As is well known to many people in the medicinal plant research community and dietary supplement industry, dietary supplements, including herbal products, are not subject to the same regulatory guidelines for pre-market testing as conventional pharmaceutical drugs in the United States. This is due to a variety of regulatory reasons regarding dietary supplements’ being viewed more as foods rather than drugs that are not relevant for further discussion here. However, some health professionals and others have expressed varying degrees of interest and concern regarding the potential for clinically relevant interactions between conventional pharmaceutical medications and herbal and other dietary supplements.1,2 Considerations such as history of safe use (within context of traditional versus modern usages), literature data from pharmacology and toxicity studies, and constituent amounts in supplement products provide some guidance on whether to assess herb-drug interactions (HDIs) experimentally. The scientific literature is replete with pre-clinical reports of various herbal extracts and constituents as potent inhibitors of drug-metabolizing enzymes (Table 1).3-6 However, without the use of appropriate analytical methods for herbal product characterization and quantitation of constituents, dose performance analysis, or in vitro testing in physiologically relevant models to allow some prediction of bioavailability of key constituents, extrapolating these reports to determine whether human testing is necessary to identify clinically relevant HDIs is difficult. This lack of a clear determination of risk hinders clinicians and consumers from making informed decisions about the safety of taking herbal products with conventional medications. A suitable framework is needed that describes a flexible approach for assessing when human HDI studies are warranted, and an outline of standard methods when HDI testing is conducted.
Figure 1. A summary of the key components that should be included in a common framework for assessing potential herb-drug interactions (HDIs).
Herbal product usage in Western countries continues to increase across all age groups.7,8 Individuals in these countries also have ready access to conventional medications, and significant polypharmacy is often observed, particularly in women and older adults.8,9 Many patients are reticent to disclose herbal product usage to their healthcare providers, and many providers still do not inquire about such usage. In addition, many healthcare professionals are now recommending herbal products to counteract side effects of some conventional drugs.10 Thus, the potential for both HDIs and drug-drug interactions is frequently ignored in clinical practice because of the complexity of the problem. The net result is that the opportunity for clinically significant HDIs exists and should be evaluated in a systematic manner.
Although dietary supplements and herbal products in most countries are not subject to the same regulatory guidelines for pre-market testing as conventional drugs, there is an increasing focus by many regulatory agencies on the potential for HDIs. Likewise, consumers have an increased awareness of HDIs as a result of numerous media reports. Providing accurate information on potential HDIs facilitates informed decision-making by consumers and healthcare providers.
Table 1. Examples of potent in vitro CYP450 and/or transporter inhibition by herbal extracts or constituents as reported in the scientific literature with no current follow-up as to clinical relevance.
Herb and plant part / Individual Constituent(s)*
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CYP450/Transporter Inhibited
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Reference
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Frankincense tree resin extract, (Boswellia serrata,Burseraceae)
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CYP1A2, 2C8, 2C9, 2C19, 2D6, 3A4
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3
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β-Boswellic acid, 11-keto- β-Boswellic acid
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CYP2C8, 2C9, 3A4
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3
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Acetyl-11-keto- β-Boswellic acid,
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CYP2C9, 3A4
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3
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Acetyl- β-Boswellic acid
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CYP2C9
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3
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Schisandra fruit (aka five-flavor-fruit) extract, (Schisandra chinensis, Schisandraceae)
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CYP3A4
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4
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Gomisin C, Gomisin B, Gomisin G
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CYP3A4
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4
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Gomisin N, Gomisin A
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CYP2C19, 3A4
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4
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Rhodiola root (aka Golden root) extract, (Rhodiola rosea,Crassulaceae)
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CYP3A4, P-gP
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5
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Cat’s claw herb extract, (Uncaria tomentosa, Rubiaceae)
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CYP3A4
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6
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* Standardized common name and Latin binomial, family name per American Herbal Products Association’s Herbs of Commerce, 2d ed.(2000),14 and United States Department of Agriculture’s Agriculture Research Service (ARS) GRIN database.15
There are an increasing number of scientific papers related to the field of HDIs. However, most studies utilize simple in vitro metabolic systems (e.g., liver microsomes), and the results are likely too unreliable to provide meaningful assessment of clinically relevant HDI potential. The exposure in vitro to the complete phytochemical complexity of an herb or herbal extract does not represent the systemic exposure to the ingested and altered phytochemical matrix or its limited absorption and variable distribution. Thus, most of these reports are preliminary and often do not attempt to define the clinical relevance of such findings. There is little follow-up work conducted in more complex in vitro systems such as whole-cell hepatocytes with fully functional transporter and metabolizing enzymes, or the use of physiologic-based pharmacokinetic (PBPK)models to extrapolate to in vivo relevance. Won et al. recently reviewed a number of dietary substance-drug interactions in which both in vitro and clinical data exist, and in many cases there was no correlation of findings.11 In addition, there is sometimes poor analytical characterization of the botanical materials used, contributing in large part to inconsistent findings across studies.
