Pharmacokinetic Herb-Drug Interactions (Part 1): Origins, Mechanisms, and the Impact of Botanical Dietary Supplements

Abstract

Phytochemicals have been components of man's diet for millennia and are believed to have played a significant role in steering the functional development of xenobiotic metabolizing enzymes and transporters within the human gastrointestinal tract. Only recently, however, have plant secondary metabolites been recognized as modulators of human drug disposition. Despite exposure to thousands of structurally diverse dietary phytochemicals, only a few appear to significantly modulate human drug metabolizing enzymes and transporters. In some instances, these interactions may have beneficial effects like cancer prevention, whereas others may dramatically affect the pharmacokinetics of concomitantly administered drugs. In today's global economy, the opportunity for exposure to more exotic phytochemicals is significantly enhanced. Formulated as concentrated phytochemical extracts, botanical dietary supplements are vehicles for a host of plant secondary metabolites rarely encountered in the normal diet. When taken with conventional medications, botanical dietary supplements may give rise to clinically significant herb-drug interactions. These interactions stem from phytochemical-mediated induction and/or inhibition of human drug metabolizing enzymes and transporters.

Key words

herb-drug interaction - plant secondary metabolites - cytochrome P450 enzymes - transferases - ATP-binding cassette transporters - solute carrier membrane transport proteins

References

• 1 Gonzalez F J, Nebert D W. Evolution of the P450 gene superfamily: animal-plant “warfare,” molecular drive and human genetic differences in drug oxidation.  Trends Genet. 1990;  60 265-271
• 2 Nebert D W, Nelson D R, Feyereisen R. Evolution of the cytochrome P450 genes.  Xenobiotica. 1989;  19 1149-1160
• 3 Bock K W. Veterbrate UDP-glucuronosyl transferases: functional and evolutionary aspects.  Biochem Pharmacol. 2003;  66 691-696
• 4 Paulsen I T. Multidrug efflux pumps and resistance: regulation and evolution.  Curr Opin Microbiol. 2003;  6 446-451
• 5 Iyer M, Reschly E J, Krasowski M D. Functional evolution of the pregnane X receptor.  Expert Opin Drug Metab Toxicol. 2006;  2 381-397
• 6 Makkar H P S, Siddhuraju P, Becker K. Plant secondary metabolites. Totowa: Humana Press; 2007
• 7 Harbone J B, Baxter H, Moss G P. Phytochemical dictionary: a handbook of bioactive compounds from plants. 2nd edition. Philadelphia: Taylor & Francis; 1999
• 8 Briskin D P. Medicinal plants and phytomedicines. Linking plant biochemistry and physiology to human health.  Plant Physiol. 2000;  124 507-514
• 9 Dixon R A. Natural products and plant disease resistance.  Nature. 2001;  411 843-847
• 10 Nielsen K A, Moller B L. Cytochrome P450s in plants. In: Ortiz de Montellano P R, editor Cytochrome P450: Structure, mechanism, and biochemistry. 3rd edition. New York: Kluwer Academic/Plenum; 2005: 553-583
• 11 Ross J, Li Y, Lim E, Bowles D J. Higher plant glycosyltransferases.  Genome Biol. 2001;  2 3004.1-3004.6
• 12 Bowles D, Isayenkova J, Lim E, Poppenberger B. Glycosyltransferases: managers of small molecules.  Curr Opin Plant Biol. 2005;  8 254-263
• 13 Bowles D, Lim E-K, Poppenberger B, Vaistij F E. Glycosyltransferases of lipophilic small molecules.  Annu Rev Plant Biol. 2006;  57 567-597
• 14 Varin L, Marsolais F, Richard M, Rouleau M. Biochemistry and molecular biology of plant sulfotransferases.  FASEB J. 1997;  11 517-525
• 15 Dixon D P, Lapthorn A, Edwards R. Plant glutathione transferases.  Genome Biol. 2002;  3 3004.1-3004.10
• 16 Bowles S B, Yu Q. Evolution in action: plants resistant to herbicides.  Annu Rev Plant Biol. 2010;  61 317-347
• 17 Siminszky B. Plant cytochrome P450-mediated herbicide metabolism.  Phytochem Rev. 2006;  5 445-458
