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

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‐

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

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

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

ly affect detoxification [36].

6 Drug Discovery

with a low therapeutic index.

activity of drug-metabolizing enzymes [41].

of drugs should include a food-drug interaction screening [43].

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‐ ing to potential important nutrient-drug interactions.


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

**Table 1.** Commonly Consumed Fruits


**Table 4.** Vegetable-Drug Intractions

**5.1. Grapefruit (***Citrus paradisi***)**

The interaction of grapefruit with certain drugs was unintentionally discovered two decades ago [45]. Since then, there have been numerous reports on the effects of grapefruit and its components on CYP450 drug oxidation and transportation [46,47]. Several findings showed that grapefruit juice had a major effect on the intestinal CYP system with a minor effect at the hepatic level [48]. The predominant mechanism for this interaction is the inhibition of cytochrome *P*-450 3A4 in the small intestine, which results in a significant reduction of drug presystemic metabolism. Grapefruit juice intake has been found to decrease CYP3A4 mRNA activity through a post transcriptional activity, possibly by facilitating degradation of the en‐ zyme [49]. An additional mechanism may be the inhibition of P-glycoprotein and MRP2 mediated drug efflux, transporters that carry drugs from enterocytes back to the gut lumen, all of which results in a further increase in the fraction of drug absorbed and increased sys‐ temic drug bioavailability [50-52]. It has also been reported that the major constituents of

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

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

9

The interaction between grapefruit juice and drugs has been potentially ascribed to a num‐ ber of constituents [27]. It has been suggested that flavonoids such as naringin, naringenin, quercetin, and kaempferol, major components in grapefruit, are responsible for drug inter‐ action. Some of these chemicals are also found in other fruit juices. Pomegranate, for exam‐ ple, shares certain properties with grapefruit, suggesting that both could modify the bioavailability of drugs [55,56]. Another group of compounds that has been detected in grapefruit juice are the furanocoumarins (psoralens), which are known to be mechanism-

grapefruit significantly inhibit the OATP-B function *in vitro* [53,54].

Data from: [26,105,114,126, 151]

**Table 2.** Commonly Consumed Vegetables


**Table 3.** Fruit-Drug Interactions


**Table 4.** Vegetable-Drug Intractions

Data from: [26,105,114,126, 151]

8 Drug Discovery

**Table 3.** Fruit-Drug Interactions

**Table 2.** Commonly Consumed Vegetables
