokinetics of indinavir in healthy volunteers. Pharmacotherapy 2002; 22: 551-556
- 56 Rao BN, Srinivas M, Kumar YS, Rao YM. Effect of silymarin on the oral bioavailability of ranitidine in healthy human volunteers. Drug Metab Drug Interact 2007; 22: 175-185
- 57 van Erp NP, Baker SD, Zhao M, Rudek MA, Guchelaar HJ, Nortier JW, Sparreboom A, Gelderblom H. Effect of milk thistle (Silybum marianum) on the pharmacokinetics of irinotecan. Clin Cancer Res 2005; 11: 7800-7806
- 58 Rajnarayana K, Reddy MS, Vidyasagar J, Krishna DR. Study on the influence of silymarin pretreatment on metabolism and disposition of metronidazole. Arzneimittelforschung 2004; 54: 109-113
- 59 Han Y, Guo D, Chen YY, Tan ZR, Zhou HH. Effect of silymarin on the pharmacokinetics of losartan and its active metabolite E-3174 in healthy Chinese volunteers. Eur J Clin Pharmacol 2009; 65: 585-591
- 60 Gurley BJ, Barone GW, Williams DK, Carrier J, Breen P, Yates CR, Song PF, Hubbard MA, Tong Y, Cheboyina S. Effect of milk thistle (Silybum marianum) and black cohosh (Cimicifuga racemosa) supplementation on digoxin pharmacokinetics in humans. Drug Metab Disp 2006; 34: 69-74
- 61 Han Y, Guo D, Chen Y, Tan ZR, Zhou HH. Effect of continuous silymarin administration on oral talinolol pharmacokinetics in healthy volunteers. Xenobiotica 2009; 39: 694-699
- 62 Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmöller J, Johne A, Cascorbi I, Gerloff T, Roots I, Eichelbaum M, Brinkmann U. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activityin vivo . Proc Natl Acad Sci USA 2000; 97: 3473-3478
- 63 Shirasaka Y, Li Y, Shibue Y, Kuraoka E, Spahn-Langguth H, Kato Y, Langguth P, Tamai I. Concentration-dependent effect of naringin on intestinal absorption of beta(1)-adrenoceptor antagonist talinolol mediated by p-glycoprotein and organic anion transporting polypeptide (Oatp). Pharm Res 2009; 26: 560-567
- 64 Deng JW, Shon JH, Shin HJ, Park SJ, Yeo CW, Zhou HH, Song IS, Shin JG. Effect of silymarin supplement on the pharmacokinetics of rosuvastatin. Pharm Res 2008; 25: 1807-1814
- 65 Niemi M. Transporter pharmacogenetics and statin toxicity. Clin Pharmacol Ther 2010; 87: 130-133
- 66 Barnes PM, Bloom B, Nahin RL. Complementary and alternative medicine use among adults and children: United States, 2007. Natl Health Stat Rep 2008; 12: 1-23
- 67 Helms S. Cancer prevention and therapeutics:Panax ginseng . Alternat Med Rev 2004; 9: 259-274
- 68 Attele AS, Wu JA, Yuan CS. Ginseng pharmacology: multiple constituents and multiple actions. Biochem Pharmacol 1999; 58: 1685-1693
- 69 An G, Morris ME. Herbal supplement-based interactions. In: Pang KS, Rodrigues AD, Peter RM, editors Enzyme- and transporter-based drug-drug interactions. New York: Springer; 2010: 555-584
- 70 Anderson GD, Rosito G, Mohustsy MA, Elmer GW. Drug interaction potential of soy extract andPanax ginseng . J Clin Pharmacol 2003; 43: 643-648
- 71 Donovan JL, DeVane CL, Chavin KD, Taylor RM, Markowitz JS. Siberian ginseng (Eleutheroccus senticosus) effects on CYP2D6 and CYP3A4 activity in normal volunteers. Drug Metab Dispos 2003; 31: 519-522
- 72 Andrade AS, Hendrix C, Parsons TL, Caballero B, Yuan CS, Flexner CW, Dobs AS, Brown TT. Pharmacokinetic and metabolic effects of American ginseng (Panax quinquefolius) in healthy volunteers receiving the HIV protease inhibitor indinavir. BMC Complement Alternat Med 2008; 8: 50
- 73 Lee LS, Wise SD, Chan C, Parsons TL, Flexner C, Lietman PS. Possible differential induction of phase 2 enzyme and antioxidant pathways by American ginseng,Panax quinquefolius . J Clin Pharmacol 2008; 48: 599-609
- 74 Jiang X, Blair EYL, McLachlan AJ. Investigation of the effects of herbal medicines on warfarin response in healthy subjects: a population pharmacokinetic-pharmacodynamic modeling approach. J Clin Pharmacol 2006; 46: 1370-1378
