Constituent percent of extracts should be referred to as strength, with potency measurements to define the biological impact.
Steven Dentali, PhD, Herbalife International of America, Inc.09.09.13
The first two columns of this “Botanical Basics” series provided tools to 1) understand how a single name can refer to a variety of botanical materials, such as the plant itself, the ingredient, finished product, etc. and 2) understand extract types with regard to complexity, solvents and herb-to-extract ratios. Last time (June issue) I preempted exploring the connection between strength and potency, and how it relates to standardization of botanical ingredients, for in-depth coverage of botanical ingredient identification. Now I return to strength and potency.
The botanical ingredients used by industry are generally identified by three elements: name, price and a percent of something, as if these ingredients were fine chemicals of a specified purity. Herb X, constituent Y and Z percent are presented as if that, and price, is all one needs to know in order to make a wise purchasing decision. I’d like to take a deeper look at this Z percent-constituent Y designation and determine what it means, and doesn’t mean, with regard to strength and potency. Perhaps this will change your thinking on the topic, or if you haven’t considered it before, then to get you thinking about it.
Fine chemicals are different than botanical ingredients. The former are single, chemically defined materials to which a purity can be assigned. Vitamins and minerals are available for purchase in supplement products in different forms at different purity levels. Botanical ingredients are much more complex because they are comprised of multiple groups of multiple constituents; they cannot be accurately represented as a fine chemical, unless of course, it is essentially a fine chemical extracted from a botanical.
There are cases where it may make sense to think of a botanical more or less as a chemical, such as when its bioactivity is derived from a single constituent, or a group of constituents. This is the case when the desired effect from a botanical ingredient can be obtained from those constituents administered alone. For example, the anti-anxiety effect of kava’s underground parts can be obtained from its kavalactone constituents, of which there are six that are known to occur in substantial concentrations. If those six constituents are consumed in the same ratio and amount as they occur in a crude kava extract, their pharmacological effects are virtually the same as those from the extract.
When the bioactivity of an extract can be accounted for by an individual or group of constituents, it is most like a drug in the sense that the identified chemicals account for the activity of that extract. This is true only when the bioactivity is fully accounted for by those constituents. In such cases, the source of the chemical hardly matters. Caffeine is stimulating whether it is found in coffee, tea, guaraná or yerba mate, and whether isolated, synthesized or purified. Herbal substances and herbal preparations containing such constituents with known therapeutic activity are defined as “standardized” by the European Medicines Agency and adjustment of these constituent concentrations by the mixing of production batches or with excipients is allowed. It is their potency, as well as their chemistry, that is standardized.
Although the term “potency” has other powerful connotations, I’m using it to refer to pharmacological activity: the capacity to produce a physiological effect. This is, after all, what drugs do; they produce physiological effects. Their potency is assumed to be in direct relationship to the amount of drug substance present. This is true for nutrients too, and how we buy supplements. Twice the amount of vitamin C is, well, just that. However, different forms of vitamins and minerals can be absorbed differently and have varying levels of pharmacological activity. In these cases their potency differs while the amount of source nutrient may remain the same.
However, the measured amount of a botanical constituent doesn’t always equate to the amount of its biological activity. For example, the percent of an identified botanical constituent is rarely a direct measure of the bioactivity of the source botanical. By bioactivity I mean the size, magnitude of pharmacological activity, or biological response, which must be measured in a biological system, not a purely analytical chemical one. There are chemical assays to measure the amount of chemical, and biological assays to measure the amount of biological response.
Biological assays are not new. When digitalis and its extracts were used to treat congestive heart failure, biological assays were suited to measure the potency of the drug, because chemical assays were not. An official drug was made from the leaves of Digitalis purpurea (foxglove) and sold in powder form, after adjusting to a standard pharmacological strength, along with tablets, tinctures and injections. Related drugs were made from D. lanata, (Grecian or woolly foxglove), D. lutea (straw foxglove), and D. thapsi (Spanish foxglove) said to be 2-3 times more potent than D. purpurea (Pharmacognosy, SB Gokhale, Pragati Books Pvt. Ltd. 2008).
The therapeutic dose of digitalis is not a whole lot less than the toxic dose, so a measure of its potency was critically important for doctors and their human patients, and quite unfortunate for the frogs and pigeons it was tested on. The use of another bioassay, a rather curious one, is mentioned in a 1972 paper from the Journal of Pharmaceutical Sciences titled “Biological and chemical evaluation of a 43-year-old sample of Cannabis fluidextract” authored by Kubena RK, Barry H, Segelman AB, Theiner M, and Farnsworth NR (Jan;61(1):144-5) in which not only did the chemical constituents of a 43-year-old cannabis liquid extract hold up after room temperature storage over that time, but it also produced the “characteristic ataxia in dogs” after oral administration! Indeed, among the biological assays present in the Pharmacopoeia of the United States of America, Ninth Decennial Revision, of 1916 (pages 605-606) is a description of the assay used, in which a standard cannabis tincture is defined as producing incoordination in dogs when administered in a dose of 0.3 milliliters for each kilogram (2.2 pounds) of the weight of the dog. Fox terriers are noted as serving very well for the purpose. I wonder if that’s true for Jack Russell terriers too.