• 18 Yazaki K, Shitan N, Sugiyama A, Takanashi K. Cell and molecular biology of ATP-binding cassette proteins in plants.  Int Rev Cell Mol Biol. 2009;  276 263-299
• 19 Yazaki K. Transporters of secondary metabolites.  Curr Opin Plant Biol. 2005;  8 301-307
• 20 Sundberg B E, Waag E, Jacobsson J A, Stephansson O, Rumaks J, Svirskis S, Alsio J, Roman E, Ebendal T, Klusa V, Fredriksson R. The evolutionary history and tissue mapping of amino acid transporters belonging to solute carrier families SLC32, SLC36, and SLC38.  J Mol Neurosci. 2008;  35 179-193
• 21 Kufner I, Koch W. Stress regulated members of the plant organic cation transporter family are localized to the vacuolar membrane.  BMC Res Notes. 2008;  43 1-10
• 22 Danielson P B. The cytochrome P450 superfamily: biochemistry, evolution and drug metabolism in humans.  Curr Drug Metab. 2002;  3 561-597
• 23 Radominska-Pandya A, Czernik P J, Little J M, Battaglia E, Mackenzie P I. Structural and functional studies of UDP-glucuronosyltransferases.  Drug Metab Rev. 1999;  31 817-899
• 24 Eaton D L, Bammler T K. Concise review of the glutathione s-transferases and their significance to toxicology.  Toxicol Sci. 1999;  49 156-164
• 25 Huang C, Chen Y, Zhou T, Chen G. Sulfation of dietary flavonoids by human sulfotransferases.  Xenobiotica. 2009;  39 312-322
• 26 Kauffman F C. Sulfonation in pharmacology and toxicology.  Drug Metab Rev. 2004;  36 823-843
• 27 Klaassen C D, Aleksunes L M. Xenobiotic, bile acid, and cholesterol transporters: function and regulation.  Pharmacol Rev. 2010;  62 1-96
• 28 Jones P M, O'Mara M L, George A M. ABC transporters: a riddle wrapped in a mystery inside an enigma.  TIBS. 2009;  34 520-531
• 29 Scherrmann J M. Transporters in absorption, distribution, and elimination.  Chem Biodivers. 2009;  6 1933-1942
• 30 Ho R H, Kim R B. Transporters and drug therapy: implications for drug disposition and disease.  Clin Pharmacol Ther. 2005;  78 260-277
• 31 Lewis D F V, Watson E, Lake B G. Evolution of the cytochrome P450 superfamily: sequence alignments and pharmacogenetics.  Mutat Res. 1998;  410 245-270
• 32 Schuler M A, Duan H, Bilgin M, Ali S. Arabidopis cytochrome P450s through the looking glass: a window on plant biochemistry.  Phytochem Rev. 2006;  5 205-237
• 33 Mandlekar S, Hong J L, Kong A N. Modulation of metabolic enzymes by dietary phytochemicals: a review of mechanisms underlying beneficial versus unfavorable effects.  Curr Drug Metab. 2006;  7 661-675
• 34 Li Y, Revalde J L, Reid G, Paxton J W. Interactions of dietary phytochemicals with ABC transporters: possible implications for drug disposition and multidrug resistance in cancer.  Drug Metab Rev. 2010;  42 590-611
• 35 Hernandez J P, Mota L C, Baldwin W S. Activation of CAR and PXR by dietary, environmental and occupational chemicals alters drug metabolism, intermediary metabolism, and cell proliferation.  Curr Pharmacogenomic Person Med. 2009;  7 81-105
• 36 Ma Q. Xenobiotic-activated receptors: from transcription to drug metabolism to disease.  Chem Res Toxicol. 2008;  21 1651-1671
• 37 Pascussi J M, Gerbal-Chaloin S, Duret C, Daujat-Chavanieu M, Vilarem M J, Maurel P. The tangle of nuclear receptors that controls xenobiotic metabolism and transport: crosstalk and consequences.  Annu Rev Pharmacol Toxicol. 2008;  48 1-32
• 38 Gonzalez F J. The 2006 Bernard B. Brodie Award Lecture: CYP2E1.  Drug Metab Dispos. 2007;  35 1-8
• 39 Clarke J D, Dashwood R H, Ho E. Multi-targeted prevention of cancer by sulforaphane.  Cancer Lett. 2008;  269 291-304
• 40 Farkas D, Greenblat D J. Influence of fruit juices on drug disposition: discrepancies between in vitro and clinical studies.  Expert Opin Drug Metab Toxicol. 2008;  4 381-393
