Nutrients and Therapeutic Drugs

C H A P T E R

60 Interactions between Nutraceuticals/ Nutrients and Therapeutic Drugs Arturo Anadón, María Rosa Martínez-Larrañaga, Irma Ares and María Aránzazu Martínez INTRODUCTION Interactions between foods/dietary supplements and drugs present complex and challenging problems. They may arise either from alteration of the absorption, distribution, biotransformation, or excretion of one drug by a food/dietary supplement or from a combination of their actions or effects. The interactions can have a marked influence on the success of drug treatment and on the adverse effect or side effect profiles of many drugs; however, the interactions are not always harmful to therapy, but in some cases they can be used to improve drug absorption or to minimize adverse effect. Most food/dietary supplements and drug interactions occur through one of three mechanisms: (i) reduced rate or extent of absorption; (ii) increased rate or extent of absorption; or (iii) through chemical/pharmacologic effects. Macronutrients are nutrients that humans consume in the largest quantities and that provide bulk energy. They are needed for a wide range of body functions and processes. These three macronutrients are fat, protein, and carbohydrates. Micronutrients are essential vitamins and minerals required by the body in miniscule amounts. Drug–nutrient interactions are defined as alterations of pharmacokinetics or pharmacodynamics of a drug or nutritional element or a compromise in nutritional status as a result of the addition of a drug. Failure to identify and properly manage drug–nutrient interactions can lead to serious consequences. For instance, food–nutrient interactions can result in reduced absorption of certain oral antibiotics and may lead to suboptimal antibiotic concentrations at the site of infection. This predisposes the patient to treatment failure.

Nutraceuticals. DOI: http://dx.doi.org/10.1016/B978-0-12-802147-7.00060-7

Food–drug interactions can result in two main clinical effects: (i) decreased bioavailability of a drug, which predisposes to treatment failure or (ii) increased bioavailability, which increases the risk of adverse events and may even precipitate toxicities. Patient populations who have increased risks of suffering from adverse events associated with drug–nutrient interactions are elderly patients, patients with cancer and/acquired immunodeficiency syndrome, those receiving enteral nutrition, and transplant recipients. Elderly patients are particularly at risk because more than 30% of all the prescription drugs are taken by this population (Chan, 2006). The continuing aging process depends on the improvement of several factors, such as hygiene, nutritional status, sanitary conditions, and the prevention of some chronic diseases. Among the most common health problems in elderly people are cancer, spine or back diseases, arthritis/rheumatism, osteoporosis, heart diseases (i.e., congestive heart failure, coronary heart disease), chronic obstructive pulmonary disease, hypertension, dementia, diabetes mellitus, and depression. There are food–drug interactions and careful drug selection is needed (Leibovitch et  al., 2004; Schmidt and Dalhoff, 2002). Accordingly, the most common drugs used by this age group are nonsteroidal anti-inflammatory drugs (NSAIDS), antihypertensives, and antidepressants (Akamine et al., 2007). Multiple underlying chronic diseases require long-term nutritional and pharmacotherapeutic interventions. The practice of polypharmacy (i.e., using multiple drugs to manage different disease states) increases patients’ risk of food–drug interactions (Chan, 2006). Diuretics vary in their interactions with food and specific nutrients. Some diuretics cause loss of potassium,

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calcium, and magnesium. Triamterene (known as a “potassium-sparing” diuretic), blocks the kidneys’ excretion of potassium, which can cause hyperkalemia. Excess potassium may result in irregular heartbeat and heart palpitations. When using triamterene, one should avoid eating large amounts of potassium-rich foods (i.e., bananas, oranges, and green leafy vegetables) or salt substitutes that contain potassium (NCL, 2015). Angiotensin-converting enzyme (ACE) inhibitors, such as captopril, enalapril, quinapril, moexipril, relax blood vessels by preventing angiotensin II. Food can decrease the absorption of captopril and moexipril (take captopril and moexipril 1 h before or 2 h after meals). ACE inhibitors may increase the amount of potassium in the body; therefore, excess potassium can be harmful. Potassium supplements or diuretics may increase the amount of potassium in the body; for these reasons, avoid eating large amounts of foods high in potassium (NCL, 2015). Elderly patients are more likely to experience adverse events because several physiologic functions are reduced with age, such as the sense of taste and smell, chewing and swallowing, and gut motility. Pharmacokinetic peculiarities associated with aging are absorption (changes in gastric pH, decreased gastrointestinal and splanchnic blood flow), distribution (decreased lean body mass, water, serum albumin concentration, and binding serum proteins; increased total body fat, increased blood–brain barrier [BBB] permeability) and elimination (reduced renal function). Therefore, drug bioavailability, volume of distribution, clearance, and half-life of drugs are modified in the elderly. Water-soluble drugs become more concentrated and fat-soluble drugs may have longer halflives because of a slower release of the drug from fatty tissues. Activity of the cytochrome P450 (CYP450) oxidase systems is also modified in older patients. Because many of these age-related factors are difficult to predict, the ideal prescription of a drug is complex (Akamine et al., 2007). There are, however, a minority of drugs for which concomitant diet is important because the bioavailability of some drugs may be enhanced by food. For example, an acid environment is necessary for the absorption of ketoconazole. The absorption of griseofulvin, which is lipid-soluble, shows increased absorption and higher plasma concentrations when it is taken with a high-fat meal. Avoid using antifungal medications with dairy products (milk, cheese, yogurt, ice cream) or antacids (NCL, 2015). Fenofibrate, mebendazole, isotretinoin, tamsulosin, carbamazepine, and labetalol are examples of drugs that will be better absorbed when taken with food. Improved absorption of a drug may or may not have a significant effect on the drug’s efficacy (Bland, 1998). Drug–herb interactions are becoming a source of serious concern in relation to adverse effects, because

those who consume herbal supplements often take prescribed drugs concomitantly and health professionals are often unaware of possible interactions. This issue has generated significant concern within the pharmaceutical industry and among regulatory authorities in recent years. The medical community has also been concerned about the risk of patients using inaccurate dosages and poor-quality products as well as drug– nutrient and nutrient–nutrient interactions. One may assume that these interactions occur primarily with oral medications and only with those that share the CYP3A4 metabolism pathway. Consequences include increased oral bioavailability, higher serum drug concentrations, and associated adverse effects.

DRUG METABOLISM The ability to halt drug action is an important aspect of drug therapy in humans. The amount of drug that eventually reaches the target tissue in an active form depends not only on its physicochemical characteristics but also on the extent of metabolism occurring mainly in the gastrointestinal tract (GIT), liver, and lung. Metabolism and excretion by these organs before a drug can reach the systemic arterial circulation is referred to as presystemic drug elimination. Extensive presystemic (first-pass) metabolism or presystemic clearance is of considerable clinical, pharmacological, and toxicological importance and can limit the usefulness of certain drugs. Thus, many drugs are normally given by injection because when given orally, most are destroyed by presystemic metabolism. There are marked interindividual differences in the extent of its presystemic metabolism, and metabolites generated in the liver can in some instances be more toxic than the parent compound. The drug-metabolizing enzyme systems are primarily located in the liver and small intestine microsome enzymes, but they are also present to a lesser extent in other organs (e.g, lungs, adrenals). The activity of the hepatic enzymes is in general higher than that of drugmetabolizing enzymes located elsewhere in the body. Access of drugs to hepatic drug metabolizing enzymes will be determined not only by their physicochemical characteristics, which include their lipid solubility at physiological pH and extent of protein binding, but also by the pattern of blood flow through the liver. Metabolism of drugs by the liver, as well as clearance, depends on the relative affinity of plasma and hepatic proteins to bind it, the concentration gradient between blood and liver, and the activity of drug metabolizing enzymes. Drugs are metabolized by phase I (catalyzed by CYP450 enzymes) and phase II (catalyzed by conjugation enzymes such as glutathione-S-transferase [GST] and UDP-glucuronosyltranferase) enzymes.

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Drug Metabolism

When drugs enter the gut they are exposed to a number of systems with the potential to chemically modify or to chelate the drug molecules not found within the tissues of the host. These include extremes of pH, unabsorbed nutrients and xenobiotics, digestive enzymes, and intestinal microflora. Interactions between drugs and other nutrient in the gut lumen can result in the formation of a chemical complex that is absorbed poorly. Chemical interactions of this type have been described between tetracycline antibiotics and divalent or trivalent metal ions such as calcium, magnesium, and iron. Reduction of iron absorption from food occurs in the presence of antacid drugs. The Maillard reaction is an example of chemical interaction between dextrose and amino acids in parenteral nutrition. The intestine has the ability to metabolize drugs and other foreign chemicals by numerous pathways involving both phase I (oxidation, reduction, and hydrolysis) and phase II (conjugation) reactions between xenobiotic and endogenous substrates (glycine, glucuronic acid, acetic acid, etc.). Although the activities of these intestinal enzymes are generally lower than in the liver because it is a total volume organ, the gut may still make a significant contribution to the overall metabolism of certain compounds. Approximately half of all drugs used in humans are handled by CYP3A4 (Bressler and Bahl, 2003). Because of the lack of absolute specificity of the CYP enzymes, the metabolism of a drug may change with an increase in drug concentration or an inhibition of the CYP enzyme, which usually metabolizes the drug. Inhibition of drug metabolism by specific drugs, chemicals, or herbal medications causes increased levels of the parent drug, prolonged drug activity, and an increased potential for drug toxicity. Competition for the active site on a CYP enzyme by two or more drugs can result in decreased inactivation of one of the drugs and an increase of its activity and a prolongation of its effects. CYP3A4 is closely associated with P-glycoprotein (P-gp). P-gp-like CYP is active in the liver and small intestine. P-gp was discovered during a course of investigations of drug resistance in the treatment of cancer (Cordon-Cardo et  al., 1989) with an efflux pump in the apical surface of epithelial cells (enterocytes) that actively secretes absorbed drugs back into the gut lumen (“efflux” transporter). P-gp is also functionally expressed in the enterocytes that border the epithelium of the intestinal tract, where it plays a role together with intestinal metabolism and is an important part of the biochemical barrier function of the intestinal mucosa. The “efflux carrier” may be responsible for limiting the bioavailability of several drugs after oral intake by pumping them out into the intestinal lumen. Not all 3A4-metabolized drugs are P-gp substrates. The induction of P-gp activity is frequently the result of exposure to the same drugs that induce CYP3A4. This provides a mechanism to limit