A decade or two ago there was a move to not only identify botanical ingredients and to profile them chemically, but also to assign a biological standard to their activity to “biologically standardize” them. Biological standardization requires measuring bioactivity in a biological system of some kind. However, the bioassays tended to be in vitro—test tube ones, not frogs, pigeons or dogs. Since that time, other assays have been proffered as indicators of biological activity. Most notable among these has been antioxidant values, with ORAC (oxygen radical absorbance capacity) the most famous of them.
While ORAC isn’t a biological system, I mention it because it was assumed to be a proxy for one. The theory was that if certain plant constituents could quench free radicals in a test tube, then they would do the same thing in the human body, thereby preventing the nasty effects of free radical induced chronic disease. Nice theory, but it’s wrong. Plant constituents that have antioxidant activity in a test tube probably do have beneficial effects, but not through direct antioxidant activity in the body. Other, more subtle mechanisms are likely at work.
While there is good reason to believe that dark colored fruits and vegetables are good for us, there is insufficient evidence to support the concept that a higher ORAC value means a necessarily healthier ingredient. In fact, the U.S. Department of Agriculture’s concern about the misperception (and misuse) of their published ORAC values led to their removal from the USDA website. (Problems with the reproducibility of the method have also been noted.) The unfortunate result is that while ORAC values do measure something, it may not be directly relevant to human health, which is too bad. If the antioxidant value of blood was a validated biomarker for health and eating foods high in ORAC values raised it, wouldn’t life be easier? Or at least picking which colors of foods and how much of them to eat might be.
Getting back to the basics now, herbal preparations in the form of extracts with identified marker constituents are widespread commodities. Most often these extracts are incompletely defined by marker compounds; the marker compounds don’t fully account for the bioactivity of the source extract and therefore aren’t a measure of potency. Because of this, two different extracts can have the same amount of an identified constituent but produce different levels of biological effect. Let’s call the level of constituent marker a determination of strength and leave potency measurements to the pharmacologists, shall we?
Steven Dentali, PhD, vice president, Botanical Sciences, Herbalife International of America, Inc., studied herbal medicine in the Pacific Northwest, finding a disconnect between the herbal and academic communities. He subsequently earned his doctorate in Pharmaceutical Sciences with a specialization in Natural Products Chemistry from the University of Arizona, Tucson. An American Foundation for Pharmaceutical Education Fellow, Dr. Dentali is recognized as a foremost expert in the natural products industry. He is a member of the United States Pharmacopoeia 2010-2015 Convention, Editorial Board Chair of AOAC International, and is an advisory board member of the American Botanical Council and the American Herbal Pharmacopeia. A frequent lecturer, he also serves as a reviewer for the National Center for Complementary and Alternative Medicine at NIH. He can be reached at email@example.com; Website: www.herbalife.com.
Overington, J. P., Al-Lazikani, B. & Hopkins, A. L.How many drug targets are there?Nature Rev. Drug. Discov.5, 993–996 (2006).
Li, D. & Kerns, E. H.Application of pharmaceutical profiling assays for optimization of druglike properties. Curr. Opin. Drug Discov. Devel.8, 495–504 (2005).
Peck, R. W.Driving earlier clinical attrition: if you want to find the needle, burn down the haystack. Considerations for biomarker development. Drug Discov. Today12, 289–294 (2006).
Paul, S. M.et al.How to improve R&D productivity: the pharmaceutical industry's grand challenge. Nature Rev. Drug Discov.9, 203–214 (2010).
Kalgutkar, A. S.et al.A comprehensive listing of bioactivation pathways of organic functional groups. Curr. Drug Metabol.6, 161–225 (2005).
Keseru, G. M. & Makara, G. M.The influence of lead discovery strategies on the properties of drug candidates. Nature Rev. Drug Discov.8, 203–212 (2009).
Lackey, K.Lessons from the drug discovery of lapatinib, a dual ErbB1/2 tyrosine kinase inhibitor. Curr. Topics Med. Chem.6, 435–460 (2006).
Lipinski, C. A., Lombardo, F., Dominy, B. W. & Feeney, P. J.Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev.23, 3–25 (1997). This paper highlighted for the first time the link between drug-likeness and key physicochemical properties (that is, the rule of 5).
Teague, S. J., Davis, A. M., Leeson, P. D &, Oprea. T.The design of leadlike combinatorial libraries. Angew. Chem. Int. Ed.38, 3743–3748 (1999).
Hann, M. M., Leach, A. R. & Harper, G.Molecular complexity and its impact on the probability of finding leads for drug discovery. J. Chem. Inf. Comput. Sci.41, 856–864 (1999).
Leeson, P. D., Davis, A. M. & Steele, J.Drug-like properties: guiding principles for design — or chemical prejudice?Drug Discov. Today1, 189–195 (2004).