- 75 Jiang X, Williams KM, Liauw WS, Ammit AJ, Roufogalis BD, Duke CC, Day RO, McLachlan AJ. Effect of St Johnʼs wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. Br J Clin Pharmacol 2004; 57: 592-599
- 76 Yuan CS, Wei G, Dey L, Karrison T, Nahlik L, Maleckar S, Kasza K, Ang-Lee M, Moss J. Brief communication: American ginseng reduces warfarinʼs effect in healthy patients. Ann Intern Med 2004; 141: 23-27
- 77 Weber HA, Zart MK, Hodges AE, Molloy HM, OʼBrien BM, Moody LA, Clark AP, Harris RK, Overstreet JD, Smith CS. Chemical comparison of goldenseal (Hydrastis canadensis L.) root powder from three commercial suppliers. J Agric Food Chem 2003; 51: 7352-7358
- 78 Ettefagh KA, Burns JT, Junio HA, Kaatz GW, Cech NB. Goldenseal (Hydrastis canadensis L.) extracts synergistically enhance the antibacterial activity of berberine via efflux pump inhibition. Planta Med 2011; 77: 835-840
- 79 Sandhu RS, Prescilla RP, Simonelli TM, Edwards DJ. Influence of goldenseal root on the pharmacokinetics of indinavir. J Clin Pharmacol 2003; 43: 1283-1288
- 80 Penzak SR, Acosta EP, Turner M, Edwards DJ, Hon YY, Desai HD, Jann MW. Effect of Seville orange juice and grapefruit juice on indinavir pharmacokinetics. J Clin Pharmacol 2002; 42: 1165-1170
- 81 US Department of Health and Human Services Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for industry drug interaction studies – study design, data analysis, implications for dosing, and labeling recommendations (February 2012). Available athttp://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292362.pdf Accessed June 06, 2012
- 82 Gurley BJ, Swain A, Barone GW, Williams DK, Breen P, Yates CR, Stuart LB, Hubbard MA, Tong Y, Cheboyina S. Effect of goldenseal (Hydrastis canadensis) and kava kava (Piper methysticum) supplementation on digoxin pharmacokinetics in humans. Drug Metab Dispos 2007; 35: 240-245
- 83 Wu X, Li Q, Xin H, Yu A, Zhong M. Effects of berberine on the blood concentration of cyclosporin A in renal transplanted recipients: clinical and pharmacokinetic study. Eur J Clin Pharmacol 2005; 61: 567-572
- 84 Xin HW, Wu XC, Li Q, Yu AR, Zhong MY, Liu YY. The effects of berberine on the pharmacokinetics of cyclosporin A in healthy volunteers. Methods Find Exp Clin Pharmacol 2006; 28: 25-29
- 85 Breithaupt-Grögler K, Ling M, Boudoulas H, Belz GG. Protective effect of chronic garlic intake on elastic properties of aorta in the elderly. Circulation 1997; 96: 2649-2655
- 86 Silagy CA, Neil HA. A meta-analysis of the effect of garlic on blood pressure. J Hypertens 1994; 12: 463-468
- 87 Joshi BS, Kaul PN. Alternative medicine: herbal drugs and their critical appraisal – Part I. Prog Drug Res 2001; 56: 1-76
- 88 Greenblatt DJ, Leigh-Pemberton RA, von Moltke LL. Significance of garlic and its constituents in cancer and cardiovascular diseasein vitro interactions of water-soluble garlic components with human. J Nutr 2006; 136: 806-809
- 89 Lam YWF, Ernst E. Botanical products – drug interactions: focus on garlic, ginkgo and ginseng. In: Lam YWF, Huang SM, Hall SD, editors Herbal supplements – drug interactions, Volume 162. London: Taylor & Francis, Inc.; 2006: 107-121
- 90 Fisher CD, Augustine LM, Maher JM, Nelson DM, Slitt AL, Klaassen CD, Lehman-McKeeman LD, Cherrington NJ. Induction of drug-metabolizing enzymes by garlic and allyl sulfide compounds via activation of constitutive androstane receptor and nuclear factor E2-related factor 2. Drug Metab Dispos 2007; 35: 995-1000
- 91 Fukao T, Hosono T, Misawa S, Seki T, Ariga T. The effects of allyl sulfides on the induction of phase II detoxification enzymes and liver injury by carbon tetrachloride. Food Chem Toxicol 2004; 42: 743-749
- 92 Markowitz JS, Lindsay DeVane C, Chavin KD, Taylor RM, Ruan Y, Donovan JL. Effects of garlic (Allium sativum L.) supplementation on cytochrome P450 2D6 and 3A4 activity in healthy volunteers. Clin Pharmacol Ther 2003; 74: 170-177
