1490 Reviews Pharmacokinetic Herb-Drug Interactions (Part 2): Drug Interactions Involving Popular Botanical Dietary Supplements and Their Clinical Relevance Authors Bill J. Gurley1, Espero Kim Fifer2, Zoë Gardner2 Affiliations 1 Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, College of Pharmacy, Little Rock, AR, USA 2 Department of Plant, Soil & Insect Sciences, University of Massachusetts, Amherst, MA, USA Key words Abstract Nonstandard Abbreviations l" herb‑drug interaction ! ! l" plant secondary metabolites In Part 2 of this review, a critical examination of ABC: ATP-binding cassette l" cytochrome P450 enzymes the pertinent scientific literature is undertaken AhR: aryl hydrocarbon receptor l" transferases in order to assess the interaction risk that popular AUC: area under the plasma concentration- l" ATP‑binding cassette transporters dietary supplements may pose when taken con- time curve l" solute carrier membrane comitantly with conventional medications. Botan- CAR: constitutive androstane receptor transport proteins icals most likely to produce clinically important CYP: cytochrome P450 enzyme l" botanical dietary herb-drug interactions are those whose phyto- DSHEA: Dietary Supplement Health and supplements chemicals act as mechanism-based inhibitors of Education Act l" black cohosh cytochrome P450 enzyme activity (e.g., Hydrastis GMPs: good manufacturing practices l" Echinacea canadensis, Piper nigrum, Schisandra chinensis)or GST: glutathione S-transferase l" garlic l" Ginkgo biloba function as ligands for orphan nuclear receptors MDR1: multidrug resistance protein 1 l" ginseng (e.g., Hypericum perforatum). In addition, several MDP: methylenedioxyphenyl l" goldenseal external factors unrelated to phytochemical phar- MDZ: midazolam l" kava macology can augment the drug interaction po- NADPH: nicotinamide adenine dinucleotide l" black pepper tential of botanical supplements. phosphate l" piperine OATP: organic anion transporting polypeptide l" Schisandra OTC: over-the-counter l" milk thistle ‑ l" St. Johnʼs wort P gp: P-glycoprotein l" methylenedioxyphenyl‑ PSM: plant secondary metabolite containing compounds PXR: pregnane xenobiotic receptor SLC: solute carrier membrane transport protein received Dec. 22, 2011 SULT: sulfotransferase revised February 6, 2012 UGT: uridine diphosphate glycosyltransferase accepted February 10, 2012 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. UM: ultra-rapid metabolizer Bibliography XME: xenobiotic metabolizing enzyme DOI http://dx.doi.org/ 10.1055/s-0031-1298331 Published online May 7, 2012 Introduction teractions can be extended to any supplement Planta Med 2012; 78: ! 1490–1514 © Georg Thieme formulation. (For definitions of abbreviations re- Verlag KG Stuttgart · New York · In Part 1 of this review, a discussion of the origins garding various drug metabolizing enzymes and ISSN 0032‑0943 and mechanisms underlying herb-drug interac- transporters, see Part 1 of this review.) Correspondence tions was presented. In Part 2, a critical assessment Dr. Bill Gurley of the available clinical evidence regarding herb- Department of Pharmaceutical drug interaction potentials for several popular bo- Black Cohosh Sciences ! UAMS, College of Pharmacy tanical supplements sold in the United States is 4301 W. Markham St. provided. While the number of botanicals selected Actaea racemosa L, (syn. Cimicifuga racemosa [L.] Little Rock, AR 72205 for review is not extensive, the approach taken to Nutt.; family Ranunculaceae) or black cohosh, is a United States Phone: + 15016866279 discern whether a botanical extract poses a risk perennial herb native to North America used tra- Fax: + 15015266510 for producing clinically significant herb-drug in- ditionally by Native Americans for female repro- [email protected] Gurley BJ et al. Pharmacokinetic Herb-Drug Interactions (Part 2)… Planta Med 2012; 78: 1490–1514 Reviews 1491 Fig. 1 Representative phytochemicals (triterpene glycosides, phenylpropanoids) present in black cohosh. ductive system ailments and is now popular for the relief of meno- ately inhibited (~ 47%) uptake of estrone-3-sulfate, a SLCO2B1 pausal symptoms such as hot flashes [1,2]. The purported ability substrate, into human embryonic kidney cells stably expressing of black cohosh to help alleviate climacteric symptoms, premen- the transporter [14]. Whether this effect translates to the in vivo strual syndrome, and osteoporosis has secured its ranking among condition remains to be determined. the 10 top-selling supplements in the United States [3]. Spiroke- As with most commercially available botanical supplements, tal triterpene glycosides (l" Fig. 1) are believed responsible for black cohosh products exhibit