One of the major concerns about the safety of dietary supplement ingredients is that interactions between a supplement and other ingested substances (e.g., drugs, other dietary supplements,1 conventional foods) will result in adverse clinical outcomes due to an increase or decrease in the level of the dietary supplement in the organism, an increase or decrease in the level of other xenobiotics,2 or combined toxicities. Potential adverse clinical outcomes may result if a dietary supplement lowers a drug’s effective concentration. Such a drop in active drug concentration can have serious consequences, especially for persons whose health depends on the therapeutic effects of a drug. As examples, AIDS patients must maintain a therapeutic
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Dietary Supplements: A Framework for Evaluating Safety 8 Interactions GUIDING PRINCIPLE: The principles used in identifying drug-food and drug-drug interactions should be applied to identifying possible dietary supplement-induced interactions with other bioactive compounds, including drugs, foods, and other dietary supplement ingredients. One of the major concerns about the safety of dietary supplement ingredients is that interactions between a supplement and other ingested substances (e.g., drugs, other dietary supplements,1 conventional foods) will result in adverse clinical outcomes due to an increase or decrease in the level of the dietary supplement in the organism, an increase or decrease in the level of other xenobiotics,2 or combined toxicities. Potential adverse clinical outcomes may result if a dietary supplement lowers a drug’s effective concentration. Such a drop in active drug concentration can have serious consequences, especially for persons whose health depends on the therapeutic effects of a drug. As examples, AIDS patients must maintain a therapeutic 1 Many dietary supplement products are mixtures of two or more substances, some of unknown structure, making an evaluation of interactions more complex, but also more likely to be of clinical concern as they are consumed simultaneously. 2 A chemical substance or compound that is foreign to the human body or to other living organisms.
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Dietary Supplements: A Framework for Evaluating Safety level of antiviral activity, cancer patients must maintain an effective concentration of chemotherapeutic agents, those with organ transplants must maintain a therapeutic level of immunosuppressant, and those with hypertension must maintain effective levels of antihypertensive drugs. Conversely, interactions can raise a drug’s level (or that of the dietary supplement ingredient itself) above the therapeutic range, which may lead to toxic effects. Interactions can be detected with human, animal, or in vitro studies or predicted on the basis of how related substances behave. Therefore, types of interactions are discussed in this chapter, experimental methods for identifying ingredients that may cause these types of interactions are described, and guidance on how to interpret the results from studies using these methods is provided. In addition, types of individuals most vulnerable to the various types of interactions are discussed. TYPES OF INTERACTIONS There are numerous mechanisms for interactions among xenobiotics, but most can be categorized as direct chemical-chemical, pharmacodynamic, or pharmacokinetic interactions. Direct Chemical-Chemical Interactions The formation of chemical-chemical complexes can modify the action of one or both chemicals. In general, these types of interactions require ingestion of both chemicals within a relatively short time of each other. An example of a direct chemical-chemical interaction occurs in the small intestine, where calcium carbonate taken as a supplement may bind to an acid substance, such as the antibiotic tetracycline, to form an insoluble product (Gugler and Allgayer, 1990). In this case, since the acid was a drug, the action of the drug would be reduced or lost. Other examples include cholestyramine, which adsorbs other drugs, thereby decreasing their availability for absorption, and antacids, which can block iron or zinc uptake. In addition to forming complexes, antacids may significantly change the rate of absorption of other chemicals by altering gastric pH or gastric emptying time, depending on the extent to which pH affects the amount of chemical in the un-ionized state (Azarnoff and Hurwitz, 1970; Hurwitz, 1971, 1977; Hurwitz and Scholzman, 1974; Hurwitz and Sheehan, 1971; Hurwitz et al., 1976). Pharmacodynamic Interactions Pharmacodynamic interactions are interactions that result in a change in the response to either the dietary supplement ingredient or the xenobiotic,
