Effects of Herbal Supplements on Drug Glucuronidation. Review of Clinical, Animal, and In Vitro Studies

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  • Abstract!

    The use of herbal supplements has increasedsteadily over the last decade. Recent surveys showthat many people who take herbal supplementsalso take prescription and nonprescription drugs,increasing the risk for potential herb-drug inter-actions. While cytochrome P450-mediated herb-drug interactions have been extensively charac-terized, the effects of herbal extracts and con-stituents on UDP-glucuronosyl transferase (UGT)enzymes have not been adequately studied. Thus,the purpose of this review is to evaluate currentevidence on the glucuronidation of phytochemi-cals and the potential for UGT-mediated herb-drug interactions with the top-selling herbal sup-

    plements in the United States and Europe. In vitroand animal studies indicate that cranberry, Gink-go biloba, grape seed, green tea, hawthorn, milkthistle, noni, soy, St. Johns wort, and valerian arerich in phytochemicals that can modulate UGTenzymes. However, the in vivo consequences ofthese interactions are not well understood. Onlythree clinical studies have investigated the effectsof herbal supplements on drugs cleared primarilythrough UGT enzymes. Evidence on the potentialfor commonly used herbal supplements to modu-late UGT-mediated drug metabolism is summar-ized. Moreover, the need for further research todetermine the clinical consequences of the de-scribed interactions is highlighted.

    Effects of Herbal Supplements on DrugGlucuronidation. Review of Clinical, Animal,and In Vitro Studies

    Authors Mohamed-Eslam F. Mohamed, Reginald F. Frye

    Affiliation Department of Pharmacotherapy and Translational Research, College of Pharmacy,University of Florida, Gainesville, Florida, USA

    received June 29, 2010revised Sept. 7, 2010accepted Sept. 29, 2010

    BibliographyDOI http://dx.doi.org/10.1055/s-0030-1250457Published online November 3,2010Planta Med 2011; 77: 311321 Georg Thieme Verlag KGStuttgart New York ISSN 00320943

    CorrespondenceDr. Reginald F. Frye,Associate ProfessorDepartmentof Pharmacotherapy andTranslational ResearchCollege of PharmacyUniversity of FloridaP.O. Box 100486Gainesville, FL 32610USAPhone: + 13522735453Fax: + 13522736121frye@cop.ufl.edu

    311ReviewsIntroduction!

    Herbal supplements are commonly used in manycountries around the world. Sales of herbal sup-plements in Europe and the US combined exceed$10 billion annually [1,2]. Survey studies estimatethat more than half the German, Danish, andNortheast Brazilian populations and nearly 40%of Australians use herbal supplements [35].Moreover, approximately 80% of German physi-cians regularly prescribe herbal products [3]. Inthe US, the herbal supplement market has grownsteadily in the last decade. In 2006, Americansspent $4.6 billion dollars on herbal supplements,representing a 4% growth in sales from 2005 [2].Surveys indicate that about 20% of Americansuse at least one herbal supplement. Meanwhile,one in four herbal supplement users takes one ormore prescription drugs, raising the potential forherb-drug interactions [6,7]. Additionally, pa-tients with chronic diseases, which are likely tobe treated by multiple drugs, use herbal supple-ments more frequently than the general popula-tion, thereby increasing the risk for interactionsMohamed M-E F[8,9]. The top selling herbal supplements in theUS and Europe are listed in l" Table 1.In the last decade, interest in studying the phar-macologic effects of herbal supplements, includ-ing their potential to interact with drug metabo-lizing enzymes, has grown. The number of publi-cations citing herbal supplements has increasedby nearly eightfold over the last twenty years,from about 200 to nearly 1600 annual citationsin PubMed (www.ncbi.nlm.nih.gov). This upsurgecoincided with an escalation in the use of herbalsupplements, which has also raised concern byhealth professionals regarding the potential forherbs to adversely affect drugs pharmacokineticsand pharmacodynamics [10].Several milestone events have contributed to theincreased interest in studying herb-drug interac-tions as summarized in l" Fig. 1. These eventsshaped the current widespread use of herbal sup-plements and highlighted the knowledge gap re-garding their safety. In 1994, the United StatesCongress passed the Dietary Supplement Healthand Education Act (DSHEA). Under the provisionsof this law, dietary supplements, including herb-, Frye RF. Effects of Herbal Planta Med 2011; 77: 311321

  • Table 1 Top selling herbal supplements in the United States and Europe.Source: NBJs Supplement Business Report, October 2007 [2] and IMS Health2009 (http://www.imshealth.com).