• 41 Schmiedlin-Ren P, Edwards D J, Fitzsimmons M E, He K, Lown K S, Woster P M, Rahman A, Thummel K E, Fisher J M, Hollenberg P F, Watkins P B. Mechanisms of enhanced oral availability of CYP3A4 substrates by grapefruit constituents: decreased enterocyte CYP3A4 concentration and mechanism-based inactivation by furanocoumarins.  Drug Metab Dispos. 1997;  25 1228-1233
• 42 Guengerich F P, Kim D H, Iwasaki M. Role of human cytochrome P-450 IIE1 in the oxidation of many low molecular weight cancer suspects.  Chem Res Toxicol. 1991;  4 168-179
• 43 Yang C S, Yoo J S, Ishizaki H, Hong J Y. Cytochrome P450IIE1: roles in nitrosamine metabolism and mechanisms of regulation.  Drug Metab Rev. 1990;  22 147-159
• 44 Yang C S, Chhabra S K, Hong J Y, Smith T J. Mechanisms of inhibition of chemical toxicity and carcinogenesis by diallyl sulfide (DAS) and related compounds from garlic.  J Nutr. 2001;  131 1041S-1045S
• 45 Park K A, Kweon S, Choi H. Anticarcinogenic effect and modification of cytochrome P4502E1 by dietary garlic powder in diethylnitrosamine-initiated rat hepatocarcinogenesis.  J Biochem Mol Biol. 2002;  35 615-622
• 46 Gurley B J, Gardner S F, Hubbard M A, Williams D K, Gentry W B, Cui Y, Ang C Y W. Cytochrome P450 phenotypic ratios for predicting herb-drug interactions in humans.  Clin Pharmacol Ther. 2002;  72 276-287
• 47 Leclercq I, Desager J P, Horsmans Y. Inhibition of chlorzoxazone metabolism, a clinical probe for CYP2E1, by a single ingestion of watercress.  Clin Pharmacol Ther. 1998;  64 144-149
• 48 Zhang Y, Talalay P. Anticarcinogenic activities of organic isothiocyanates: chemistry and mechanisms.  Cancer Res. 1994;  54 1976s-1981s
• 49 Gonzalez F J, Gelboin H V. Role of human cytochromes P450 in the metabolic activation of chemical carcinogens and toxins.  Drug Metab Rev. 1994;  26 165-183
• 50 Nebert D W. Polymorphisms in drug-metabolizing enzymes: what is their clinical relevance and why do they exist?.  Am J Hum Genet. 1997;  60 265-271
• 51 Neafsey P, Ginsberg G, Hattis D, Sonawane B. Genetic polymorphism in cytochrome P450 2D6 (CYP2D6): population distribution of CYP2D6 activity.  J Toxicol Environ Health B. 2009;  12 334-361
• 52 Lewis D F V, Eddershaw P J, Goldfarb P S, Tarbit M H. Molecular modeling of cytochrome P4502D6 (CYP2D6) based on an alignment with CYP102: structural studies on specific CYP2D6 substrate metabolism.  Xenobiotica. 1997;  27 319-340
• 53 Ingelman-Sundberg M. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity.  Pharmacogenomics J. 2005;  5 6-13
• 54 Sullivan R J, Hagen E H, Hammerstein P. Revealing the paradox of drug reward in human evolution.  Proc Biol Sci. 2008;  275 1231-1241
• 55 Ingelman-Sundberg M. The human genome project and novel aspects of cytochrome P450 research.  Toxicol Appl Pharmacol. 2005;  207 S52-S56
• 56 Schmidt B, Ribnicky D M, Poulev A, Logendra S, Cefalu W T, Raskin I. A natural history of botanical therapeutics.  Metab Clin Exp. 2008;  57 S3-S9
• 57 Craig W J. Phytochemicals: guardians of our health.  J Am Diet Assoc. 1997;  97 S199-S204
• 58 Hu F B. Plant-based foods and prevention of cardiovascular disease: an overview.  Am J Clin Nutr. 2003;  78 544S-551S
• 59 Heber D. Vegetables, fruits and phytoestrogens in the prevention of diseases.  J Postgrad Med. 2004;  50 145-149
• 60 Graf B A, Milbury P E, Blumberg J B. Flavonols, flavones, flavanones, and human health: epidemiological evidence.  J Med Food. 2005;  8 281-290
• 61 Thomasset S C, Berry D P, Garcea G, Marczylo T, Steward W P, Gescher A J. Dietary polyphenolic phytochemicals–promising cancer chemopreventative agents in humans? A review of their clinical properties.  Int J Cancer. 2006;  120 451-458
• 62 Kim J, Lee H J, Lee K W. Naturally occurring phytochemicals for the prevention of Alzheimer's disease.  J Neurochem. 2010;  112 1415-1430
• 63 Dietary Supplement Health and Education Act (DSHEA), Public Law 103 – 417, 1994; Act 42 U.S.C. 287C–11. 