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cytoplasmic concentrations of drug metabolites formed by the action of CYP3A4. Moreover, the inhibition of CYP3A4 by drugs or other xenobiotics is often accompanied by inhibition of P-gp (Soldner et al., 1999), which can slow drug absorption. Absorption is also a factor in drug handling. The organic anion transporting polypeptide (OATP) system is an intestinal system that plays a role in absorption of specific drugs and may be involved in drug interactions with grapefruit juice (Dresser et al., 2002). CYP is a large multigene family of heme-containing enzymes located in the endoplasmic reticulum (ER) of cells throughout the body. It is especially concentrated in the liver and intestinal wall, where it is involved in the oxidative biotransformation of various endogenous and exogenous substances. CYP3A isoforms constitute 70% of CYP enzymes in enterocytes. P-gp is a 170- to 180-kDa transmembrane protein that acts as a multidrug resistance factor in tumor cells, thereby reducing the intracellular accumulation of drugs. This phosphorylated glycoprotein belongs to a member of the ABC transporter superfamily (ATP-binding cassette), which is another membrane transporter located in the apical brush border of enterocytes and other important barriers such as the kidney, liver, and BBB. The transporter protein P-gp is a major trans-membranous efflux transporter of the intestinal mucosa, which shares its tissue distribution and substrate specificity with many CYP enzymes (Wacher et  al., 1995). The ABC transporters hydrolyze ATP to drive the flux of their substrates against a concentration gradient. CYP enzymes and P-gp are regulated via pregnane X-receptor (PXR), which controls the transcription their genes (P-gp serves as a key factor in conferring the multidrug resistance [MDR] phenotype to cancer cells). Pytochemicals can modify the first-pass effect of drugs through changes of the PXR activity or by direct competitive or allosteric interference at the active substrate bending regions of CYP enzymes and transporter protein (Zhou et  al., 2004). P-gp can affect the oral bioavailability, biliary or renal clearance, and brain uptake of drug. The substrate range for these proteins is diverse and includes drugs, nutrients, amino acids, sugars, and peptides. Once taken up by the enterocytes, a lipophilic drug may be metabolized by CYP3A4 or be pumped back into the lumen by the P-gp. Hence, the oral delivery of many drugs is limited by the actions of CYP3A4 or P-gp. Metabolism by CYP3A4 will also occur in the liver before the drug finally enters the systemic circulation.

Induction of Drug Metabolism Induction or inhibition of enzymes in the gut by nutrients may lead to a significant change in oral bioavailability of drugs or vice versa. Enzyme induction effect is

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the ability of numerous foods or drugs to stimulate the production of drug-metabolizing enzymes in the liver, which may result in increased metabolism of the administered drug as well as other related or even unrelated drugs. The activity of the drug-metabolizing enzymes in liver microsomes, as well as the structure and amount of ER and even the size of the liver, are influenced to a great extent by the administration of drugs and hormones, and by age, sex, temperature, nutritional status, and psychological and pathological states of the subject. Enzyme induction involves an adaptive increase in the number of molecules of a specific enzyme in response to an enzyme-inducing agent. Inducers of drug oxidation have several features in common, such as lipophilicity, the ability to bind to CYP450 enzymes, and relatively long biological half-lives. Many drugs share these properties without inducing enzyme synthesis. When drugs metabolized in the GIT after entering the gut, they are exposed to a number of systems with the potential to chemically modify or to chelate the drug molecules that are not found within the tissues of the host. These include extremes of pH, unabsorbed nutrients and xenobiotics, digestive enzymes, and intestinal microflora. The intestinal microorganisms represent a potent, diverse, and adaptable metabolizing force that has large potential for the metabolism of drugs and environmental nutrients. The gut flora consists of a complex, dynamic mixture of aerobic organisms that may show large variations (Enterobacteria, Lactobacilli, Enterococci, Bacteroides, Clostridia, and Bifidobacteria). This gut flora may be altered by changes in the diet, by diseases, and by the administration of foreign compounds. The gut microorganisms thus represent an adaptable changing source of metabolic activity that may show large interindividual and intraindividual variations in the numbers and types of organisms present. In addition, intestinal transit time and defecation frequency may affect the duration of exposure of a drug to the gut flora in vivo and produce pronounced temporal variations in levels of metabolites. The bacteria of intestinal flora have been shown to be capable of performing a large number of different metabolic reactions, most of which are degradative in some way (i.e., hydrolysis, reduction or removal of functional groups). However, the use of the various tissue preparations has provided the recognition of a wide variety of drug metabolism reactions in the gut such as C-oxidation, hydroxylation, dealkylation, N-oxidation, S-oxidation, desulfuration reduction and hydrolysis, and conjugation reactions. The enzyme activity in the small intestine is less than that detected in the liver, but the ratio of hepatic to small intestinal activity is highly variable (Anadón, 1983). Enzyme inducers may modify toxicological effects, both short-term and long-term, produced by foreign compounds. Certain types of drug metabolites, so-called

chemically reactive metabolites, may produce a range of toxic drug effects by reacting covalently with essential cellular components. However, many enzyme-inducing agents can enhance their own metabolism as well as that of other drugs. When prolonged treatment with a drug results in a decrease of its action, a phenomenon known as tolerance (enzyme induction) may be suspected but is not always the cause. The induction of microsomal enzymes by the concomitant use of another food/drug may lead to increased pharmacological effects or even toxicity caused by the active metabolites (Anadón, 1983).

Inhibition of Drug Metabolism Variously termed Kcat inhibitors, suicide enzyme inactivators, enzyme-activated irreversible inhibitors, and suicide enzyme inhibitors represent a relatively new approach to specific irreversible inactivation of enzymes. Simply stated, this approach requires the inhibitor to contain a latent reactive grouping and to be accepted as a substrate by the target enzyme, following which the normal catalytic activity of the enzyme results in its own irreversible inactivation or “suicide.” A number of food– drug reactions are based on the inhibition of metabolism of certain drugs by food; the result of such interactions is an increase in the duration and intensity of pharmacological activity. Two points of view are seen regarding the clinical value of enzyme inhibitors: (i) as potential food/drugs, and (ii) as causing side effects or food–drug interactions (Anadón, 1983).

TYPES OF DRUG–NUTRIENTS INTERACTIONS Several types of drug–nutrient interactions are categorized based on their nature and mechanisms. They may arise either from alterations of the absorption, distribution, biotransformation, or excretion of one drug by another nutrient or from a combination of their actions or effects. Drug–nutrients interaction in vitro: These are ex vivo bio-inactivations that refer to interactions between the drug and the nutritional element or formulation through biochemical or physical reactions, such as hydrolysis, oxidation, neutralization, precipitation, or complexation. They usually occur in the delivery device. These interactions are most common with drugs and nutrients administered intravenously. There are several recommendations to minimize these drug–nutrient interactions. For instance, drugs should not be mixed directly with feeding enteral or parenteral formulas. Tubes should be flushed with water before and after drug administration. Preformulated oral solutions or suspensions should be preferred instead of crushing tablets when

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Types of Drug–Nutrients Interactions

administering drugs through enteral feeding tubes. For drugs with a narrow therapeutic range, monitoring of drug levels should be taken into consideration. Drug–nutrients interactions in the GIT: These interactions affect absorption. They cause either an increase or decrease of oral bioavailability. The precipitant agents may modify the function of enzymes or transport mechanisms that are responsible for biotransformation. Complexation, binding, and/or other deactivating processes occur in the GIT and reduce absorption. The effect of diet on drug absorption is also an important factor. An example of this type of interaction is the influence of oral absorption of a drug by concurrent meal intake. The rate of absorption, the magnitude of the absorption, or both can be changed. Meal intake stimulates gastric and intestinal secretions, which usually improve the dissolution of drugs and facilitate absorption. Meals with higher fat content stimulate the release of bile salts, which increase the intestinal uptake of highly lipophilic drugs or of substances that require bile salts for optimal absorption. In addition, high fat content of the food also stimulates the release of cholecystokinin, which slows gastrointestinal motility and increases the contact time between the drug and the intestine and possibly also absorption. However, the potential physicochemical interactions, the potential binding of drug and food contents, the dose of the drug administered, and the composition of the meals make drug absorption in the presence of food unpredictable in specific cases. For that reason, the bioavailability of drugs should be tested with and without concurrent meal intake. It has been shown that certain drugs should be taken with food to maximize absorption. Among these drugs are the antibiotics cefuroxime and erythromycin ethylsuccinate, the HMGCoA-reductase inhibitor lovastatin, and lithium (used for psychiatric diseases). Lovastatin should be taken with the evening meal to enhance absorption (NCL, 2015). However, several drugs should not be taken with food to allow optimal absorption: the antibiotics ampicillin, ciprofloxacin, doxycycline or tetracycline; captopril (used for elevated blood pressure), or the HIV protease inhibitor indinavir (Chan, 2006). It should be mentioned, however, that delayed absorption of a drug by food does not necessarily lead to reduced absorption and that pharmacokinetic changes do not necessarily have clinically relevant effects (Schmidt and Dalhoff, 2002). Conversely, there is considerable evidence that specific drug therapy may cause malabsorption of many of the essential components of the diet. One example is oral contraceptives. These drugs have initiated serious anemia in apparently normal women due to a significant suppression of their intestinal absorption of dietary polyglutamic folate. A similar complication can result from chronic anticonvulsant