    US Europe

    Top herbs Sales

    ($ millions)

    Top herbs Sales

    ($ millions)

    1 Noni juice 257 Ginkgo biloba 300

    2 Garlic 155 Saw palmetto 114

    3 Mangosteen juice 147 Valerian 61

    4 Green tea 144 English ivy 54

    5 Sawpalmetto

    134 Pelargoniumsidoides

    52

    6 Echinacea 129 Psyllium 50

    7 Ginkgo biloba 106 Diosmin 45

    8 Ginseng 98 Grape seed 43

    9 Milk thistle 93 Myrtol 43

    10 Psyllium 85 Echinacea 40

    11 Soy 69 Milk thistle 40

    12 Cranberry 68 St. Johns wort 40

    13 Maca 66 Sennosides A & B 34

    14 Goji 65 Hawthorn 34

    15 Green foods 64 Cranberry 33

    16 St. Johns wort 60

    17 Aloe 60

    18 Stevia 58

    19 Black cohosh 57

    20 Valerian 55

    312 Reviewsals, are exempt from regulations applied to drugs, including pre-marketing safety and efficacy studies [11]. Concurrently, the In-ternet becamewidely accessible andwas commonly used tomar-ket herbal products, which led to an increase in the use of herbalsupplements in the mid to late 1990s [12]. In 1998, the Congressestablished the National Center for Complementary and Alterna-tive Medicine (NCCAM) with the goal of funding research on thesafety and efficacy of complementary and alternative medicine,including herbal supplements (nccam.nih.gov). Two years later,a milestone case report published in The Lancet described an in-teraction between St. Johns wort, an herbal supplement com-monly used for depression, with the immunosuppressant drugcyclosporine [13]. This case report sparked a wave of clinical, invitro, and animal studies addressing St. Johns wort interactionsMohamed M-E F, Frye RF. Effects of Herbal Planta Med 2011; 77: 311321with drug metabolizing enzymes and transporters [14]. Mean-while, reports emerged associating ephedra use with heart at-tacks; these reports eventually led to a ban in sales of over thecounter ephedra-containing products in several countries includ-ing the US, Canada, Australia, and Germany (http://www.erowid.org; accessed May 2010). These events set off an alarm that re-search was needed to characterize the safety of herbal supple-ments as well as their potential to interact with conventionaldrugs.In general, regulation of herbal products is greater in the Euro-pean Union (EU) than in the US. A 2004 EU directive mandatesmanufacturers of herbal products to register and license theirproducts by the European Agency prior tomarketing. In addition,it mandates premarketing safety evaluations as well as postmar-keting surveillance for serious adverse events [1]. In the US, thescientific community has recently requested that the FDA play amore rigorous role in evaluating safety and efficacy of herbal sup-plements with calls for premarketing safety data and studies oninteractions with drug metabolizing enzymes [15].Several case studies, reports, and review articles have describedthe potential of herbal supplements and phytochemicals to mod-ulate cytochrome P450 (CYP) enzymes. Conversely, the effect ofherbal extracts on glucuronidation, a major conjugative metabo-lism pathway, has not been sufficiently studied. The aim of thisreview is to summarize evidence regarding the potential of thetop-selling herbal supplements in the US and Europe to interactwith UGT enzymes.Potential for Herb-Drug Interactionsthrough Drug Metabolizing Enzymes!

    Enzymatic biotransformation (i.e., metabolism) plays amajor rolein the disposition of endogenous and exogenous compounds in-cluding both drugs and herbal constituents. Biotransformationreactions are generally divided into phase I and phase II reac-tions, each of them encompassing a wide range of enzymes andcatalytic activities [16]. Phase I reactions involve hydrolysis, re-duction, and oxidation and usually result in only a small increasein hydrophilicity [17]. In phase I, CYP enzymes rank first in termsof clinical importance and number of substrates. On the otherhand, phase II reactions include conjugation of compounds withFig. 1 Timeline for milestone events that have in-creased interest in studying herb-drug interactions.Abbreviations: DSHEA, Dietary Supplement Healthand Education Act; HS, Herbal Supplements;NCCAM, the National Center for Complementaryand Alternative Medicine; FDA, the Food and DrugAdministration.

  • Fig. 2 Expression of UGT enzymes in the liver and the small intestine.A Relative expression of hepatic UGT enzyme based on 20 human liversamples. Adapted from Izukawa et al. [28]. B Relative expression of UGTenzymes in the small intestine based on 3 human intestine samples.Adapted from Ohno and Nakajin [27].

    313Reviewsa hydrophilic group producing a more hydrophilic and easily ex-creted product (except for acetylation and methylation). Phase IIreactions may or may not be preceded by phase I reactions. Forsome substrates, such as morphine andmycophenolic acid, phaseII conjugation with glucuronic acid represents the primary meta-bolic pathway [17].Herbal supplements contain a myriad of natural chemicals thatshare the same metabolic pathways with prescription drugs[18]. This may result in activation or inhibition of the metabolismof concomitantly taken drugs, under- or overexposure to drugs,and consequently, treatment failure or toxicity. At least 30 clini-cally proven herb-drug interactions mediate