• 64 Gurley B J. Clinical pharmacology and dietary supplements: an evolving relationship.  Clin Pharmacol Ther. 2010;  87 235-238
• 65 Barnes P M, Bloom B. Complementary and alternative medicine use among adults and children: United States, 2007. National Health Statistics Reports No 12. Hyattsville: US Department of Health and Human Services; 2008
• 66 Nahin R L, Barnes P M, Stussman B J, Bloom B. Costs of complementary and alternative medicine (CAM) and frequency of visits to CAM practitioners: United States, 2007. National Health Statistics Reports No 18. Hyattsville: US Department of Health and Human Services; 2009
• 67 Gardiner P, Graham R E, Legedza A T, Eisenberg D M, Phillips R S. Factors associated with dietary supplement use among prescription medication users.  Arch Intern Med. 2006;  166 1968-1974
• 68 Wold R S, Lopez S T, Yau L, Butler L M, Pareo-Tubbeh S L, Waters D L, Garry P J, Baumgartner R N. Increasing trends in elderly persons' use of nonvitamin, nonmineral dietary supplements and concurrent use of medications.  J Am Diet Assoc. 2005;  105 54-63
• 69 Qato D M, Alexander G C, Conti R M, Johnson M, Schumm P, Lindau S T. Use of prescription and over-the-counter medications and dietary supplements among older adults in the United States.  JAMA. 2008;  300 2867-2878
• 70 Bruno J J, Ellis J J. Herbal use among US elderly: 2002 National Health Interview Survey.  Ann Pharmacother. 2005;  39 643-648
• 71 AARP .What people 50 and older are using and discussing with their physicians. Washington DC: AARP; 2007
• 72 Kishiyama S S, Leahy M J, Zitzelberger T A, Guariglia R, Zajdel D P, Calvert J F, Kaye J A, Oken B S. Patterns of dietary supplement usage in demographically diverse older people.  Altern Ther Health Med. 2005;  11 48-53
• 73 Foster D F, Phillips R S, Hamel M B, Eisneberg D M. Alternative medicine use in older Americans.  J Am Geriatr Soc. 2000;  48 1560-1565
• 74 Mehta D H, Gardiner P M, Phillips R S, McCarthy E P. Herbal and dietary supplement disclosure to health care providers by individuals with chronic conditions.  J Altern Complement Med. 2008;  14 1263-1269
• 75 Paine M F, Ludington S S, Chen M L, Stewart P W, Huang S M, Watkins P B. Do men and women differ in proximal small intestinal CYP3A or P-glycoprotein expression?.  Drug Metab Dispos. 2005;  33 426-433
• 76 Canaparo R, Finnstrom N, Serpe L, Nordmark A, Muntoni E, Eandi M, Rane A, Zara G P. Expression of CYP3A isoforms and p-glycoprotein in human stomach, jejunum and ileum.  Clin Exp Pharmacol Physiol. 2007;  34 1138-1144
• 77 Niemi M. Role of OATP transporters in the disposition of drugs.  Pharmacogenomics. 2007;  8 787-802
• 78 Tomlinson B, Hu M, Lee V W Y. In vivo assessment of herb-drug interactions: possible utility of a pharmacogenetic approach?.  Mol Nutr Food Res. 2008;  52 799-809
• 79 Yin O Q P, Tomlinson B, Waye M M Y, Chow A H L, Chow M S S. Pharmacogenetics and herb-drug interactions: experience with Ginkgo biloba and omeprazole.  Pharmacogenetics. 2004;  14 841-850
• 80 Yang L J, Fan L, Liu Z Q, Mao Y M, Guo D, Liu L H, Tan Z R, Peng L, Han C T, Hu D L, Wang D, Zhou H H. Effects of allicin on CYP2C19 and CYP3A4 activity in healthy volunteers with different CYP2C19 genotypes.  Eur J Clin Pharmacol. 2009;  65 601-608
• 81 Han Y, Guo D, Chen Y, Chen Y, Tan Z R, Zhou H H. 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
• 82 Williamson E M. Synergy and other interactions in phytomedicines.  Phytomedicine. 2001;  8 401-409
• 83 Gilbert B, Alves L F. Synergy in plant medicines.  Curr Med Chem. 2003;  10 13-20
• 84 Obach R S. Inhibition of human cytochrome P450 enzymes by constituents of St. John's wort, an herbal preparation used in the treatment of depression.  J Pharmacol Exp Ther. 2000;  29 88-95
• 85 Budzinski J W, Foster B C, Vandenhoek S, Arnason J T. An in vitro evaluation of human cytochrome P450 3A4 inhibition by selected commercial herbal extracts and tinctures.  Phytomedicine. 2000;  7 273-282