In the prescription medicine world, there is clear guidance on how to assess potential drug-drug interactions.12,13 Because there is no standard/systematic regulatory guidance on testing for HDI potential, there is an opportunity in the scientific community to lead the way in establishing a framework for assessing HDI potential.
From a dietary supplement industry perspective, an ideal framework approach for assessing HDI potential would include the following criteria:
- A screening approach that can encompass a pipeline (i.e., “higher throughput”);
- Cost and resource efficiency;
- Must be readily transferable to external partners (e.g., contract research organizations) since many companies do not have the internal expertise and/or testing facilities;
- Be consistently applied across the industry;
- Include a decision tree on when more in-depth studies may be warranted (e.g., tiered approach);
- Provide guidance on how to design and interpret studies;
- Provide guidance on how to apply HDI information to dose adjustment, labeling, and/or post-marketing surveillance strategy.
The key components that should be included in a common framework for assessing HDI potential are summarized in Figure 1. Likewise, there are a number of important considerations that should be included within each component (Table 2). Follow-up studies may be warranted in situations where there is an inconsistent history of safe use or insufficient literature data on HDI potential — e.g., no data available on cytochrome P450 (CYP450)/transporter inhibition/induction potential, or literature data reporting potent in vitro inhibition of CYP450s/transporters. When testing is necessary, one can borrow, where relevant, from the drug-drug interaction guidances of the US Food and Drug Administration and European Medicines Agency.12,13
Table 2. Important considerations that warrant inclusion within each component of a framework for assessing potential HDIs.
History of Safe Use:
- How do geography and culture of historical use compare to proposed product market?
- Is historical use the same as proposed product use?
- Same form (whole plant vs. plant part vs. single ingredient)?
- What is known about the consumer population that product targets (acute vs. chronic use, underlying disease/conditions, co-medications, age group)?
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Literature Data:
- PK studies on constituents provide understanding of which constituents are readily absorbed and what relevant concentrations to use in in vitro assays.
- Which drug metabolizing enzymes/transporters are affected may guide the need to do additional studies (e.g., potent inhibition of CYP3A4 would likely be more concerning than moderate inhibition of CYP1A2).
- Are there clues in the clinical chemistry and/or histopathology from animal toxicity studies that may indicate potential effects on drug metabolizing enzymes or transporters (e.g., increases in bilirubin, cholestasis, increased liver weight, etc.)?
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Incorporation of Analytical Characterization:
- Useful for assessing toxicity potential, but can also be applied to assessing HDI potential.
- Enables further data mining of literature for HDI information.
- Are there any structure-activity relationship (SAR) alerts for individual constituents of the herbal extract/constituent?
- Quantitation of individual constituents can be useful in predicting potential exposure levels, designing in vitro studies, or whether additional testing is necessary (cost effective).
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Dose Performance:
- Disintegration of dose form
- Dissolution of constituents
- Physical-chemical data on constituents
- Solubility information on extract/constituents
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In summary, there is a need to form an academia/industry/regulatory-wide expert working group to develop a framework for assessing HDI potential. Expertise is needed in diverse areas including in vitrometabolism/transporter studies, PBPK modeling, clinical pharmacokinetics, analytical chemistry, biopharmaceutics, and risk assessment. The objective of an expert working group would be to develop a comprehensive strategy that incorporates these key components into an overall HDI “risk assessment” that facilitates informed decision-making by consumers and healthcare providers.