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Dietary Supplements: A Framework for Evaluating Safety but with no change in the plasma concentration of either. Pharmacodynamic interactions can result when two xenobiotics with similar pharmacological action produce an additive or synergistic response or when two xenobiotics with opposing pharmacological effects produce a reduced response. Predicting when a pharmacodynamic interaction may occur and the clinical results of this interaction depends on understanding the sites and mechanism of biological activity of both chemicals and predicting whether adequate levels are achieved at the sites of action. Direct Pharmacodynamic Interactions Direct pharmacodynamic interactions occur at the same site, such as an extracellular receptor or an enzyme where each xenobiotic exerts its pharmacological effect. The two xenobiotics may produce an additive physiological effect or, in the case of one being an antagonist or a weaker agonist, the result may be to decrease the response to the stronger agonist. Indirect Pharmacodynamic Interactions Indirect pharmacodynamic interactions occur when two xenobiotics act on the same physiological pathway from the receptor to the effector, but at different molecular sites of action. For example, two substances may each affect the same organ, but in different ways, and when taken together may greatly increase the propensity for organ damage, even if toxic effects are not detected independently. Interactions with Dietary Supplements There are examples of pharmacodynamic interactions that have been noted with dietary supplement ingredients. The antihypertensive effect of guanabenz acetate (a drug used for hypertension) is due to its central agonistic α-2-adrenoceptor activity (Grossman et al., 1993; Wenzel et al., 2001). Thus concomitant consumption of yohimbine bark, which contains an α-2-adrenoreceptor antagonist, may diminish the antihypertensive activity of guanabenz through its opposing pharmacodynamic effect. Another example is between the inotropic drug digitalis (Katzung, 2001) and hawthorne leaf or flower; data suggest that both the hawthorne leaf and the flower may also have a positive inotropic and electrophysiological effect on the heart (Schwinger et al., 2000). If digitalis and the hawthorne leaf or flower are taken together, the additive response may be excessive and lead to a serious adverse event (Schwinger et al., 2000). Another additive effect would be exhibited by the ginkgo leaf if its purported antagonism of platelet-activating factor occurred; if ingested with a cyclooxygenase inhibitor,
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Dietary Supplements: A Framework for Evaluating Safety such as aspirin, an increased propensity for bleeding would occur (Braquet, 1987; Lenoir et al., 2002; Vale, 1998; Vogensen et al., 2003). Pharmacokinetic Interactions Pharmacokinetic interactions are interactions that occur when one substance affects the absorption, distribution, metabolism, or excretion of another substance, resulting in altered levels of one of the substances or its metabolites. These interactions include effects caused by the chemicals on xenobiotic metabolizing enzymes and transporters that affect the time course of the concentration of one or both of the chemicals in the body. These interactions commonly take place in the intestines, liver, or kidney and are further categorized based on their site of action. Altered Metabolism Interactions that alter metabolism warrant attention. Xenobiotics often undergo extensive metabolic alteration by enzymes, resulting in the formation of structurally modified derivatives (metabolites) that may possess different pharmacologic activities (either greater or less) when compared with that of the consumed parent compound. There are more than 30 families of xenobiotic metabolizing enzymes in humans, many of which may be limiting for biotransformation of the consumed xenobiotic. If an ingested xenobiotic increases or decreases the amount or activity of a given enzyme, its own rate of metabolism may be altered, as well as that of other consumed compounds. The clinical effect of changes in enzyme metabolism rates will depend on the xenobiotic(s) involved and their metabolites and potencies. An important group of xenobiotic metabolizing enzymes are the cytochrome P450 (CYP) enzymes, a superfamily of hemoproteins that mediate the biotransformation of endogenous and exogenous compounds (Nelson et al., 1996) in the liver, as well as in the intestine and elsewhere. Some CYP isozymes found to be involved with significant pharmacokinetic reactions in humans are CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 (Health Canada, 2000; Ingelman-Sundberg, 2001). In addition, CYP2A6 and CYP2B6 are involved in metabolizing certain xenobiotics (Health Canada, 2000). Since many chemicals are substrates for the same CYP isozymes, one compound may inhibit the activity of the enzyme metabolizing another compound that is ingested concomitantly. In addition, ingestion of a chemical hours before another chemical may induce the production of more enzyme or inhibit normal enzyme synthesis, thus affecting the rate of metabolism of a second chemical metabolized by that same enzyme. While not without controversy, grapefruit juice provides one example of an interaction associated with