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therapy with phenytoin (Hoffbrand and Necheles, 1968). Malabsorption of fat and vitamin B12 may be caused by para-aminosalicylic acid (Levine, 1968). There are other examples of drugs altering the normal rates of vitamin uptake and metabolism. One of the simplest of these is deficiency in the fat-soluble vitamins A and D caused by chronic consumption of liquid paraffin as a laxative. Liquid paraffin is poorly absorbed in the gut; by local action it takes up fat-soluble vitamins, thus preventing their absorption. A more serious example of this type of reaction is related to the interference of vitamin K with anticoagulant therapy (Booth et al., 1997). Oral dosage with some antibiotics (e.g., chloramphenicol, tetracyclines, or neomycin) reduces the intestinal population of microorganisms and thereby reduces the microbial synthesis of vitamin K. Vitamin K synthesis by intestinal bacteria can be inhibited by this alteration of the GI flora, which may result in an increased anticoagulant effect in patients using oral anticoagulants. Thus, the hypoprothrombinemia of patients on chronic anticoagulant treatment might be dangerously potentiated by concomitant dosage with intestinal flora-destroying antibiotics. It is also of importance that the actual intestinal absorption of vitamin K can be reduced by cholestyramine, para-amino salicylic acid, and other drugs that induce malabsorption states (Koch-Weser and Sellers, 1971). Changes in the intestinal flora by antibiotic therapy may markedly alter the state of digitalization. This phenomenon occurs in a minority of patients who have the ability to substantially convert digoxin to cardio-inactive metabolites in the gut. The digoxin is inactivated by GI bacteria, and the coadministration of erythromycin or tetracycline appears to reduce this process. Components of food may antagonize the desired effect of the drug, as in the case of warfarin. Foods that are high in vitamin K, or that enhance vitamin K production by intestinal microorganisms, can reduce the effectiveness of warfarin anticoagulant by diminishing the body’s supply of vitamin K, which is needed to activate clotting factors. Changing to a diet with increased consumption of leafy and/or dark green vegetables, such as broccoli, spinach, kale, turnip greens, cauliflower, and Brussel sprouts, could lessen the degree of anticoagulation made possible by warfarin by supplying additional vitamin K. High doses of vitamin E (400 IU or more) may prolong clotting time and increase the risk of bleeding (NCL, 2015). Drugs and certain foods may affect enzyme transport systems and thereby alter intestinal absorption of specific drugs. For example, allopurinol and iron preparations should not be administered simultaneously because allopurinol blocks the enzyme that prevents iron absorption. Overabsorption and iron overload in patients may occur, resulting in hemosiderosis.

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Drug–nutrients interactions during transport: These interactions affect the systemic or physiologic disposition and occur after the drug or the nutritional element has been absorbed from the GIT and has entered the systemic circulation. Changes of the cellular or tissue distribution, systemic transport, or penetration to specific organs or tissues can occur. Drug–nutrients interactions associated with metabolism: The metabolism of orally ingested drugs before reaching the systemic circulation (first-pass metabolism) has been shown to have clinically relevant influences on the potency and efficacy of drugs. Both the intestine and the liver account for the presystemic metabolism in humans. One of the major groups of drug-metabolizing enzymes is the CYP450 3A4 enzymes. Grapefruit juice is a classic example of a selective intestinal CYP3A4 inhibitor. It causes an interaction with certain drugs by deactivating and destroying intestinal CYP3A4 enzymes. Grapefruit juice has pharmacokinetic effects on drugs that are substrates for metabolism by the CYP3A4 intestinal drug-metabolizing enzyme. This drug class constitutes approximately half of all prescription drugs. Grapefruit juice contains chemicals that inhibit intestinal CYP3A4 (the inhibition does not affect the liver enzymes). This inhibition of the intestinal drug-metabolizing enzymes CYP3A4 and P-gp, which decreases first-pass metabolism, causes an increase in maximal drug concentration in plasma (Cmax) and in drug bioavailability (AUC). The increased plasma drug concentrations constitute a potential for adverse reactions. The finding that grapefruit juice can markedly augment oral drug bioavailability was originally based on an unexpected observation from an interaction study between the dihydropyridine calcium channel antagonist felodipine and ethanol, in which grapefruit juice was used to mask the taste of the ethanol (Bailey et al., 1998). Grapefruit juice has inhibitory actions on intestinal OATP, decreasing absorption of some drugs. Effects of grapefruit juice persist for at least 24 h. Some compounds in grapefruit juice responsible for inhibitory actions on CYP3A4 have been identified. Grapefruit juice administration did not inhibit CYP3A4 substrate drugs given intravenously, whereas it inhibited the metabolism of these drugs when given orally (Durcharme et al., 1995). The overall exposure of some drugs can be increased by more than five-fold when taken with grapefruit juice. It has been shown that furanocoumarin derivatives in the juice are primarily responsible for enzymatic inhibition (Paine et al., 2006). The onset of the interaction is immediate and the magnitude of the enzymatic inhibition increases with repeated grapefruit juice consumption. The effect continues for several days after the discontinuation of grapefruit juice consumption. The increased oral absorption of certain drugs can lead to increased risk for adverse reactions of the specific drugs. For instance,

drowsiness and prolonged sedation may result from taking the tranquilizers diazepam or midazolam in combination with grapefruit juice. Hypotension can result in people treated with calcium-channel blockers (nifedipine, felodipine, verapamil). Patients taking the antibiotic erythromycin and consuming grapefruit juice have an increased risk for cardiovascular symptom, including cardiac dysrhythmias. Other drugs with increased absorption when taken with grapefruit juice are atorvastatin, cyclosporine, and sertralin (Chan, 2006). Drugs may also be associated with altered metabolic function or macronutrient status. Some atypical antipsychotics (clozapine, olanzapine, risperidone) are associated with glucose intolerance. Particularly when risk factors such as an underlying diabetic condition or an increase in weight are present or certain other medications are concomitantly used, more frequent monitoring of blood glucose should be considered. Alternatively, in these situations antipsychotics for which no association with glucose intolerance has been demonstrated (haloperidol, chlorpromazine) should be preferred when possible (Hedenmalm et al., 2002). Drug interactions associated with renal excretion: Interactions that influence renal excretion of drugs or nutrients are clinically significant only when the drug or nutrient or its active metabolite is appreciably eliminated by the kidney. Urinary pH can influence the activity of a drug or nutrient by altering the rate of renal clearance. When a drug is in its un-ionized form, it more readily diffuses from glomerular filtrate back into the blood. Thus, for a basic drug, a larger proportion of drug is in the un-ionized form in basic (or less acidic) urine than in normally acidic (pH 5.0 to 5.5) urine. Acidic drugs are excreted faster when the urinary pH is alkaline. Even the ingestion of nonsystemic acids (e.g., magnesium hydroxide, aluminum and magnesium hydroxide, and calcium carbonate-glycine suspensions) may increase the urinary pH by 0.5 to 0.9 pH units, and these antacids in normal doses have the potential to influence the elimination kinetics of amphetamine and other drugs. However, basic drugs (e.g., antihistamines, meperidine, and imipramine) are excreted faster when the urinary pH is acid; this acidification may be brought about by the administration of ammonium chloride or glutamic acid hydrochloride. In general, if the drug remains ionized in the urine, then the half-life is decreased and vice versa. These interactions refer to the elimination or clearance of drugs or nutrients, which may involve the antagonism, impairment, or modulation of renal and/ or enterohepatic elimination (Chan, 2006). This type of interaction may involve the antagonism, impairment, or modulation of renal and/or enterohepatic elimination. It should be noted that it is best to take prescription antihistamines on an empty stomach to increase their effectiveness.

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Nutrient–Drug Interactions

Drugs that interfere with food intake: Medications can lead to altered food choices. Many drugs are reported to directly affect the sense of taste and smell, and some drugs themselves have an unpleasant taste that might interfere with food intake (Brownie, 2006). It is well known that chemotherapeutic drugs (and to a lesser extent other drugs) induce nausea and vomiting and therefore are associated with an increased risk of malnutrition. However, drugs that decrease acute and delayed emesis (e.g., aprepitant) may have adverse effects such as fatigue, dysphagia, taste disturbance, constipation, diarrhea, or anorexia, and could therefore by themselves adversely affect nutritional status (Santos and Boullata, 2005). Limiting drug prescriptions to essential medications for as short a period as possible and periodic re-evaluations of the treatment chosen are essential to minimize adverse drug–nutrient interactions (Schmidt and Dalhoff, 2002).

NUTRIENT–DRUG INTERACTIONS Fortified foods are also recommended in cases of chewing difficulty. In an intermediate stage of obstruction (e.g., insufficient swallowing), an enteral formula is necessary in the diet to provide the proper nutritional requirements. Foods are most often fortified with multivalent cationic minerals, such as calcium, iron, magnesium, aluminum, and vitamins, like C, D, E, and B-complex. Although it is clear that certain drugs should not be taken with antacids, multivitamins, and mineral supplements, many do not consider the implications of taking their daily medications with food. Currently, the Food and Drug Administration (FDA) standardized meal used in product labeling of drug–food interactions is a high-fat, high-caloric diet that provides only a small amount of dietary vitamins and minerals (FDA, 2007). High-fat meals may increase the amount of theophylline in the body, whereas high-carbohydrate meals may decrease it. It is important to check which form the patient is taking because food can have different effects depending on the dose form (e.g., regular release, sustained release, or sprinkles). Food increases the absorption of theophylline, which can result in side effects of nausea, vomiting, headache, and irritability. As a result, many drugs are labeled may be taken with or without food while they may be also labeled do not take with antacids. The biochemical mechanisms that cause drug antacid interactions are the same mechanisms that cause drug interactions with fortified foods. Chelation and adsorption interactions, which cause decreased drug absorption, will certainly occur between fortified foods and drugs. However, due to the fact that some fortified foods contain a quantity of polyvalent ions that approaches or