• 86 Zou L, Harkey M R, Henderson G L. Effects of herbal components on cDNA-expressed cytochrome P450 enzyme catalytic activity.  Life Sci. 2002;  71 1579-1589
• 87 Mathews J M, Etheridge A S, Black S R. Inhibition of human cytochrome P450 activities by kava extract and kava lactones.  Drug Metab Dispos. 2002;  30 1153-1157
• 88 Foster B C, Vandenhoek S, Hana J, Krantis A, Akhtar M H, Bryan M, Budzinski J W, Ramputh A, Arnason J T. In vitro inhibition of human cytochrome P450–mediated metabolism of marker substrates by natural products.  Phytomedicine. 2003;  10 334-342
• 89 Raucy J L. Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products.  Drug Metab Dispos. 2003;  31 533-539
• 90 Chatterjee P, Franklin M R. Human cytochrome P450 inhibition and metabolic-intermediate complex formation by goldenseal extract and its methylenedioxyphenyl components.  Drug Metab Dispos. 2003;  31 1391-1397
• 91 Iwata H, Tezuka Y, Usia T, Kadota S, Hiratsuka A, Watabe T. Inhibition of human liver microsomal CYP3A4 and CYP2D6 by extracts from 78 herbal medicines.  J Tradit Med. 2004;  21 42-50
• 92 Unger M, Frank A. Simultaneous determination of the inhibitory potency of herbal extracts on the activity of six major cytochrome P450 enzymes using liquid chromatography/mass spectrometry and automated online extraction.  Rapid Commun Mass Spectrom. 2004;  18 2273-2281
• 93 He N, Edeki T. The inhibitory effects of herbal components on CYP2C9 and CYP3A4 catalytic activities in human liver microsomes.  Am J Ther. 2004;  11 206-212
• 94 Zou L, Henderson G L, Harkey M R, Sakai Y, Li A. Effects of kava (kava-kava, ‘Awa, Yaqona, Piper methysticum) on c-DNA-expressed cytochrome P450 enzymes and human cryopreserved hepatocytes.  Phytomedicine. 2004;  11 285-294
• 95 Strandell J, Neil A, Carlin G. An approach to the in vitro evaluation of potential for cytochrome P450 enzyme inhibition from herbals and other natural remedies.  Phytomedicine. 2004;  11 98-104
• 96 Gross-Steinmeyer K, Stapleton P L, Liu F, Tracy J H, Bammler T K, Quigley S D, Farin F M, Buhler D R, Safe S H, Strom S C, Eaton D L. Phytochemical-induced changes in gene expression of carcinogen-metabolizing enzymes in cultured human primary hepatocytes.  Xenobiotica. 2004;  34 619-632
• 97 von Moltke L L, Weemhoff J L, Bedir E, Khan I A, Harmatz J S, Goldman P, Greenblatt D J. Inhibition of human cytochromes P450 by components of Ginkgo biloba.  J Pharm Pharmacol. 2004;  56 1039-1044
• 98 Iwata H, Tezuka Y, Kadota S, Hiratuska A, Watabe T. Identification and characterization of potent CYP3A4 inhibitors in Schisandra fruit extract.  Drug Metab Dispos. 2004;  32 1351-1358
• 99 Whitley A C, Sweet D H, Walle T. The dietary polyphenol ellagic acid is a potent inhibitor of hOAT1.  Drug Metab Dispos. 2005;  33 1097-1100
• 100 Yale S H, Glurich I. Analysis of the inhibitory potential of Ginkgo biloba, Echinacea purpurea, and Serenoa repens on the metabolic activity of cytochrome P450 3A4, 2D6, and 2C9.  J Altern Complement Med. 2005;  11 433-439
• 101 Scott I M, Leduc R I, Burt A J, Marles R J, Arnason J T, Foster B C. The inhibition of human cytochrome P450 by ethanol extracts of North American botanicals.  Pharm Biol. 2006;  44 315-327
• 102 Fuchikami H, Satoh H, Tsujimoto M, Ohdo S, Ohtani H, Sawada Y. Effects of herbal extracts on the function of human organic anion-transporting polypeptide OATP-B.  Drug Metab Dispos. 2006;  34 577-582
• 103 Foti R S, Wahlstrom J L, Wienkers L C. The in vitro drug interaction potential of dietary supplements containing multiple herbal components.  Drug Metab Dispos. 2007;  35 185-188
• 104 Lee S S, Zhang B, He M L, Chang V S C, Kung H F. Screening of active ingredients of herbal medicine for interaction with CYP450 3A4.  Phytother Res. 2007;  21 1096-1099