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Dietary Supplements: A Framework for Evaluating Safety CYP enzymes; it is reported to suppress CYP3A4 and change the concentration of drugs metabolized by the enzyme (Fuhr, 1998). When considering dietary supplement ingredient safety, assays for xenobiotic alterations of enzyme metabolism may generate important signals of possible concern, as discussed below. Altered Absorption, Distribution, and Excretion Until recently, pharmacokinetic interactions were considered as primarily attributable to the effects on xenobiotic metabolizing enzymes. However, an increasing number of transporters that affect chemical absorption, distribution, and excretion now seem to also play a significant role in pharmacokinetic interactions (Evans and Relling, 1999; Meyer, 2000). Transporters regulate the flux of substances into and out of cells or perform a variety of transmembrane transport functions. Depending on their location and activity, they may have a significant effect on the concentration of a chemical at its site of action (Kim, 2002). Important transporters are the multidrug resistance transporters, which include P-glycoproteins encoded by the MDR1 gene. P-glycoprotein functions as an efflux pump located in the cell membranes of enterocytes and hepatocytes, as well as the renal tubule epithelium (Fleisher et al., 1999; Yu, 1999). Interactions between chemicals resulting from competition at transporters are not uncommon. Thus in vitro methods to evaluate the effect of chemicals on particular transporters have been developed (Cummins et al., 2001). Due to differences in human and animal transporters, the methods often employ human transporter proteins expressed in artificial in vitro systems, enabling the detailed study of human transporter protein functions with regard to drugs and other xenobiotic substances, including dietary supplement ingredients. The concentration of the immunosuppressant drug cyclosporine attained in blood is controlled by the MDR1-encoded transporter and CYP. St. John’s wort is an example of a dietary supplement that has been shown to affect both the MDR1-encoded transporter and the enzyme CYP3A4 (Markowitz et al., 2003; Wang et al., 2001). St. John’s wort consumption by organ transplant patients requiring immunosuppressance can result in significant reductions in the concentration of cyclosporine, leading to organ rejection (Bauer et al., 2003; Karliova et al., 2000; Ruschitzka et al., 2000). Another example is the reported interaction between St. John’s wort and oral contraceptives. Circulating estrogen levels following oral contraceptive intake is regulated in part by the activity of MDR1-encoded transporters (Barnes et al., 1996). A woman who was taking oral contraceptives became pregnant after consuming St. John’s wort, which may have been
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Dietary Supplements: A Framework for Evaluating Safety due to enhanced efflux leading to ineffective levels of the oral contraceptive (Schwarz et al., 2003). Competition for Protein Binding Another type of potential pharmacokinetic interaction is binding to plasma proteins. Competition for protein binding sites by xenobiotics can alter the amount of unbound xenobiotic (i.e., free drug or other substance) available to exert its pharmacological effect (Shoeman and Azarnoff, 1975). The concern is that displacement of a highly plasma protein-bound xenobiotic by another compound may result in increased activity of the displaced compound. Although protein binding has long been described as a potential site of interaction, its actual importance has recently come under debate as some have provided evidence that changes in plasma protein binding are not clinically relevant (Benet and Hoener, 2002). It will be necessary to evaluate the potential for displacement from protein binding sites as an interaction on a case-by-case basis. The extent of protein binding, the protein binding site, and the concentration in blood of each substance are the main factors to consider. Effects on Excretion Renal or biliary excretion of xenobiotics, and thus the steady-state plasma concentration of xenobiotics, may also be affected by other xenobiotics. Changes in renal clearance of one xenobiotic can occur through effects of another substance on the urinary pH. Another mechanism for interaction is the effect of one substance on the active secretion of another substance into the renal tubule. Methods to evaluate the effects of a xenobiotic on excretion are available; they include measurement of tubular uptake, such as perfused kidney assays, or assays at the cellular level. Dietary supplement ingredients that inhibit tubular uptake or in any other way disrupt molecular mechanisms important to excretion of other xenobiotics should be considered of potential concern. PREDICTING THE POTENTIAL OF INGREDIENTS TO CAUSE PHARMACOKINETIC INTERACTIONS Techniques currently available allow the determination of the extent to which one substance may impact the concentration of other concomitantly ingested substances. There are numerous well-accepted in vitro assays designed specifically to determine if a drug may interact with other substances. There are also approaches for describing structures of chemicals