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exceeds that contained in antacid formulations, changes in gastric pH, changes in urinary pH, and otherwise unspecified decreases in absorption are also possible. The implications of these interactions can range from clinically insignificant to severe. There are several mechanisms by which minerals interact with drugs. When described in the literature, they are often listed as drug–antacid interactions. However, as emphasized here, it is important to consider the nutrient content of foods, especially those that have been fortified with minerals, as containing sufficient quantities of minerals to be equivalent to antacids with interaction capability. Chelation, adsorption, changes in gastric pH, changes in urinary pH with resultant changes in renal clearance (CLR), and uncharacterized decreases in absorption are the five causes of moderate to major drug–mineral interactions described in the literature. Foods containing significant quantities of multiple minerals could cause moderate or major interactions, although each mineral individually may cause only a minor interaction (Wallace and Amsden, 2002). Chelation is the formation of a complex involving a metal ion and two or more polar groupings of a single molecule. The overwhelming majority of the drugs affected by chelation with multivalent ions are antibiotics, particularly the quinolones, tetracyclines, and some oral cephalosporin. Many studies have characterized the decrease in bioavailability of ciprofloxacin due to chelation with multivalent ions in particular aluminumcontaining antacids and dialysate (Anadón and MartínezLarrañaga, 1992; Wallace and Amsden, 2002). Most of these involved the administration of ciprofloxacin with concomitant antacids (containing calcium, magnesium, and/or aluminum), iron supplements, and multivitamin/mineral tablets (Albert and Rees, 1956). Quinolones (e.g., ciprofloxacin, levofloxacin, ofloxacin, and trovafloxacin) should be taken on an empty stomach 1 h before or 2 h after meals. If the stomach becomes upset, these medications must be taken with food. However, avoid calcium-containing products like milk, yogurt, vitamins or minerals containing iron, and antacids because they significantly decrease drug concentration (NCL, 2015). Drug–food and drug–antacid interactions with all the tetracyclines (minocycline, doxycycline, tetracycline, oxytetracycline) have been well described in the literature. The complexity of tetracycline antibiotics may occur when these drugs are administered along with dairy products or aluminum, calcium, and magnesium antacid products. It has been described as decreased bioavailability of demethylchlortetracycline when administered with aluminum hydroxide gel and with whole milk. Ferrous sulfate has been shown to impair the absorption of tetracycline, oxytetracycline, methacycline, and doxycycline. Aluminium- and magnesium-containing

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antacid products can interfere with the absorption of digoxin and digitoxin. Tetracyclines should therefore be taken on an empty stomach 1 h before or 2 h after meals, and it is important to avoid taking tetracycline with dairy products, antacids and vitamins containing iron because these can interfere with the medication’s effectiveness (NCL, 2015). Iron absorption is also decreased. It is established that the absorption of doxycycline or minocycline is not markedly influenced by simultaneous administration of antacids, and ferrous sulfate has been shown to decrease their absorption. If gastric irritation occurs when taking these tetracycline products, it is recommended that they be taken with food and milk (NCL, 2015). Adsorption is the phenomenon in which a solid substance attaches other substances to its surface without covalent binding. Multivalent cationic minerals can adsorb some drugs, causing less drug to be bioavailable from the GIT. Two classic examples of this interaction are with chloroquine and propranolol.

HERB–DRUG INTERACTIONS Because the efficacy and safety of conventional prescription drugs could be changed by coadministration with herbal medicines, there is an effective way to identify the potential herb–drug interactions. Concurrent use of herbs may mimic, magnify, or oppose the effect of drugs. Many medicinal herbs and pharmaceutical drugs are therapeutic at one dose and toxic at another. Interactions between herbs and drugs may increase or decrease the pharmacological or toxicological effects of either component. Although herbal remedies are perceived as being natural and therefore safe, many have adverse effects that can sometimes produce life-threatening consequences. Herb–drug interactions, like drug–drug interactions, can occur via a number of mechanisms usually involving, in most cases, inhibition or induction of CYP enzymes or transporters such as P-gp. P-gp, a transmembrane ATP-binding cassette transporter, can affect drug absorption in the intestinal tract, distribution to the brain, and elimination by the liver and kidney (Ho and Kim, 2005). As a result, inhibition or induction of P-gp may cause potential herbal–drug interactions. Oxidations metabolism represents a major route of elimination for many drugs, and because many herbals compounds/drugs compete for the same enzyme, inhibition of CYPs is one of the main reasons for drug interactions. Herbs can inhibit CYPs by three mechanisms: competitive, noncompetitive, and irreversible inhibition. The clinical relevance of drug inhibition will depend on a number of considerations; one of the most important considerations is the therapeutic index of the drug. The lower the therapeutic index, the greater the risk that

increased plasma drug concentrations will induce toxicity. For example, patients receiving anticoagulants (e.g., warfarin), antidepressants, or cardiovascular drugs (e.g., digoxin) are at a much greater risk due to the narrow therapeutic index of these drugs than patients receiving other kinds of drugs.

Ginkgo Tree (Ginkgo biloba L.) The seeds and fruits of Ginkgo biloba have been part of traditional Chinese medicine (TCM), particularly for the treatment of asthma, indigestion, cough, and chilblains (i.e., pedal edema related to cold exposure). G. biloba is one of the world’s oldest living tree species, dating back to the Permian period. During food shortages ginkgo seeds are an important source of food and its ingestion has produced numerous case reports of ginkgo seed poisoning (Ginnan food poisoning). In recent decades, medicinal uses of the extract of G. biloba include Alzheimer’s disease (AD), dementia, memory loss, cerebral ischemia, cardiovascular disease, premenstrual syndrome, impotence, stress, depression, dementia, and altitude sickness. The active ingredient of ginkgo extracts has not been identified. However, the extracts are standardized to total flavonoid glycosides and terpenoid content, and the most clinically important compounds are these flavonoids (kaempferol, quercetin, isorhamnetin) and terpenoids (ginkgolides A/B, bilobalide) (Kleijnen and Knipschild, 1992). Consumption of gingko seeds containing 4ʹ-O-methylpyridoxine inhibits the formation of GABA and increases the formation of glutamate, resulting in the occurrence of seizures. In vitro animal and clinical studies on the effect of ginkgo extracts on platelet aggregation, coagulation, and various CYP450 isoenzymes are conflicting. The concurrent use of ginkgo with antiplatelet, anticoagulant, or antithrombotic agents increases the risk of bleeding. Hyphema, subphrenic hematoma, and intracranial hemorrhage have been reported (Gertz and Kiefer, 2004). In clinical trials, ginkgo has also been shown to reduce the effectiveness of nicardipine by interacting with the CYP450 system. The administration of a 12-day course of 140 mg ginkgo extract twice daily to healthy Chinese subjects induced CYP2C19 activity. This interaction could reduce the effects of drugs (e.g., omeprazole) metabolized by this enzyme (Yin et al., 2004). However, the clinical significance of the interactions of ginkgo extract with CYP450 isoenzymes remains undetermined.

Garlic (Allium sativum L.) Garlic has been mentioned in medicinal texts since the Ebers papyrus (c. 1550 BC). Garlic extracts are commonly used by HIV-infected patients, because these extracts possess antiseptic, bacteriostatic, antiviral, immune-enhancing,

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Herb–Drug Interactions

hypotensive, and antihelmintic properties. Traditionally, garlic has been used to treat respiratory catarrh, recurrent colds, bronchitic asthma, influenza, and chronic bronchitis. Currently, garlic and garlic preparations are investigated for their antihypertensive, antiatherogenic, antithrombotic, antimicrobial, fibrinolytic, cancer preventive, and lipid-lowering effects (Reuter, 1995) and have been used for preventing cardiovascular disease. The active component ajoene in garlic inhibits collagen-induced platelet aggregation (Apitz-Castro et  al., 1983), and garlic is used for its antiplatelet and fibrinolytic effects in patients with cardiovascular disease. However, the risk of bleeding in people using anticoagulant or antiplatelet agents increases, so its concomitant use should be avoided (Rose et  al., 1990). The use of large amounts of garlic can cause platelet disorders and/or hemorrhage. Garlic supplements should be discontinued approximately 10 days before elective surgical procedures, especially by patients using aspirin or warfarin (German et al., 1995). The use of dried garlic powder causes some modest short-term reduction (8–12 weeks) in total cholesterol concentrations, but these effects are not sustained over 6 months. In the presence of garlic supplements, blood concentrations of saquinavir decreased by approximately 50% among our study participants. Garlic contains a large number of biologically active constituents. The constituents of garlic can be divided simply into two groups: sulfur-containing and nonsulfur-containing compounds. Most of the medicinal effects of garlic are referable to the sulfur compounds and the alliin splitting enzyme alliinase, which converts alliin into allicin (responsible for the characteristic garlic odor). The major flavoring constituents of garlic are sulfur compounds (diallyl disulfide, allyl sulfide, and diallyl trisulfide). Garlic is available in different forms of pharmaceutical preparations, such as dry powder products, oil macerates, volatile garlic oil (obtained by water vapor distillation), and juices of fresh garlic. Researchers have found garlic supplements can cause a potentially harmful side effect when combined with a type of medication used to treat HIV/AIDS. In healthy volunteers, oral administration of a garlic preparation for 3 weeks decreased the AUC and Cmax of HIV-1 protease inhibitors saquinavir (Piscitelli et al., 2002) and, to a lesser extent, ritonavir. Although the exact mechanism of these effects was not clear, the similarity in the reduction of the AUC, the mean maximum concentration, and the 8-h concentration of saquinavir suggested that garlic affected the bioavailability of saquinavir and its systemic clearance.