The topic of assessing HDI potential will be highlighted at the 41st Annual Summer Meeting of the Toxicology Forum, July 12-16, 2015. A plenary presentation entitled, “Assessing Potential Natural Product-Drug Interactions: Need for a Common Framework Approach,” which further defines the concepts captured herein, will be presented by a number of experts in this field. Details related to this meeting can be found at:http://toxforum.org/next_meeting.
Amy L. Roe, PhD, is a senior toxicologist in the personal healthcare division at The Procter & Gamble Company in Cincinnati, Ohio. She received her PhD in toxicology from the University of Kentucky in 1997 and conducted post-doctoral work at the University of Cincinnati. Her expertise includes general and regulatory toxicology, drug/xenobiotic metabolism, and pharmacokinetics. She is a diplomate and current board member of the American Board of Toxicology, and serves as councilor on the Regulatory and Safety Evaluation Specialty Section of the Society of Toxicology. She can be contacted at roe.al@pg.com.
DisclosureThe Procter & Gamble Company is a distributor of dietary supplement products.
AcknowledgementsThe author would like to acknowledge discussions and input to this framework approach from Mary Paine, PhD (Washington State University), Bill Gurley, PhD (University of Arkansas for Medical Sciences), Rick Kingston, PharmD (SafetyCall International), Hellen Oketch, PhD (United States Pharmacopeia), and James Griffiths, PhD (Council for Responsible Nutrition).
References
3. Frank A, Unger M. Analysis of frankincense from various Boswellia species with inhibitory activity on human drug metabolising cytochrome P450 enzymes using liquid chromatography mass spectrometry after automated on-line extraction. J Chromatogr A. 2006;1112(1-2):255-262.
4. Iwata H, Tezuka Y, Kadota S, Hiratsuka A, Watabe T. Identification and characterization of potent CYP3A4 inhibitors in schisandra fruit extract. Drug Metab Dispos. 2004;32(12):1351-1358.
5. Hellum BH, Tosse A, Hoybakk K, Thomsen M, Rohloff J, Nilsen OG. Potent in vitro inhibition of CYP3A4 and P-glycoprotein by Rhodiola rosea. Planta Med. 2010;76(4):331-338.
6. Budzinski JW, Foster BC, Vandenhoek S, Arnason JT. An in vitro evaluation of human cytochrome P450 3A4 inhibition by selected commercial herbal extracts and tinctures. Phytomedicine. 2000;7(4):273-282.
7. Gahche J, Bailey R, Burt V, et al. Dietary supplement use among U.S. adults has increased since NHANES III (1988-1994). NCHS Data Brief. 2011;(61):1-8.
8. Djuv A, Nilsen OG, Steinsbekk A. The co-use of conventional drugs and herbs among patients in Norwegian general practice: a cross-sectional study. BMC Complement Altern Med. 2013;13:295. doi: 10.1186/1472-6882-13-295.
9. Farina EK, Austin KG, Lieberman HR. Concomitant dietary supplement and prescription medication use is prevalent among US adults with doctor-informed medical conditions. J Acad Nutr Diet. 2014;114(11):1784-1790.e2. Available at: www.andjrnl.org/article/S2212-2672(14)00106-3/pdf. Accessed April 27, 2015.
11.Won CS, Oberlies NH, Paine MF. Mechanisms underlying food-drug interactions: inhibition of intestinal metabolism and transport. Pharmacol Ther. 2012;136(2):186-201.
14.McGuffin M, Kartesz JT, Leung AY, Tucker AO, eds. American Herbal Products Association’s Herbs of Commerce, 2nd ed. Silver Spring, MD: American Herbal Products Association; 2000.
15.USDA, ARS, National Genetic Resources Program. Germplasm Resources Information Network (GRIN) Online Database, National Plant Germplasm Sytem. Available at: www.ars-grin.gov/npgs/. Accessed April 27, 2015.
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