• 105 Etheridge A S, Black S R, Patel P R, So J, Mathews J M. An in 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
• 106 Raner G M, Cornelious S, Moulick K, Wang Y, Mortensen A, Cech N B. Effects of herbal products and their constituents on human P4502E1 activity.  Food Chem Toxicol. 2007;  45 2359-2365
• 107 Hellum B H, Hu Z, Nilsen O G. The induction of CYP1A2, CYP2D6 and CYP3A4 by six trade herbal products in cultured primary human hepatocytes.  Basic Clin Pharmacol Toxicol. 2007;  100 23-30
• 108 Hellum B H, Nilsen O G. The in vitro inhibitory potential of trade herbal products on huan CYP2D6-mediated metabolism and the influence of ethanol.  Basic Clin Pharmacol Toxicol. 2007;  101 350-358
• 109 Budzinski J W, Trudeau V L, Drouin C E, Panahi M, Arnason J T, Foster B C. 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
• 110 Budzinski J W, Foster B C, Trudeau V L, Drouin C E, Bafi-Yeboa N, Arnason J T. The interaction of selected phytochemicals, HIV drugs, and commercial-source herbal teas and capsules with human cytochrome P450 3A4 and P-glycoprotein.  Pharm Biol. 2008;  46 53-65
• 111 Hellum B H, Nilsen O G. In vitro inhibition of CYP3A4 metabolism and P-glycoprotein-mediated transport by trade herbal products.  Basic Clin Pharmacol Toxicol. 2008;  102 466-475
• 112 Engdal S, Nilsen O G. Inhibition of P-glycoprotein in Caco-2 cells: effects of herbal remedies frequently used by cancer patients.  Xenobiotica. 2008;  38 559-573
• 113 Satsu H, Hiura Y, Mochizuki K, Hamada M, Shimizu M. Activation of pregnane X receptor and induction of MDR1 by dietary phytochemicals.  J Agric Food Chem. 2008;  56 5366-5373
• 114 Roderio I, Donato M T, Jimenez N, Garrido G, Molina-Torres J, Menendez R, Castell J V, Gomez-Lechon M J. Inhibition of human P450 enzymes by natural extracts used in traditional medicine.  Phytother Res. 2009;  23 279-282
• 115 Hellum B H, Hu Z, Nilsen O G. Trade herbal products and induction of CYP2C19 and CYP2E1 in cultured human hepatocytes.  Basic Clin Pharmacol Toxicol. 2009;  105 58-63
• 116 Tiong K H, Yiap B C, Tan E L, Ismail R, Ong C E. In vitro modulation of naturally occurring flavonoids on cytochrome P450 2A6 (CYP2A6) activity.  Xenobiotica. 2010;  40 458-466
• 117 Satsu H, Hiura Y, Mochizuki K, Hamada M, Shimizu M. Activation of pregnane X receptor and induction of MDR1 by dietary phytochemicals.  J Agric Food Chem. 2008;  56 5366-5373
• 118 Okura T, Ibe M, Umegaki K, Shinozuka K, Yamada S. Effects of dietary ingredients on function and expression of P-glycoprotein in human intestinal epithelial cells.  Biol Pharm Bull. 2010;  33 255-259
• 119 Najar I A, Sachin B S, Sharma S C, Satti N K, Suri K A, Johri R K. Modulation of P-glycoprotein ATPase activity by some phytoconstituents.  Phytother Res. 2010;  24 454-458
• 120 Kimura Y, Ito H, Ohnishi R, Hatano T. Inhibitory effects of polyphenols on human cytochrome P450 3A4 and 2C9 activity.  Food Chem Toxicol. 2010;  48 429-435
• 121 Sevior D K, Hokkanen J, Tolonen A, Abass K, Tursas L, Pelkonen O, Ahokas J T. Rapid screening of commercially available herbal products for the inhibition of major human hepatic cytochrome P450 enzymes using the N-in-one cocktail.  Xenobiotica. 2010;  40 245-254
• 122 Nahrstedt A, Butterweck V. Lessons learned from herbal medicinal products: the example of St John's wort.  J Nat Prod. 2010;  73 1015-1021
• 123 Gurley B J, Gardner S F, Hubbard M A. Content versus label claims in ephedra-containing dietary supplements.  Am J Health Syst Pharm. 2000;  57 963-969
• 124 Harkey M R, Henderson G L, Gershwin M E, Stern J S, Hackman R M. Variability in commercial ginseng products: an analysis of 25 preparations.  Am J Clin Nutr. 2001;  73 1101-1106
• 125 Garrard J, Harms S, Eberly L E, Matiak A. Variations in product choices of frequently purchased herbs.  Arch Intern Med. 2003;  163 2290-2295