Ginseng (Panax species) Ginseng refers to the root of Panax species. The most commonly examined species are Panax ginseng (Asian

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ginseng), Panax quinquefolius (American ginseng), and Panax japonicus (Japanese ginseng). The origin of the ginseng root and its manner of extraction can produce wide variations in ginseng products. The terms “red” and “white” refer to different methods of ginseng preparation, not different species. It is administered as a whole dried root, extract, tea, or capsule. Ginseng is advertised as an immune system stimulant that increases vigor, sexual potency, well-being, and longevity, and for use as an antihyperglycemic agent. Ginseng has both hypertensive and hypotensive effects, with the latter caused by the enhanced synthesis of nitric oxide (NO) (Sung et al., 2000). In Chinese medicine, ginseng is used for myocardial infarction, congestive heart failure, and angina pectoris; however, current evidence does not support its use for cardiovascular conditions. Ginseng abuse syndrome causes hypertension, behavioral changes, and diarrhea (Siegel, 1979). When administered with warfarin, ginseng produced reduced prothrombin time. Ginseng may also produce effects similar to those of estrogen because its active components, ginsenosides, have a chemical structure similar to that of testosterone, estrogen, and glucocorticoids. The active compounds are heterogeneous triterpene saponin glycosides, collectively termed ginsenosides. Typical doses are 100 to 400 mg ginseng extract. Ginseng should not be used by women who are pregnant or receiving hormone replacement therapy. Neonatal death has been related to maternal use (Awang, 1991). Increased levels of digoxin are associated with Siberian ginseng, which interferes with the digoxin assay (Dasgupta, 2003).

Motherwort (Leonurus cardiaca) Motherwort has a long history of use in both European and Asian traditional medicine because of its purported sedative and antispasmodic properties. Traditionally, it has been used for “cardiac debility,” tachycardia, anxiety, insomnia, and amenorrhea. It is also used as a hypotensive and a diuretic. When administered intravenously, motherwort reduces platelet aggregation and fibrinogen levels (Zou et  al., 1989). It potentiates antithrombotic and antiplatelet effects and increases the risk of bleeding taken with benzodiazepines, Motherwort can have a synergistic sedative effect and may result in coma.

Hawthorn (Crataegus species) Chinese hawthorn (Crataegus pinnatifida Bunge, Crataegus cuneata Siebold & Zucc.) contains tartaric acid in grapes. Most data demonstrated that the active ingredients in hawthorn extracts are flavonoid compounds. Hawthorn extract is commonly used by herbalists for treatment of angina, congestive heart failure, bradyarrhythmia, and cerebral insufficiency. Hawthorn has

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60.  Interactions between Nutraceuticals/Nutrients and Therapeutic Drugs

positive inotropic, negative chronotropic and coronary artery vasodilatory effects similar to phosphodiesterase inhibitors (amrinone, milrinone), and is thought to increase myocardial perfusion and reduce afterload. As an adjunct treatment for congestive heart failure, hawthorn has been reported to have beneficial effects on symptom control and physiologic outcomes (Tauchert, 2002), but the efficacy and safety of its supposed inotropic activity and effect on morbidity and mortality have not been systematically assessed. Hawthorn enhances the activity of digitalis (Mashour et al., 1998), and its concomitant use should be monitored carefully for potential toxic effects. Hawthorn also inhibits the biosynthesis of thromboxane A2, and it could potentially increase the risk of bleeding in patients taking antiplatelet or anticoagulant agents. Without additional data on safety and efficacy, clinicians should discourage unsupervised use of hawthorn in patients with congestive heart failure who are taking heart failure medications. The ingestion of hawthorn extract causes mild induction of P-gp activity, but this induction does not necessarily result in decreased absorption of P-gp-dependent substrates, such as digoxin.

Saw Palmetto (Serenoa repens) The extracts of saw palmetto have been used for treatment of abdominal disorders and dysentery, whereas the fruit of the plant is a food and nutrient. The crude extracts have been used for centuries to improve breast size, sperm production, and sexual vigor. Currently, saw palmetto is one of the top five most popular herbal products to treat the symptoms related to benign prostatic hypertrophy; it is also a diuretic and urinary antiseptic. The primary use of saw palmetto was the short-term treatment of urinary symptoms associated with benign prostatic hypertrophy (BPH). The drug is a complex mixture primarily of free fatty acids (90%) and related esters (7%) along with small amount of phytosterols (campesterol, β-sitosterol, stigmasterol), aliphatic alcohols, and various other compounds (arabinose, flavonoids, galactose, glucose, and uronic acid). The unsaturated fatty acids include capric, caproic, caprylic, lauric, linolenic, myristic, isomyristic, oleic, palmitic, and stearic acids, whereas the phytosterols include β-sitosterol, campesterol, stigmasterol, cycloartenol, lupeol, and lupenone. The major free fatty acids are oleic acid, lauric acid, myristic acid, and palmitic acid. The exact biological mechanism of action of saw palmetto is not clear. Despite claims that saw palmetto helps relieve BPH symptoms, recent clinical trials did not demonstrate any beneficial effects on BPH symptoms or postvoid residual bladder volume (Bent et al., 2006). Additional prospective studies are needed to establish the role of herbal extracts in alleviating BPH symptoms. When saw palmetto is used

for BPH, the prothrombin time (PT) and activated partial thromboplastin time (aPTT) were normal, but the bleeding time was prolonged to 21 min (normal: 2–10 min). After cessation of saw palmetto, the bleeding time returned to normal values within 5 days. Saw palmetto inhibits cyclooxygenase and increases bleeding with warfarin (Bressler, 2005). In addition, its unsupervised use can result in cholestatic hepatitis, acute pancreatitis, and intraoperative floppy iris syndrome during cataract removal because of loss of iris tone (Yeu and Grostern, 2007). Ophthalmologists should be aware of this important association so that they can take the necessary steps to prevent surgical complications. The lack of significant change in activity suggests that short-term saw palmetto therapy does not alter the metabolism of drugs dependent on CYP2D6 and CYP3A4 isoenzymes.

Danshen (Salvia miltiorrhiza Bunge) Danshen is used in TCM for treatment of coronary artery disease and menstrual abnormalities. Danshen reduces elimination of warfarin and inhibits cyclic adenosine monophosphate phosphodiesterase, which results in additive antiplatelet effects and increased risk of bleeding. Concomitant use with warfarin increases prothrombin time (Izzat et al., 1998). Danshen may also interfere with digoxin assay. In the absence of signs or symptoms of digoxin toxicity, the possibility of a false elevation of digoxin concentration should be explored.

Purple Coneflower (Echinacea purpura L.) The main three medicinal species of Echinacea are E. purpurea, E. angustifolia (narrow-leaved Echinacea), and E. pallida (pale-flowered Echinacea), with the cultivated species E. purpurea being the most common constituent in herbal preparations containing Echinacea. The chemical composition of extracts from medicinal Echinacea species is complex, consisting of alkamides (straightchain fatty acids with olefinic and/or acetylenic bonds), polyacetylenes, phenolic caffeic acid conjugates (phenylpropanoids), polysaccharides, and glycoproteins. This herb was considered an immunostimulant that promoted wound healing and increased resistance to colds. Additionally, this herb was a treatment for hemorrhoids, wound infections, syphilis, gangrene, malaria, typhoid, flu, and skin infections. Currently, it is a common herbal treatment for upper respiratory tract infections based on potential immunomodulatory properties, such as macrophage activation and enhanced neutrophil phagocytosis. The results of a controlled double-blind study indicated that Echinacea had no clinically significant effects on rhinovirus infection (Turner et al., 2005). The administration

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Herb–Drug Interactions

of Echinacea (400 mg E. purpurea root 4 times daily for 8 days) reduced the mean oral clearance of caffeine (CYP1A2) by approximately 25% (Gorski et  al., 2004). Persistent use may result in or potentiate the hepatotoxic effects of other medications (e.g., statins, fibrates, niacins, or amiodarone). Side effects include nausea, dizziness, dyspnea, rash, and dermatitis. Flavonoids from Echinacea may inhibit or induce CYP450 enzymes, depending on their structure and assay conditions.

Tetrandrine (Stephania tetrandra) Tetrandrine is a vasoactive alkaloid used in Chinese medicine to treat hypertension and angina. Its vasodilative effect is due to inhibition of the L-type calcium channels and possible competition with other calcium channel blockers. Tetrandrine lowers plasma glucose and causes hepatotoxicity and renal toxicity (Seeff, 2007).

Aconite (Aconitum napellus L.) Aconite is a crude extract of dried leaves and roots from various species of Aconitum plants (or monkshood) that contain aconitine and other diterpenoid ester alkaloids (aconitine, mesaconitine, jesaconitine, hypaconitine). Aconite was a medicinal drug as well as a homicidal agent and arrow poison in Asia. The use of aconite may account for some deaths in antiquity attributed to stroke, even though substantial physical pain accompanies fatal aconite poisoning. Traditional Chinese practitioners use aconite for pain relief caused by trigeminal and intercostal neuralgia, rheumatism, migraine, and general debilitation. Aconite initially stimulates and then paralyzes nerves that communicate pain, touch, and temperature, producing anesthesia mediated by numerous different alkaloids blocking sodium current (voltage-gated sodium channels). The aconitine alkaloid binds with a high-affinity to site 2 of the α-subunit of the Na+ channel protein. This binding of aconitine to the open Na+ channels shifts the voltage dependence of activation to more hyperpolarized potentials and reduces channel inactivation from the open state. Thus aconitine initially stimulates and then activates the voltage-gated sodium channels in the heart and nervous system, resulting in interference with the propagation of the action potential. Aconite is also used as a mild diaphoretic and to slow pulse rate by its effect on brainstem centers. Atrial or ventricular fibrillation, however, may result from the direct effect of aconite on the myocardium. Side effects occur even after contact with leaves or sap from Aconitum plants, and can range from bradycardia and hypotension to fatal ventricular arrhythmia induced by triggered activity (Lowe et  al., 2005).