- 93 Loizou GD, Cocker J. The effects of alcohol and diallyl sulphide on CYP2E1 activity in humans: a phenotyping study using chlorzoxazone. Hum Exp Toxicol 2001; 20: 321-327
- 94 Gwilt PR, Lear CL, Tempero MA, Birt DD, Grandjean AC, Ruddon RW, Nagel DL. The effect of garlic extract on human metabolism of acetaminophen. Cancer Res 1994; 3: 155-160
- 95 Jacek H, Rentsch KM, Steinert HC, Pauli-Magnus C, Meier PJ, Fattinger K. No effect of garlic extract on saquinavir kinetics and hepatic CYP3A4 function measured by the erythromycin breath test. Clin Pharmacol Ther 2004; 75: P80
- 96 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
- 97 Lunn DJ, Aarons L. The pharmacokinetics of saquinavir: a Markov chain Monte Carlo population analysis. J Pharmacokinet Biopharm 1998; 26: 47-74
- 98 Gisolf EH, van Heeswijk RP, Hoetelmans RW, Danner SA. Decreased exposure to saquinavir in HIV-1-infected patients after long-term antiretroviral therapy including ritonavir and saquinavir. AIDS 2000; 14: 801-805
- 99 Blumenthal M. The complete German commission E monographs, therapeutic guide to herbal medicines. Austin: American Botanical Council; 1998
- 100 Gorski JC, Huang SM, Pinto A, Hamman MA, Hilligoss JK, Zaheer NA, Desai M, Miller M, Hall SD. The effect of echinacea (Echinacea purpurea root) on cytochrome P450 activityin vivo . Clin Pharmacol Ther 2004; 75: 89-100
- 101 Moltó J, Valle M, Miranda C, Cedeno S, Negredo E, Barbanoj MJ, Clotet B. Herb-drug interaction betweenEchinacea purpurea and darunavir-ritonavir in HIV-infected patients. Antimicrob Agents Chemother 2011; 55: 326-330
- 102 Penzak SR, Robertson SM, Hunt JD, Chairez C, Malati CY, Alfaro RM, Stevenson JM, Kovacs JA.Echinacea purpurea significantly induces cytochrome P450 3A activity but does not alter lopinavir-ritonavir exposure in healthy subjects. Pharmacotherapy 2010; 30: 797-805
- 103 Abdul MI, Jiang X, Williams KM, Day RO, Roufogalis BD, Liauw WS, Xu H, Matthias A, Lehmann RP, McLachlan AJ. Pharmacokinetic and pharmacodynamic interactions of echinacea and policosanol with warfarin in healthy subjects. Br J Clin Pharmacol 2010; 69: 508-515
- 104 Wittkowsky AK. Warfarin and other coumarin derivatives: pharmacokinetics, pharmacodynamics, and drug interactions. Semin Vasc Med 2003; 3: 221-230
- 105 Gurley B, Swain A, Williams D. Gauging the clinical significance of P‐glycoprotein‐mediated herb‐drug interactions: comparative effects of St. Johnʼs wort, Echinacea, clarithromycin, and rifampin on dogoxin pharmacokinetics. Mol Nutr Food Res 2008; 52: 772-779
- 106 Mills E, Wu P, Johnston BC, Gallicano K, Clarke M, Guyatt G. Natural health product-drug interactions: a systematic review of clinical trials. Ther Drug Monit 2005; 27: 549-557
- 107 Fuhr U, Jetter A, Kirchheiner J. Appropriate phenotyping procedures for drug metabolizing enzymes and transporters in humans and their simultaneous use in the “cocktail” approach. Clin Pharmacol Ther 2007; 81: 270-283
- 108 Meijerman I, Beijnen JH, Schellens JHM. Herb-drug interactions in oncology: focus on mechanisms of induction. Oncologist 2006; 11: 742-752
- 109 Lee LS, Andrade AS, Flexner C. Interactions between natural health products and antiretroviral drugs: pharmacokinetic and pharmacodynamic effects. Clin Infect Dis 2006; 43: 1052-1059
- 110 Nowack R, Andrassy J, Fischereder M, Unger M. Effects of dietary factors on drug transport and metabolism: the impact on dosage guidelines in transplant patients. Clin Pharmacol Therap 2009; 85: 439-443
- 111 Sparreboom A, Cox MC, Acharya MR, Figg WD. Herbal remedies in the United States: potential adverse interactions with anticancer agents. J Clin Oncol 2004; 22: 2489-2503
- 112 Gore-Felton C, Vosvick M, Power R, Koopman C, Ashton E, Bachmann MH, Israelski D, Spiegel D. Alternative therapies: a common practice among men and women living with HIV. J Assoc Nurses AIDS Care 2003; 14: 17-27