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Dietary Supplements: A Framework for Evaluating Safety likely to cause interactions. These in vitro studies and other approaches have focused on determining which drugs affect metabolizing enzymes and transporters and could similarly be used to determine which dietary supplements may lead to interactions. Whether an interaction predicted on the basis of in vitro studies actually occurs clinically will depend on whether the dietary supplement compound attains a concentration in vivo adequate to reproduce the effect observed in vitro, as discussed in more detail below. In Vitro Prediction of Pharmacokinetic Effects In vitro studies for determining which xenobiotics affect transporters and metabolic enzymes ideally employ human transporter proteins or human metabolic enzymes. For example, subcellular fractions of human liver tissue are commonly used, as are whole-cell models such as isolated human hepatocytes (Li, 1997; Sinz, 1999), liver slices (Ferrero and Brendel, 1997), and cell lines derived from human cancer cells (Yee and Day, 1999). Human transporters and enzymes can also effectively be studied by expressing them in other cell types (Crespi and Penman, 1997; Rodrigues, 1999). Changes in either the activity or amount of enzyme or transporter are detected with activity assays, pharmacological assays, and immunochemical or mRNA assays that detect changes in protein or transcription (Li, 1997). In vitro assays for predicting possible interactions are a well-accepted staple of the drug development process. The limitation to using these assays to predict clinical interactions lies, like most in vitro assays, in relating the dose at which enzyme or transporter effects are observed with the amount of unbound xenobiotic present at the active site in vivo. If information about the concentration of xenobiotic reached in vivo is available, a comparison of a dietary supplement ingredient’s inhibitory binding constants (Ki) for the CYP enzymes and the in vivo concentration (Cmax) may place the in vitro information in the appropriate perspective. Animal and Human In Vivo Data in Predicting Pharmacokinetic Effects Given the inter- and intraspecies differences in xenobiotic metabolizing enzymes, it is ideal to study xenobiotic metabolism using human cells, subcellular fractions of human tissue, or heterologously expressed human proteins (see Health Canada, 2000), although information about effects on animal proteins may serve as a preliminary indicator of concern. The study of human proteins in transgenic animals may improve ability to relate effects observed in animals or animal cells to humans. Humans themselves may also be studied to determine if a given xenobiotic may cause an observable interaction. Such tests are usually designed to compare the levels of a test substrate with and without the
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Dietary Supplements: A Framework for Evaluating Safety xenobiotic in question. For example, a study of St. John’s wort in humans demonstrated that it increased the metabolism of CYP3A4 substrates (Markowitz et al., 2003). Even if specific interaction assays are not done, information about the in vivo concentrations achieved in humans is useful in placing in vitro information in perspective. Databases for Predicting Interactions Databases helpful for identifying substances likely to interact with other substances have been organized. For example, the database produced by the University of Washington is useful for locating information about potential interactions of particular dietary supplements with other substances (UW, 2003). The database also organizes information, such as drug effects on CYP enzymes, that may be useful for identifying potential interactions between particular drugs and supplements. A publicly available website at the Indiana University School of Medicine provides information about drugs metabolized by specific P450 isoforms (Indiana University, 2003). Vulnerable Subpopulations Some individuals are particularly sensitive to adverse effects from xenobiotic interactions because of polymorphic differences that affect the metabolism of some xenobiotics (Ingelman-Sundberg et al., 1999). There are recognized genetic polymorphisms that account for diminished or absent expression of one or more forms of xenobiotic-metabolizing enzymes. There are documented adverse effects directly resulting from the altered metabolism of certain drugs metabolized by these enzymes. A well-known example is people who exhibit little or no CYP2D6 activity in the liver because of inherited genes defective in expression of this form of CYP—a condition that affects 7 to 10 percent of Caucasians, by one estimate (Cascorbi, 2003). As a result, such individuals are found to experience toxic effects from ordinary doses of the antihypertensive agent debrisoquine, as well as many other drugs for which metabolic elimination is primarily catalyzed by CYP2D6 (Cascorbi, 2003). It would be reasonable to expect that any dietary supplement ingredient dependent on CYP2D6 for metabolic conversion could potentially produce toxic effects in such persons. Numerous other polymorphisms in xenobiotic metabolism have been or are being identified. Such data can serve to identify people who may be particularly sensitive to dietary supplements cleared by these polymorphic xenobiotic metabolizing systems.