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Yohimbe Bark and Yohimbine (Pausinystalia yohimbe) Yohimbine is isolated from yohimbe, the bark of the tree Pausinystalia yohimbe. Yohimbe bark is a traditional treatment for a variety of disorders in addition to the treatment of sexual disorders (i.e., erectile dysfunction). These uses include the treatment of dementia, diabetic complications (e.g., neuropathy), exhaustion, fevers, insomnia, leprosy, low blood pressure, obesity and syncope. Analyses of yohimbe bark indicate that the average total indole alkaloid content is approximately 3–6%, with approximately 10–15% of the alkaloids being yohimbine; in addition to yohimbine and its isomers (α-yohimbine, β-yohimbine, allo-yohimbine), these alkaloids include ajmaline, dihydroyohimbine, corynantheidine, dihydrocorynantheine, and corynanthine (rauhimbin). Currently, the yohimbe bark extract is used to enhance athletic performance and weight loss. The main medical indication for yohimbine hydrochloride is the treatment of male impotence. Many of its effects are attributed to its α2-adrenergic receptor antagonist activity, which increases central sympathetic outflow and raises blood pressure, heart rate, and norepinephrine levels. Yohimbine increases the release of norepinephrine, resulting in inadequate blood pressure control in people also using antihypertensive and diuretic agents (Tam et al., 2001). It also interacts with tricyclic antidepressants, so that pressor effects occur at lower doses and may potentiate the alpha-adrenergic blocking properties of phenothiazines. The recommended dose is 5.4 mg three times daily; pressor effects are associated with doses of 15 to 20 mg (De Smet and Smeets, 1994). Use of yohimbine is contraindicated in patients with hypertension, angina, and renal impairment.

Gynura (Gynura procumbens) Widely used in Chinese folk medicine, gynura purportedly improves microcirculation and relieves pain; however, it has been associated with hepatic toxicity (Chitturi and Farrell, 2008). Resultant conditions include hepatic veno-occlusive disease, which is characterized by painful hepatomegaly, fluid avidity, weight gain, and jaundice (Dai et al., 2007).

Licorice (Glycyrrhiza glabra) Licorice, an extract of the root of Glycyrrhiza glabra, is used as a sweetening and flavoring agent. It is also used as an herbal remedy for gastritis and upper respiratory tract infections (as an expectorant). Modern cough syrups often include licorice extract. It can result in pseudoaldosteronism with concomitant hypokalemia, hypertension, and edema that may reduce the

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60.  Interactions between Nutraceuticals/Nutrients and Therapeutic Drugs

effectiveness of antihypertensive drugs (Mansoor, 2001). The active constituent of licorice is glycyrrhizic acid. A metabolite, glycyrrhetinic acid, inhibits renal 11β-hydroxysteroid dehydrogenase and causes a state of mineralocorticoid excess by impeding the inactivation of cortisol (Walker and Edwards, 1994). Case reports link licorice to hypertension, hypertensive encephalopathy, pulmonary edema, edema, hypokalemia, arrhythmias, congestive heart failure, muscle weakness, and acute renal failure (Olukoga and Donaldson, 2000). Licoriceinduced hypokalemia can lead to increased risk for ventricular arrhythmia, particularly torsades de pointes (i.e., a ventricular tachycardia that is characterized by fluctuation of the QRS complexes around the electrocardiographic baseline and is typically caused by a long QT interval) (Bryer-Ash et  al., 1987). It can also potentiate the effects of spironolactone and digoxin and can cause hyperglycemia, rendering antidiabetic agents less effective. Its ability to inhibit thrombin and platelet aggregation enhances the risk of bleeding with antiplatelet and anticoagulant agents. Susceptibility to licorice varies greatly; subjects with underlying hypertension and women may be more sensitive. Adverse effects may take weeks to reverse because of suppression of the renin angiotensin-aldosterone axis and because glycyrrhetinic acid has a large volume of distribution (Walker and Edwards, 1994).

Black cohosh (Actaea racemose L.) Black cohosh contains triterpene glycosides and has been used in remedies for relief of symptoms of menopause, premenstrual tension, and other gynecologic problems. The mechanism of action is unclear. It may bind to estrogen and serotonin receptors. After estrogen replacement therapy it was shown to increase the risk of thromboembolic and cardiovascular events and breast cancer. Commercially available dietary supplements made from black cohosh inhibit CYP3A4 and potentially increase the risk of adverse effects from some drugs. Hepatotoxicity has been reported (Chow et  al., 2008), and black cohosh should not be used during pregnancy or lactation.

St. John’s Wort (Hypericum perforatum) St. John’s wort (Hypericum perforatum) is a well-known herb used worldwide for the treatment of mild to moderate forms of depression in humans (Butterweck and Schmidt, 2007; Shelton, 2009), anxiety, sleep disorders, the common cold, herpes, and human immunodeficiency virus. It is used as a topical analgesic, and even as an enema for ulcerative colitis. Although its mechanisms of action have not been fully elucidated, inhibition of the uptake of serotonin and norepinephrine reportedly

contributes to the antidepressant effect of St. John’s wort (Neary and Bu, 1999). Several case reports have identified clinically relevant interaction between St. John’s wort and prescription drugs. The St. John’s wort and pharmacokinetics drug interactions are the following: digoxine (18% decreased of digoxin plasma concentrations after a single oral dose of 0.5 mg), indinavir (reduced indinavir plasma concentrations), theophylline (the dosage should be change), and cyclosporine (reduction in cyclosporine plasma concentration and acute transplant rejection) (Ha et al., 1995; Koudriakowa et al., 1988). A potential mechanism for these interactions includes induction of the hepatic CYP450 system, particularly CYP3A4, which is the most abundant hepatic and intestinal phase I enzyme and is involved in oxidative metabolism of more than 50% of all prescription medications, which is mediated by activating the pregnane X receptor (PXR), a transcription factor that is activated by structurally diverse foreign chemicals. Both CYP3A4 and P-gp have been found to be highly expressed in enterocytes and hepatocytes, which are important in drug absorption and metabolism (Durr et al., 2000). Many P-gp inhibitors studied in vitro and in vivo are also known or suspected to be the substrates and/or inhibitors of CYP3A4 (Wandel et al., 1999). Although there is a considerable overlap in the activity of the inhibitors of P-gp on CYP3A4, a varying degree of selectivity was present in the investigated herbal constituents. To assess the clinical interaction potential of the herbal inhibitors with P-gp, the International Transporter Consortium recently recommended a cutoff value of [I]1/ IC50 (or Ki) ≥0.1 or [I]2/IC50 (or Ki) ≥10, where [I]1 represents the mean steady-state total (free and bound) Cmax following the administration of the highest proposed clinical dose and [I]2 = dose of inhibitor (in mol)/250 mL. It has been shown that hyperforin, a phloroglucinol derivative found in St. John’s wort, is a potent inducer of CYP3A4 in primary human hepatocytes. Theophylline is metabolized by CYP1A2 and CYP3A, cyclosporine is metabolized by CYP3A, and indinavir is metabolized by CYP3A. The digoxin interactions were due to induction of P-gp, although a potential role for CYP3A in digoxin metabolism has been reported. St. John’s wort was found to increase the duodenal P-gp expression by 1.4-fold in healthy volunteers after multiple administrations. Reactions resulting from induction of metabolism by St. John’s wort can potentially result in therapeutic failure if two drugs are given concomitantly. Conversely, toxicity could occur if dosage is not adjusted appropriately following discontinuation of St. John’s wort. Coadministration of this herb and drugs metabolized by CYP3A4 should be avoided because it may result in reduced bioavailability and effectiveness with subsequent recurrence of arrhythmia, hypertension, or other undesirable effects.

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Food and Nutrient–Drug Interactions

FOOD AND NUTRIENT–DRUG INTERACTIONS Diet–Drug Interactions A dietary component may influence the absorption of drugs from the intestine. The presence of food in the stomach may also exert a nonspecific effect in reducing or slowing the absorption of some drugs, thus lowering peak plasma concentrations. With some drugs, the presence of increased amounts of stomach acid results in the destruction of acid-labile drugs, such as penicillin G, ampicillin, and dicloxacillin. In other cases, the components of the food, such as calcium or iron, may form complexes with the drug that are less easily absorbed. Examples include tetracycline, sodium fluoride and ciprofloxacin.

Grapefruit Juice The interaction between grapefruit juice and a variety of drugs has been widely reported (Bressler, 2006; Table 60.1). It appears that one or more flavonoids found in grapefruit juice inhibit CYP enzymes. This results in reduced metabolism of drugs that are cleared by the same system; drug bioavailability can markedly augment by as much as 200%. Patients should avoid drinking grapefruit juice for 2 h before and 4 h after taking drugs in this category. If the drug is in an extendedrelease dosage form, patients should wait until 6 h have passed before drinking grapefruit juice. Many drugs interact with grapefruit (juice, segments, extract, and certain related citrus fruits, e.g., Seville oranges, pomelos, and some exotic orange varieties). Several components in grapefruit called furanocoumarins (two of the most common are bergamottin and 6ʹ7ʹ-dihydroxybergamottin) irreversibly inhibit CYP3A4 in the small intestine, which results in a significant reduction in drug presystemic metabolism of affected drugs taken up to 72 h after grapefruit consumption. Intestinal 3A4 activity can remain inhibited during this time as the body produces more enzymes. Greater amounts of 3A4-metabolized drugs can then enter the systemic circulation. The resulting increase in drug levels can lead to an increase in therapeutic effect, adverse effects, and/or toxicity. An additional mechanism for this interaction is the inhibition of P-gp, a transporter that carries the drug from the enterocyte back to the lumen, resulting in a further increase in the fraction of drug absorbed (Lown et al., 1997b). After uptake by the enterocyte, many lipophilic drugs are either metabolized by CYP3A4 or pumped back into the lumen by the P-gp transporter. In consequence, CYP3A4 and P-gp may act in tandem as a barrier to oral delivery of many drugs (e.g., decreased bioavailability of cyclosporin in the presence of hyperforin-rich St. John’s wort preparations). Interactions are more pronounced