Lajiness, M. S., Vieth, M. & Erickson, J.Molecular properties that influence oral drug-like behaviour. Curr. Opin. Drug Disc. Devel.7, 470–477 (2004).
Hann, M. M. & Oprea, T. I.Pursuing the leadlikeness concept in pharmaceutical research. Curr. Opin. Chem. Biol.8, 255–263 (2004).
Leeson, P. D. & Davis, A. M.Time-related differences in the physical property profiles of oral drugs. J. Med. Chem.47, 6338–6348 (2004).
Li, D. & Kerns, E. H.Biological assay challenges from compound solubility: strategies for bioassay optimization. Drug Discov. Today11, 446–451 (2006).
Wunberg, T.et al.Improving the hit-to-lead process: data-driven assessment of drug-like and lead-like screening hits. Drug Discov. Today11, 175–180 (2006).
De Witte, R. S.Avoiding physicochemical artefacts in early ADME–Tox experiments. Drug Discov. Today11, 855–859 (2006).
Leeson, P. & Springthorpe, B.The influence of drug-like concepts on decision-making in medicinal chemistry. Nature Rev. Drug Discov.6, 881–890 (2007). An excellent paper that describes, with well-chosen examples, the importance of physicochemical properties in medicinal chemistry research.
Proudfoot, J.The evolution of synthetic oral drug properties. Bioorg. Med. Chem. Lett.15, 1087–1090 (2005).
Johnson, T. J., Dress, K. R. & Edwards, M.Using the Golden Triangle to optimize clearance and oral absorption. Bioorg. Med. Chem. Lett.19, 5560–5564 (2009).
Waring, M. J.Defining optimum lipophilicity and molecular weight ranges for drug candidates — molecular weight dependent lower logD limits based on permeability. Bioorg. Med. Chem. Lett.19, 2844–2851 (2009).
Hopkins, A. L., Groom, C. R. & Alex, A.Ligand efficiency: a useful metric for lead selection. Drug Discov. Today9, 430–431 (2004).
Gleeson, M. P.Generation of a set of simple, interpretable ADMET rules of thumb. J. Med. Chem.51, 817–834 (2008). An interesting paper that assesses the link between molecular mass, logP and ionization state for a range of ADMET parameters that are routinely measured in industry.
Sneader, W.Drug Prototypes and their Exploitation. (Wiley, Chichester, 1996).
Oprea, T. I., Davis, A. M., Teague, S. J. & Leeson, P. D.Is there a difference between leads and drugs? A historical perspective. J. Chem. Inf. Comput. Sci.41, 1308–1315 (2001).
Hadjuk, P. J.Fragment-based drug design: how big is too big?J. Med. Chem.49, 6972–6976 (2006). This paper highlighted the benefits of selecting the most ligand-efficient molecular templates in lead generation.
Wenlock, M. C., Austin, R. P., Barton, P., Davis, A. M. & Leeson P. D.A comparison of physiochemical property profiles of development and marketed oral drugs. J. Med. Chem.46, 1250–1256 (2003). This study showed that, as compounds in different phases of development get closer to the market, their mean molecular mass and logP tend to converge towards those of marketed drugs.
Tyrchana, C., Blomberga, N., Engkvista, O., Kogeja, T. & Muresan, S.Physicochemical property profiles of marketed drugs, clinical candidates and bioactive compounds. Bioorg. Med. Chem. Lett.19, 6943–6947 (2009).
Oprea, T. I.et al.Lead-like, drug-like or ''pub-like'': how different are they?J. Comput. Aided Mol. Des.21, 113–119 (2007).
Andrews, P. R., Craik, D. J. & Martin, J. L.Functional group contributions to drug-receptor interactions. J. Med. Chem.27, 1648–1657 (1984).
Kuntz, I. D., Chen, K., Sharp, K. A. & Kollman P. A.The maximal affinity of ligands. Proc. Natl Acad. Sci. USA96, 9997–10002 (1999).
Abad-Zapatero, C. & Metz, J. T.Ligand efficiency indices as guideposts for drug discovery. Drug Discov. Today10, 464–469 (2005).
Perola, E.An analysis of the binding efficiencies of drugs and their leads in successful drug discovery programs. J. Med. Chem.53, 2986–2997 (2010).
Hadjuk, P. J., Huth, J. R. & Tse, C.Predicting protein druggability. Drug Discov. Today10, 1675–1682 (2005).
Vieth, M. & Sutherland, J. J.Dependence of molecular properties on proteomic family for marketed oral drugs. J. Med. Chem.49, 3451–3453 (2009).
Goh, K.et al.The human disease network. Proc. Natl Acad. Sci. USA104, 8685–6690 (2007).
Zimmermann, G. R., Lehár, J. & Keith, C. T.Multi-target therapeutics: when the whole is greater than the sum of the parts. Drug Discov. Today12, 34–42 (2007).
Hopkins, A. L., Mason, J. S. & Overington, J. P.Can we rationally design promiscuous drugs?Curr. Opin. Struct. Biol.16, 127–136 (2006).