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Dietary Supplements: A Framework for Evaluating Safety Practical Impact of Shared Pharmacokinetic Pathways on Predicting Interactions A dietary supplement that affects the pharmacokinetics of one xenobiotic may be of concern when concomitantly consumed with any of a number of other xenobiotics because the pharmacokinetic pathways are shared by so many substances. This is especially true for dietary supplements that interact with the CYP enzymes. CYP3A, for example, is considered to be largely responsible for the metabolism of a large number (some have estimated 50 percent) of clinically prescribed drugs and probably a large share of other xenobiotics, including other chemicals and dietary supplements (Ingelman-Sundberg et al., 1999). The state of scientific understanding in this field is such that it is unnecessary to test each and every combination of xenobiotics to predict potential risks. Reasonable scientific inferences can be made to anticipate risks without accumulating clinical examples of each combination. For example, there is sufficient knowledge about the catalytic functions of human CYP3A to confidently predict that if St. John’s wort causes the loss of function of HIV drugs by inducing CYP3A (Piscitelli et al., 2000), the same interaction extends to some of the other known substrates of CYP3A. The same thought process and scientific reasoning would apply to the other xenobiotic metabolizing and transporting systems, as well. That is, the more general the pathway affected by the dietary supplement ingredient, the more widespread the potential for interaction. SUMMARY Dietary supplements have a potential to adversely affect public health by interacting with other substances. Whether this concern is addressed by labeling precautions, withdrawal of such dietary supplements from the market or requiring warning labels related to usage with other xenobiotics is a regulatory decision. Pharmacists and physicians are made aware of drugs and foods that can potentially interact with other drugs, and drug labeling warns about potential problems. There is no analogous prescribed mechanism to prevent dietary supplement-mediated interactions. A number of pieces of information can suggest a possible interaction between a dietary supplement ingredient and other substances. The potential seriousness of these interactions varies and is placed in perspective by considering if a particular interaction leads to serious adverse events and the likelihood that the interaction will occur. This relative spectrum of concern is illustrated in Table 8-1.
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Dietary Supplements: A Framework for Evaluating Safety TABLE 8-1 Spectrum of Concern for Interactions Increasing Concern Pharmacokinetic and/or pharmacodynamic data suggesting a supplement-drug/food/other dietary supplement interaction that might lead to a serious adverse event and/or identifying a population at risk for a serious adverse event Pharmacokinetic and/or pharmacodynamic data documenting a supplement-drug/food/ other dietary supplement interaction that might leads to a serious adverse event and/or identifying a population at risk for a serious adverse event Pharmacokinetic and/or pharmacodynamic data documenting a supplement-drug/food/other dietary supplement interaction that lead to a serious adverse event REFERENCES Azarnoff DL, Hurwitz A. 1970. Drug interactions. Pharmacol Physicians 4:1–7. Barnes KM, Dickstein B, Cutler GB Jr, Fojo T, Bates SE. 1996. Steroid transport, accumulation, and antagonism of P-glycoprotein in multidrug-resistant cells. Biochemistry 35:4820–4827. Bauer S, Stormer E, Johne A, Kruger H, Budde K, Neumayer HH, Roots I, Mai I. 2003. Alterations in cyclosporin A pharmacokinetics and metabolism during treatment with St John’s wort in renal transplant patients. Br J Clin Pharmacol 55:203–211. Benet LZ, Hoener BA. 2002. Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther 71:115–121. Braquet P. 1987. The ginkgolides: Potent platelet-activating factor antagonists isolated from Ginko biloba L: Chemistry, pharmacology and clinical applications. Drugs Future 12:643–699. Cascorbi I. 2003. Pharmacogenetics of cytochrome P4502D6: Genetic background and clinical implications. Eur J Clin Invest 33:17S–22S. Crespi CL, Penman BW. 1997. Use of cDNA-expressed human cytochrome P450 enzymes to study potential drug-drug interactions. Adv Pharmacol 43:171–188. Cummins CL, Mangravite LM, Benet LZ. 2001. Characterizing the expression of CYP3A4 and efflux transporters (P-gp, MRP1, and MRP2) in CYP3A4-transfected Caco-2 cells after induction with sodium butyrate and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate. Pharm Res 18:1102–1109. Evans WE, Relling MV. 1999. Pharmacogenomics: Translating functional genomics into rational therapeutics. Science 286:487–491. Ferrero JL, Brendel K. 1997. Liver slices as a model in drug metabolism. Adv Pharmacol 43:131–169. Fleisher D, Li C, Zhou Y, Pao LH, Karim A. 1999. Drug, meal and formulation interactions influencing drug absorption after oral administration. Clinical implications. Clin Pharmacokinet 6:233–254. Fuhr U. 1998. Drug interactions with grapefruit juice. Extent, probable mechanism and clinical relevance. Drug Safe 18:251–272. Grossman E, Rosenthal T, Peleg E, Holmes C, Goldstein DS. 1993. Oral yohimbine increases blood pressure and sympathetic nervous outflow in hypertensive patients. J Cardiovasc Cardiol 22:22–26.
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