• 126 Brinker F. Managing and interpreting the complexities of botanical research.  HerbalGram. 2009;  82 42-49
• 127 Hines E. Standardizing botanical extracts: can the part exceed the whole?.  Pharm Formul Qual. 1999;  3 28-33
• 128 van Breeman R B, Fong H H S, Farnsworth N R. Ensuring the safety of botanical dietary supplements.  Am J Clin Nutr. 2008;  87 509S-513S
• 129 Goldman P. Herbal medicines today and the roots of modern pharmacology.  Ann Intern Med. 2001;  135 594-600
• 130 Wanwimolruk S, Wong K, Wanwimolruk P. Variable inhibitory effect of different brands of commercial herbal supplements on human cytochrome P-450 CYP3A4.  Drug Metab Drug Interact. 2009;  24 17-35
• 131 Gurley B J. Dosage form performance: an overlooked determinant of phytochemical efficacy and safety.  Planta Med. 2010;  76 504
• 132 Schulz H U, Schurer M, Krumbiegel G, Wachter W, Weyhenmeyer R, Seidel G. Investigation of dissolution and bioequivalence of silymarin products.  Arzneimittelforschung. 1995;  45 61-64
• 133 Westerhoff K, Kaunzinger A, Wurglics M, Dressman J, Schubert-Zsilavecz M. Biorelevant dissolution testing of St John's wort products.  J Pharm Pharmacol. 2002;  54 1615-1621
• 134 Nair V D P, Kanfer I. Development of dissolution tests for the quality control of complementary/alternate and traditional medicines: application to African potato products.  J Pharm Pharm Sci. 2008;  11 35-44
• 135 United States Pharmacopeial Convention .Disintegration and dissolution of dietary supplements. Rockville; USP 33-NF 28 2010
• 136 Current good manufacturing practice in manufacturing, packaging, labeling, or holding operations for dietary supplements; Final rule.  Fed Reg. 2007;  72 34751-34958
• 137 Venkataramanan R, Komoroski B, Strom S. In vitro and in vivo assessment of herb drug interactions.  Life Sci. 2006;  78 2105-2115
• 138 Markowitz J S, von Moltke L L, Donovan J L. Predicting interactions between conventional medications and botanical products on the basis of in vitro investigations.  Mol Nutr Food Res. 2008;  52 747-754
• 139 Ruschitzka F, Meier P J, Turina M, Luscher T F, Noll G. Acute heart transplant rejection due to Saint John's wort.  Lancet. 2000;  355 548-549
• 140 Breidenbach T H. Profound drop of cyclosporine A whole blood trough levels caused by St. John's wort (Hypericum perforatum).  Transplantation. 2000;  69 2229-2232
• 141 Barone G W, Gurley B J, Ketel B L, Lightfoot M L, Abul-Ezz S R. Drug interaction between St John's wort and cyclosporine.  Ann Pharmacother. 2000;  34 1013-1016
• 142 Barone G W, Gurley B J, Ketel B L, Abul-Ezz S R. Herbal dietary supplements: a source for drug interactions in transplant recipients.  Transplantation. 2001;  71 239-241
• 143 Moore L B, Goodwin B, Jones S A, Wisely W B, Serabjit-Singh C J, Willson T M, Collins J L, Kliewer S A. St John's wort induces hepatic drug metabolism through activation of the pregnane X receptor.  Proc Natl Acad Sci USA. 2000;  97 7500-7502
• 144 Wentworth J M, Agostini M, Love J, Schwabe J W, Chatterjee V K K. St John's wort, a herbal antidepressant, activates the steroid X receptor.  J Endocrinol. 2000;  166 R11-R16
• 145 Johne A, Brockmöller J, Bauer S, Maurer A, Langheinrich M, Roots I. Pharmacokinetic interaction of digoxin with an herbal extract from St John's wort (Hypericum perforatum).  Clin Pharmacol Ther. 1999;  66 338-345
• 146 Roby C A, Anderson G D, Kantor E, Dryer D A, Burstein A H. St John's wort: effect on CYP3A4 activity.  Clin Pharmacol Ther. 2000;  67 451-457
• 147 Wang Z, Gorski C, Hamman M A, Huang S M, Lesko L J, Hall S D. The effects of St John's wort (Hypericum perforatum) on human cytochrome P450 activity.  Clin Pharmacol Ther. 2001;  70 317-326
• 148 Sugimoto K, Ohmori M, Tsuruoka S, Nishiki K, Kawaguchi A, Harada K, Arakawa M, Sakamoto K, Masada M, Miyamori I, Fujimura A. Different effects of St John's wort on the pharmacokinetics of simvastatin and pravastatin.  Clin Pharmacol Ther. 2001;  70 518-524
