**4. Foods and drug-metabolizing enzyme**

There are four types of accepted drug-food interactions based on their nature and mecha‐

**•** Type I are *ex vivo* bioinactivations, which refer to interactions between the drug and the nutritional element or formulation through biochemical or physical reactions, such as hy‐ drolysis, oxidation, neutralization, precipitation or complexation. These interactions usu‐

**•** Type II interactions affect absorption. They cause either an increase or decrease in the oral bioavailability of a drug. The precipitant agent may modify the function of enzymes or

**•** Type III interactions affect the systemic or physiologic disposition and occur after the drug or the nutritional element has been absorbed from the gastrointestinal tract and en‐ tered the systemic circulation. Changes in the cellular or tissue distribution, systemic

**•** Type IV interactions refer to the elimination or clearance of drugs or nutrients, which may involve the antagonism, impairment or modulation of renal and/or enterohepatic elimina‐

Drug metabolizing enzymes and drug transporters play important roles in modulating drug absorption, distribution, metabolism, and elimination. Acting alone or in concert with each other, they can affect the pharmacokinetics and pharmacodynamics of a drug. The interplay between drug metabolizing enzymes and transporters is one of the confounding factors that

The oral administration of drugs to patients is convenient, practical, and preferred for many reasons. Oral administration of drugs, however, may lead to limited and variable oral bioa‐ vailability because of absorption across the intestinal barrier [15,16]. Drug absorption across the gastrointestinal tract is highly dependent on affinity for membrane transporters as well as lipophilicity [17]. On the other hand, the liver plays a key role in the clearance and excre‐ tion of many drugs. Hepatic transporters are membrane proteins that primarily facilitate nu‐ trient and endogenous substrate transport into the cell via uptake transporters, or protect the cell by pumping out toxic chemicals via canalicular transporters [18]. Consequently, drug transporters in both the gut and the liver are important in determining oral drug dis‐

The major uptake transporters responsible for nutrient and xenobiotic transport, both up‐ take and efflux transporters, belong to the two solute carrier (SLC and SLCO) superfamilies [20]. The SLC superfamily encompasses a variety of transporters, including the organic anion transporters (OAT, SLC22A), the organic cation transporters (OCT, SLC22A), the elec‐ troneutral organic cation transporters (OCTN, SLC22A), the equilibrative nucleoside trans‐

have been recently shown to contribute to potential complex drug interactions [14].

transport mechanisms that are responsible for biotransformation.

transport, or penetration to specific organs or tissues can occur.

nisms.

4 Drug Discovery

tion [13].

ally occur in the delivery device.

**3. Food and drug transporters**

position by controlling absorption and bioavailability [19]

It has been shown that, before reaching the systemic circulation, the metabolism of orally in‐ gested drugs ('first-pass metabolism' or 'presystemic clearance') has clinically relevant influ‐ ences on the potency and efficacy of drugs. Both the intestine and liver account for the presystemic metabolism in humans. Drug metabolism reactions are generally grouped into 2 phases. Phase I reactions involve changes such as oxidation, reduction, and hydrolysis and are primarily mediated by the cytochrome P450 (CYP) family of enzymes. Phase II reactions use an endogenous compound such as glucuronic acid, glutathione, or sulfate, to conjugate with the drug or its phase I–derived metabolite to produce a more polar end product that can be more readily excreted [33].

The CYP enzymes involved in drug metabolism in humans are expressed predominantly in the liver. However, they are also present in the large and small intestine, lungs and brain [34]. CYP proteins are categorized into families and subfamilies and can metabolize almost any organic xenobiotic [35]. CYP enzymes combined with drug transport proteins constitute the first-pass effect of orally administered drugs [33]. On the other hand, the Phase II drug metabolizing or conjugating enzymes consist of many enzyme superfami‐ lies, including sulfotransferases (SULT), UDP-glucuronosyltransferases (UGT), DT-dia‐ phorase or NAD(P)H:quinone oxidoreductase (NQO) or NAD(P)H: menadione reductase (NMO), epoxide hydrolases (EPH), glutathione S-transferases (GST) and *N*-acetyltransfer‐ ases (NAT). The conjugation reactions by Phase II drug-metabolizing enzymes increase hydrophilicity and thereby enhance excretion in the bile and/or the urine and consequent‐ ly affect detoxification [36].