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for drugs that normally undergo a large amount of presystemic metabolism (low oral bioavailability). Since the effect of grapefruit juice can last 24 h, repeated juice consumption can result in a cumulative increase in drug concentrations. Clinically relevant interactions seem likely for most dihydropyridine calcium channel antagonists, terfenadine, saquinavir, cyclosporin, midazolam, triazolam, and verapamil, and may also occur with lovastatin, cisapride, and astemizole (Kronbach et al., 1988; Saito et al., 2005). Elevated plasma concentrations of these compounds are particularly worrisome because grapefruit juice and medications are commonly consumed together at breakfast. The increased drug concentrations might be associated with an increased frequency of dosedependent adverse effects. The importance of these interactions appears to be influenced by individual patient susceptibility, the type and amount of grapefruit juice, and the dosing-related fact. Although the clinical consequence of grapefruit juice interaction with most of the listed drugs has not been evaluated, increased plasma concentrations of many of these drugs could result in adverse outcomes. Examples include excessive lowering of blood pressure with calcium channel antagonists, rhabdomyolysis and the potential for renal impairment with the HMG-CoA reductase inhibitors or statins (i.e., atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, simvastatin), and adverse pulmonary effects caused by amiodarone (Dreier and Endres, 2004; Saito et al., 2005). The fruit has been proven to be a good source of vitamins C and the B complexes, as well as calcium, potassium, and magnesium. The three major types of grapefruit that exist today are white, pink/red, and ruby/rio red varieties. Traditionally grapefruit juice has been found to contain antioxidant, antinitrosaminic, antiseptic, aperitif, cardiotonic, detoxicant, hypocholesterolemic, sedative, and stomachic activities. Grapefruit juice interacts with a number of medications. As little as 250 mL of grapefruit juice can change the metabolism of some drugs. This drug–food interaction occurs because of a common pathway involving a specific isoform of CYP450, CYP3A4, present in both the liver and the intestinal wall. Studies suggest that grapefruit juice exerts its effect primarily at the level of the intestine, inhibiting metabolism of those drugs that are substrates for intestinal CYP3A4 and P-gp. It is an inhibition of the first-pass metabolism of the CYP3A4 substrates leading to an increase in maximal plasma drug concentrations (Cmax) and the amount of drug, that is, area under the concentration time curve (AUC). Grapefruit juice administration did not inhibit CYP3A4 substrate drugs given intravenously, whereas it inhibited the metabolism of these drugs given orally. This action is, in essence, similar to that caused by CYPinhibiting drugs like itraconazole, ketoconazole, and erythromycin.

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TABLE 60.1 Effect on Drug Metabolism and Possible Interactions of Grapefruit Juice with Specifically Affected Drugs Drug class

Drug

Metabolism

Effect

Possible adverse effects

Increased oral bioavailability

Management

Mechanism

Antiarrhythmics

Amiodarone

CYP3A4

Increased Cmax 84%

Arrhythmias

Yes

Avoid GJ

CYP3A4 inhibition

CYP2C8

Increased AUC 50%

CYP3A4

Delayed absorption

None

No

None

CYP2D6

Increased Cmax from 1.6 to 3.3 h

P-glycoprotein

Decreased AUC

Inhibition of hepatic CYP3A4 and quinidine absorption by OATP

Quinidine

Reduced quinidine ECG effects Digoxin Antibiotics

No effect on Cmax or AUC

Terfenadine

CYP3A4

Increased Cmax 52%

P-glycoprotein

Increased AUC 49%

Not metabolized

Decreased Cmax Decreased AUC

Anxiolytics

Buspirone

CYP3A4

Increased Cmax 4-fold Increased AUC 9-fold Delayed time to Cmax 188%

Diazepam

CYP3A4

Midazolam

CYP3A4

Increased Cmax 56% Increased AUC 52%

No

None

CYP3A4 inhibition CYP3A4 inhibition

Arrhythmias, prolonged Q–T interval

Yes

Avoid GJ

Inhibition of OATP decreasing absoption

Decreased psychomotor performance, increased sedation

Yes

Avoid GJ

CYP3A4 inhibition

Decreased psychomotor performance, increased sedation

Yes

Avoid GJ

CYP3A4 inhibition

Decreased psychomotor performance, increased sedation

Yes

Avoid GJ

CYP3A4 inhibition

Yes

Avoid GJ

CYP3A4 inhibition

Slowed absorption by inhibition of OATP

CYP3A4

Increased Cmax 1.3-fold

P-glycoprotein

Increased AUC 1.5-fold

Decreased psychomotor performance, increased sedation

CYP3A4

Increased Cmax 15%

Tachycardia, hypotension

Yes

Avoid GJ

CYP3A4 inhibition

Tachycardia, hypotension

Yes

Avoid GJ

CYP3A4 inhibition

Tachycardia, hypotension

Yes

Avoid GJ

CYP3A4 inhibition

Nimodipine

Tachycardia, hypotension

Yes

Avoid GJ

CYP3A4 inhibition

Diltiazem

None

No

None

CYP3A4 inhibition

None

No

None

CYP3A4 inhibition

Triazolam Calcium-channel blockers

CYP3A4 inhibition None

Clarithromycin Erythromycin

Antihistamines

P-glycoprotein OATP

Amlodipine

Increased AUC 14% Felodipine

CYP3A4

Increased Cmax 127% to 310% Increased AUC 123% to 330%

Nifedipine

Verapamil

CYP3A4

Increased Cmax 15%

CYP2D6

Increased AUC 40%

CYP3A4 less

Increased AUC 41%

CYP1A2 less

S 36%, R 28%

CYP2E1

Cmax S isomer 57%, R isomer 40%

CYP2C8

Increase of PR interval to 350 msec in 2 of 24 subjects

TABLE 60.1 Effect on Drug Metabolism and Possible Interactions of Grapefruit Juice with Specifically Affected Drugs Drug class

Drug

Metabolism

Effect

Possible adverse effects

Increased oral bioavailability

Corticosteroids

Ethinyl estradiol

CYP3A4

Increased Cmax 37%

Unknown

P-glycoprotein

Increased AUC 28%

Management

Mechanism

Yes

Monitor for side effects

CYP3A4 inhibition

Progesterone

CYP3A4

Unknown

Possible

Monitor for side effects

CYP3A4 inhibition

Prednisone

CYP3A4

None

No

None

CYP3A4 inhibition

HMG–CoA reductase Atorvastatin inhibitors

CYP3A4

Myopathy, headache, rhabdomyolysis

Yes

Avoid GJ

CYP3A4 inhibition

Cerivastatin

CYP3A4

Myopathy, headache, rhabdomyolysis

Possible

Monitor for side effects

CYP3A4 inhibition

Lovastatin

P-glycoprotein

Myopathy, headache, rhabdomyolysis

Yes

Avoid GJ

CYP3A4 inhibition

No change Cmax, AUC

Myopathy, headache, rhabdomyolysis

Yes

Avoid GJ

CYP3A4 inhibition

CYP3A4

Increased Cmax 9-fold

Avoid GJ

CYP3A4 inhibition

Increased AUC 16-fold

Myopathy, headache, rhabdomyolysis

Yes

P-glycoprotein CYP3A4

Increased Cmax 50%

Unknown

Yesa

CYP3A4 inhibition

P-glycoprotein

Increased AUC 100%

Monitor for side effects

CYP3A4

Increased AUC 8% to 71%

Yes

Avoid GJ

CYP3A4 inhibition

P-glycoprotein

Increased Cmax 0 to 78%

Renal/hepatic dysfunction, increased immunosuppression

Renal/hepatic dysfunction, increased immunosuppression

Yes

Avoid GJ

CYP3A4 inhibition

Drowsiness, ataxia, nausea

Yes

Avoid GJ

CYP3A4 inhibition CYP3A4 inhibition

Increased Cmax 12-fold Increased AUC 15-fold

Pravastatin

Small % CYP3A4 Most eliminated unchanged

Simvastatin

HIV protease inhibitors

Saquinavir

Immunosuppressants

Cyclosporine

Delayed time to Cmax 93%

Neuropsychiatrics

Tacrolimus

CYP3A4

Carbamazepine

CYP3A4

Increased Cmax 40%

P-glycoprotein

Increased AUC 40.8%

Clomipramine

CYP3A4

Drowsiness, respiratory depression

Yes

Monitor for side effects

Phenytoin

CYP3A4

None

No

None

Sertraline

CYP3A4 CYP2D6

Increased plasma trough levels 47%

CYP3A4 inhibition

CYP2C19 Fluoxamine

CYP3A4

CYP3A4 inhibition

CYP2D6

Increased Cmax 1.3-fold

CYP2C19

Increased AUC 1.6-fold (Continued)

TABLE 60.1 Effect Continued on Drug Metabolism and Possible Interactions of Grapefruit Juice with Specifically Affected Drugs Drug class

Drug

Metabolism

Other

Carvedilol

CYP3A4

Methadone

CYP3A4

Effect

Increased Cmax 17% Increased AUC 17%

Dextromethorphan CYP3A4 Sildenafil

CYP3A4

Possible adverse effects

Increased oral bioavailability

Bradycardia, hypotension Respiratory depression, hypotension

Management

Mechanism

Possible

Monitor for side effects

CYP3A4 inhibition

Possible

Monitor for side effects

CYP3A4 inhibition

Increased AUC 5.4-fold Increased AUC 23%

CYP3A4 inhibition Headache, flushing, dyspepsia

Possible

Monitor for side effects

CYP3A4 inhibition

None

No

None

CYP3A4 inhibition

None

No

None

No GJ effect on warfarin metabolism

Primary metabolite N-demethylated compound increased 24% No change Cmax of either compound Theophylline

CYP3A4

Warfarin

S isomer CYP2C9 R isomer CYP1A2

No effect on Prothrombin time or international normalized ratio

CYP3A4, small contributor to metabolism Cilostazol

Losartan

CYP3A4 somo

Increased Cmax 50%

CYP2C19

No AUC effect

CYP3A4

Increased AUC 41%

CYP2C9

Losartan metabolite Decreased hepatic metabolism Less conversion of losartan to its active metabolite Less blood pressure decline

GJ: grapefruit juice and the whole fruit; OATP: organic anion transporting polypeptide (a system in the intestines involved in absorption of certain drugs). a Clinical significance unknown.