• 149 Hennessy M, Kelleher D, Spiers J P, Kavanagh B P, Back D, Mulcahy F, Feely J. St John's wort increases expression of P-glycoprotein: implications for drug interactions.  Br J Clin Pharmacol. 2002;  53 75-82
• 150 Izzo A A. Herb-drug interactions: an overview of the clinical evidence.  Fund Clin Pharmacol. 2004;  19 1-16
• 151 Zhou S, Lim L Y, Chowbay B. Herbal modulation of P-glycoprotein.  Drug Metab Rev. 2004;  36 57-104
• 152 Delogda R, Westlake A C G. Herbal interactions involving cytochrome P450 enzymes.  Toxicol Rev. 2004;  23 239-249
• 153 Mills E, Wu P, Johnston B C, Gallicano K, Clarke M, Guyatt G. Natural health product-drug interactions: a systematic review of clinical trials.  Ther Drug Monit. 2005;  27 549-557
• 154 Hu Z, Yang X, Ho P C L, Chan S Y, Heng P W S, Chan E, Duan W, Koh H L, Zhou S. Herb-drug interactions: a literature review.  Drugs. 2005;  65 1239-1282
• 155 Johne A, Roots I. Clinical drug interactions with medicinal herbs.  Evid Based Integr Med. 2005;  2 207-228
• 156 Ulbricht C, Basch E, Weissner W, Hackman D. An evidence-based systematic review of herb and supplement interactions by the Natural Standard Research Collaboration.  Expert Opin Drug Saf. 2006;  5 719-728
• 157 Borrelli F, Capasso R, Izzo A A. Garlic (Allium sativum L.): adverse effects and drug interactions in humans.  Mol Nutr Food Res. 2007;  51 1386-1397
• 158 Borrelli F, Izzo A A. Herb-drug interactions with St John's wort (Hypericum perforatum): an update on clinical observations.  AAPS J. 2009;  11 710-727
• 159 Izzo A A, Ernst E. Interactions between herbal medicines and prescribed drugs: an updated systematic review.  Drugs. 2009;  69 1777-1798
• 160 Kennedy D A, Seely D. Clinically based evidence of drug-herb interactions: a systematic review.  Expert Opin Drug Saf. 2010;  9 79-124
• 161 Gurley B, Hubbard M A, Williams D K, Thaden J, Tong Y, Gentry W B, Breen P, Carrier D J, 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
• 162 Gurley B J, Swain A, Williams D K, Barone G, Battu S K. Gauging the clinical significance of P-glycoprotein-mediated herb-drug interactions: comparative effects of St John's wort, echinacea, clarithromycin, and rifampin on digoxin pharmacokinetics.  Mol Nutr Food Res. 2008;  52 772-779
• 163 Food and Drug Administration .Drug Interaction Studies–Study Design, Data Analysis, and Implications for Dosing and Labeling. Available at http://www.fda.gov/Drugs/Guidance Compliance Regulatory Information/Guidances/ucm064982.htm. Accessed October 11, 2011
• 164 Huang S M, Temple R, Throckmorton D C, Lesko L J. Drug interaction studies: study design, data analysis, and implications for dosing and labeling.  Clin Pharmacol Ther. 2007;  81 298-304
• 165 Smolinske S C. Herbal product contamination and toxicity.  J Pharm Pract. 2005;  18 188-208
• 166 Ko R. Safety of ethnic & imported herbal and dietary supplements.  Clin Toxicol. 2006;  44 611-616
• 167 Cole M R, Fetrow C W. Adulteration of dietary supplements.  Am J Health Syst Pharm. 2003;  60 1576-1580
• 168 Fleshner N, Harvey M, Adomat H, Wood C, Eberding A, Hersey K, Guns E. Evidence for contamination of herbal erectile dysfunction products with phosphodiesterase type 5 inhibitors.  J Urol. 2005;  174 636-641
• 169 Food and Drug Administration .Warning on body building products marketed as containing steroids or steroid-like substances. Rockville, MD: US Department of Health and Human Services; Available at http://www.fda.gov/ForConsumers/ConsumerUPdates/ucm173739.html Accessed October 11, 2011
• 170 Food and Drug Administration .More weight loss products added to consumer alert. Rockville, MD: US Department of Health and Human Services; Available at http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm103184.htm Accessed October 11, 2011