considerable variability in phyto- black cohoshʼs pharmacological activity even though they are chemical profiles, and label claims for “standardized” marker not phytoestrogens [4,5]. As such, most commercial black cohosh compounds can deviate considerably from actual content [9]. products are chemically standardized to triterpene glycosides, Such variations can have considerable influence on how results with 23-epi-26-deoxyactein (also known as 27-deoxyactein) of clinical studies evaluating black cohosh efficacy or its herb- being the most abundant congener [6]. drug interaction potential are interpreted. Nevertheless, based At present, black cohosh does not appear to be a potent modula- on the currently available data, standardized black cohosh sup- tor of human drug metabolism. In vitro studies found individual plements, when taken at recommended doses, pose little risk for triterpene glycosides to be relatively weak inhibitors (IC50 herb-drug interactions. > 100 µM) of human CYP3A4 [7,8], while whole extracts elicited Interaction risk: low. greater inhibition, a finding suggestive of synergy [7]. The inhib- itory effects of whole black cohosh extracts may stem not from triterpene glycosides but rather fukinolic and cimicifugic acids. Echinacea spp. ! These compounds are potent (IC50 < 13 µM) inhibitors of CYP1A2, 2D6, 2C9, and 3A4 in vitro [8]; however, their quantities vary con- Echinacea species (e.g., Echinacea purpurea [L.] Moench,E.angus- siderably among commercially available black cohosh products tifolia DC., E. pallida [Nutt.] Nutt.) of the family Asteraceae are [9], a factor that can profoundly affect their inhibitory activity in North American perennials whose roots and aerial parts have vivo. In human liver microsomes, IC50 values for CYP2B6, 2C19, been used traditionally for a variety of medicinal purposes [15, and 2E1 were approximately 50, 30, and 10 µg/mL, respectively, 16]. Echinacea formulations containing either root or whole plant for methanolic extracts of black cohosh [10]. However, when extracts are marketed for their “immune stimulatory” properties This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. compared to standard regimens of clarithromycin (500 mg daily and for prevention of the common cold [15,16]. Echinacea’spop- for 7 days) or rifampin (600 mg daily for 7 days), black cohosh ularity as an immune stimulator has placed it among the 10 top- supplementation (40–80 mg extract daily delivering 3–6mgtri- selling botanicals in the U.S. for many years. While evidence from terpene glycosides for 14 days) produced no demonstrable effects in vitro and animal studies lend credence to Echinacea prepara- on digoxin and MDZ pharmacokinetics [11,12]. These findings tions as immunomodulators, clinical findings remain equivocal. suggest that black cohosh is not a potent modulator of human (For reviews of clinical efficacy see references [15–19].) The three CYP3A4 or ABCB1 activity in vivo. Black cohosh supplementation species most commonly encountered are chemically dissimilar. also had no clinically significant effects on phenotypic measures Both E. purpurea and E. angustifolia contain alkamides as their of human CYP1A2, 2E1, or 2D6 activity [13]. When administered major lipophilic constituents, although of differing structural orally, black cohoshʼs principal triterpene glycoside, 23-epi-26- types (l" Fig. 2). By contrast, the lipophilic fraction of E. pallida is deoxyactein, reaches the systemic circulation intact, albeit in very characterized by polyacetylenes and is practically devoid of alka- low concentrations (< 10 ng/mL) [6]. This apparent lack of bio- mides. These phytochemical dissimilarities also extend to their transformation bolsters the idea that black cohosh triterpene respective plant parts (i.e., roots vs. aerial parts). As PSMs, poly- glycosides are unlikely to be inhibitors of human XMEs in vivo. acetylenes and alkamides are natural pesticides that, when in- Black cohosh extracts incorporating DMSO as a cosolvent moder- gested in relatively high amounts, can be toxic. In low concentra- Gurley BJ et al. Pharmacokinetic Herb-Drug Interactions (Part 2)… Planta Med 2012; 78: 1490–1514 1492 Reviews Fig. 2 Representative phytochemicals (alkamides, phenylpropanoids) present in Echinacea species. tions, however, alkamides appear to have beneficial effects [20]. 80%. Mild inhibitory effects on ABCB1- [43,44] and SLCO2B1- Other PSMs like caffeic acid esters (e.g., cichoric acid, echinaco- mediated [14] transport have also been demonstrated. side), polysaccharides, and alkenes are also thought to contribute Very few prospective clinical studies examining the interaction to echinaceaʼs activity. Because commercially available