**5. Nutrient-drug interactions: examples with clinical relevance**

ing to potential important nutrient-drug interactions.

Data from: [26,52,53,55, 82, 111, 112]

**Table 1.** Commonly Consumed Fruits

Fruits and vegetables are known to be important components in a healthy diet, since they have low energy density and are sources of micronutrients, fiber, and other components with functional properties, called phytochemicals (See Figure 2). Increased fruit and vegeta‐ ble consumption can also help displace food high in saturated fats, sugar or salt. Low fruit and vegetable intake is among the top 10 risk factors contributing to mortality. According to the World Health Organization (WHO), increased daily fruit and vegetable intake could help prevent major chronic non-communicable diseases [44]. Evidence is emerging that spe‐ cific combinations of phytochemicals may be far more effective in protecting against some diseases than isolated compounds (Table 1 and 2). Observed drug-phytochemical interac‐ tions, in addition to interactions among dietary micronutrients, indicate possibilities for im‐ proved therapeutic strategies. However, several reports have examined the effects of plant foods and herbal medicines on drug bioavailability. As shown in Tables 3 and 4 and as dis‐ cussed below, we have surveyed the literature to identify reports suggesting important food and phytochemical modulation of drug-metabolizing enzymes and drug transporters lead‐

Fruit/Vegetable-Drug Interactions: Effects on Drug Metabolizing Enzymes and Drug Transporters

http://dx.doi.org/10.5772/48283

7

The metabolism of a drug can be altered by foreign chemicals and such interactions can of‐ ten be clinically significant [37]. The most common form of drug interactions entail a foreign chemical acting either as an inhibitor or an inducer of the CYP enzyme isoform responsible for metabolizing an administered medicinal drug, subsequently leading to an unusually slow or fast clearance of said drug [38,39]. Inhibition of drug metabolism will result in a con‐ centration elevation in tissues, leading to various adverse reactions, particularly for drugs with a low therapeutic index.

Often, influence on drug metabolism by compounds that occur in the environment, most re‐ markably foodstuffs, is bypassed. Dietary changes can alter the expression and activity of hepatic drug metabolizing enzymes. Although this can lead to alterations in the systemic elimination kinetics of drugs metabolized by these enzymes, the magnitude of the change is generally small [8, 40]. Metabolic food-drug interactions occur when a certain food alters the activity of a drug-metabolizing enzyme, leading to a modulation of the pharmacokinetics of drugs metabolized by the enzyme [12]. Foods, such as fruits, vegetables, alcoholic beverag‐ es, teas, and herbs, which consist of complex chemical mixtures, can inhibit or induce the activity of drug-metabolizing enzymes [41].

The observed induction and inhibition of CYP enzymes by natural products in the presence of a prescribed drug has (among other reasons) led to the general acceptance that natural therapies can have adverse effects, contrary to popular beliefs in countries with active ethno‐ medicinal practices. Herbal medicines such as St. John's wort, garlic, piperine, ginseng, and gingko, which are freely available over the counter, have given rise to serious clinical inter‐ actions when co-administered with prescription medicines [42]. Such adversities have spur‐ red various pre-clinical and *in vitro* investigations on a series of other herbal remedies, with their clinical relevance yet to be established. The CYP3A4-related interaction based on food component is the best known; it might be related to the high level of expression of CYP3A4 in the small intestine, as well as its broad substrate specificity. If we consider that CYP3A4 is responsible for the metabolism of more than 50% of clinical pharmaceuticals, all nutrientdrug interactions should be considered clinically relevant, in which case all clinical studies of drugs should include a food-drug interaction screening [43].