CYP3A4 inhibition

CYP3A4 inhibition

871

Food and Nutrient–Drug Interactions

After ingestion, a substrate contained in the grapefruit binds to the intestinal isoenzyme, impairing first-pass metabolism directly and causing a sustained decrease in CYP3A4 protein expression. Within 4 h of ingestion, a reduction in the effective CYP3A4 concentration occurs, with effects lasting up to 24 h (Lundahl et al., 1995). Individuals express CYP3A4 in different proportions, with those with the highest intestinal concentration being most susceptible to grapefruit juice–drug interactions (Lown et al., 1997a). In recent years, however, reports of grapefruit juice– drug interactions have been published, raising questions about potential adverse effects derived from these interactions. The elderly patient population has multiple diseases and uses multiple drugs (Bressler and Bahl, 2003). Moreover, like the general population, elderly patients may consume grapefruit juice as a popular breakfast food.

TABLE 60.2  Interactions of Mono Amine Oxidase (MAO) Inhibitors with Tyramine in Food Tyramine in food Normal subject = >

MAO production normal (substrates: dopamine, tyramine, serotonin) = >

Tyramine detoxified before reaching systemic circulation

MAO inhibitorstreated patient = >

MAO production inhibited = >

Toxic tyramine reaches systemic circulation = >

Hypertensive crisis (headache, heart failure, intracerebral hemorrhage)

Warning: patients being treated with MAO inhibitors and their families should be given a list of foods to avoid diet–drug interactions due to the use of any medication by patients without permission.

Mono Amine Oxidase (MAO) Inhibitors Perhaps the most feared food–drug interaction is between MAO inhibitors and the amino acid tyramine, which is found in a variety of aged, fermented, overly ripe, or pickled foods and beverages and, to a lesser extent, chocolate and yeast-containing foods. Examination of various foods and drinks has shown that many are rich in tyramine content, for example, certain cheeses, Chianti wine, some beers, yeast products, and schmaltz pickled herring, whereas others, notably citrus fruits and caffeine-containing drinks, may cause bizarre effects in patients on MAO inhibitors therapy due to their dopamine, tyramine, or serotonin (5-hydroxytryptamine) content (Walker et al., 1966). There was an effect on individuals consuming cheese or other foodstuffs high in tyramine content while using MAO inhibitors; the result was that without the detoxifying activity of MAO, the ingested tyramine entered the bloodstream and resulted in a potentially fatal hypertensive crisis (Table 60.2). Because more than 10 mg of tyramine seems to be required to produce significant hypertension, the most dangerous foods are aged cheeses and yeast products used as food supplements. Tyramine is indirectly sympathomimetic and is a pressor amine or substance capable of liberating stored catecholamines. When its metabolism is suppressed, as it is by MAO inhibitors, it can cause a significant release of norepinephrine, resulting in markedly increased blood pressure, cardiac arrhythmias, hyperthermia, and cerebral hemorrhage. The occurrence of these hypertensive side effects (forceful, heartbeat, severe headache, and hypertension) depends on the duration and intensity of action of the MAO inhibitor antidepressants, the variation in tyramine content in the diet, and the marked individual variation in responsiveness of the patient. In conclusion, foods high in tyramine that should be avoided include:

(i) American processed cheddar, blue, brie, mozzarella, and Parmesan cheese, yogurt, and sour cream; (ii) beef or chicken liver, cured meats such as sausage and salami, game meat, caviar, and dried fish; (iii) avocados, bananas, yeast extracts, raisins, sauerkraut, soy sauce, and miso soup; and (iv) broad (fava) beans, ginseng, caffeine-containing products (colas, chocolate, coffee, and tea) (NCL, 2015).

Herbs during Pregnancy When consuming herbal therapies, it should be ensured that they are healthy prior to and during pregnancy. Herbs are extracts of plants or plant roots, and they contain numerous compounds. Different forms of herbal preparations (i.e., teas or infusions, capsules, dried extracts, and tinctures) will have different compounds in herbal preparations, as well as differing concentrations. How the herb is prepared is very important to the effect and safety of the pregnant woman and fetus. The effects and safety of herbs will depend on the trimester. One of the most important concepts is that herbs should be used with caution in the first trimester. The rapid cellular development in organogenesis can be altered by any compound, and some herbs may increase uterine tone, increasing the risk of pregnancy loss. There are numerous herbs that are thought to be contraindicated during pregnancy; these herbs can be classified into five subgroups based on their potential effects on the pregnant woman (Blumenthal et al., 1998; Low Dog and Micozzi, 2005; Weed, 1986; see Table 60.3): 1. Herbs used traditionally to stimulate menstruation. These herbs may stimulate the smooth muscle of the uterus and may cause a pregnancy loss.

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60.  Interactions between Nutraceuticals/Nutrients and Therapeutic Drugs

TABLE 60.3 Herbs Contraindicated during Pregnancy 1. Herbs used traditionally to stimulate menstruation: ● Ginger (Zingiber officinale), cranberry (Vaccinium oxycoccos), evening primrose oil (Oenothera biennis), aloe vera gel (Aloe vera), Echinacea (Echinacea), St. John’s wort (Hypericum perforatum), valerian root (Valeriana officinalis) 2. Alkaloid-containing herbs: ● Autumn crocus (Colchicum autumnale), broom (Cytisus scoparius), comfrey (Symphytum officinale), mandrake (podophyllin) (Podophyllum peltatum), barberry (Berberis vulgaris), coffee (Coffea canephora/arabica), goldenseal (Hydrastis canadensis), tansy (Tanacetum vulgare), blood root (Sanguinaria canadensis), colt’s foot (Tussilago farfara) 3. Essential oils: ● Arbor vitae (Arbor vitae), juniper (Juniperus), pennyroyal (Mentha pulegium), nutmeg (Myristica fragran), catnip (Nepata cataria), rosemary (Rosmarinus officinalis), boldo (Peumus boldus) 4. Anthraquinone laxatives: ● Alder buckthorn (Rhamnus frangula), cascara (Rhamnus frangula/purshiana), purging buckthorn (Rhamnus cathartica), senna (Senna alexandrina) 5. Herbs thought to have an effect on the hormonal system: ● Ginseng (Panax ginseng), licorice (Glycyrrhiza glabra), chasteberry (Vitex agnus-castus), saw palmetto (Serenoa repens), passion flower (Passiflora spp.), isoflavones (members of the Fabaceae), red clover (Trifolium pratense), flaxseed (Linum usitatissimum), hops (Humulus lupulus)

2. Herbs controversially used during menstruation and herbs used traditionally to stimulate menstruation (not recommended during pregnancy) (angelica, celandine, goldenseal, shepherd’s purse, barberry, dong quai, motherwort, southernwood, black cohosh, ephedra, mugwort, tansy, blue cohosh, feverfew, rue, yarrow, nettle root, baldo, andrographis). 3. Alkaloid-containing herbs. These herbs are a diverse group of chemical plant constituents that have a wide range of pharmacological impacts on the body. Some alkaloids have been shown to be hepatotoxic and potentially carcinogenic. 4. Essential oils. Essential oils are frequently used by patients in many situations. Some essential oils are potentially very dangerous during pregnancy when ingested. All essential oils should be appropriately diluted when used, and none should be taken internally. 5. Anthraquinone laxatives. These are very potent compounds that can stimulate bowel peristalsis. They are frequently used as potential laxative agents. In pregnancy, overstimulation of the bowel or bladder has the potential to irritate/stimulate the uterus in some women, and may cause premature labor.

6. Herbs thought to have an effect on the hormonal system. Some herbs may have an effect on the hormonal system, and they have potential estrogenlike properties, which can cause concern regarding the possible effects on the fetus.

CONCLUDING REMARKS AND FUTURE DIRECTIONS Human medicines can treat and cure many health problems; however, they must be taken appropriately to ensure that they are safe and effective. Certain foods can interact with medications; food–drug interactions are defined as alterations of pharmacokinetics or pharmacodynamics of a drug or nutritional element or a compromise in nutritional status as a result of the addition of a drug. The most relevant nutrients to the drug–food interactions that have been described in this chapter are the multivalent minerals such as calcium. More attention has been given to the characterization of food/dietary supplement–drug interactions, particularly with any dietary supplements such as vitamins, minerals, and herbs. The various stages in which food can interact with a coadministered drug occur before and after gastrointestinal absorption, and during distribution, metabolism, and elimination. Drug–acid and other drug–mineral interactions should be extrapolated to interactions with fortified foods as well as other foods that may not be listed as fortified but contain combinations of several multivalent ions. Additional drug–food studies are needed to better characterize the extent of these interactions with fortified and nonfortified foods, as well as combinations of them. Herbal extracts or single, isolated compounds can be either inhibitors or inducers of various CYP enzymes or transporters. Dual inhibition of P-gp and CYP3A4/5 activities could occur due to the overlapping substrate specificities between herbal medicines and drugs. Interactions between herbal products and prescribed drugs are a major safety concern, especially with respect to drugs with a narrow therapeutic index. Such an interaction may cause adverse effects, which may be life-threatening. Most food–drug interactions occur through three mechanisms: (i) reduced rate or extent of absorption; (ii) increased rate or extent of absorption; or (iii) chemical/pharmacologic effects. The presence of multiple diseases, polypharmacy, malnutrition status, and impaired metabolism, common in elderly individuals, increases the risks of adverse events related to food–drug interactions.

Conflict of Interest Statement None of the authors of this chapter has a financial or personal relationship with other people or organizations

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REFERENCES

that could inappropriately influence or bias the content of the work.

Acknowledgments This review was supported by the Universidad Complutense de Madrid (Spain), Project Ref. Santander-UCM/GR14 (category-A), and Comunidad de Madrid (Spain), Programme Ref. no S2013/ABI-2728 (ALIBIRD-CM).

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