**6. Drug-food interaction in specific diets with high content of fruits and vegetables**

Weight-reduction diets, vegetarian diets, hospitalization, or post-operative regimes all lead to dietary modifications. These diets are often maintained for long periods of time and are likely to result in metabolic changes due to subsequently administered drugs or exposure to environmental chemicals. Several epidemiologic, clinical, and experimental studies have es‐ tablished that certain types of diet may have beneficial effects on health. For example, the traditional Mediterranean diet has been shown to reduce overall mortality and coronary heart disease events [162]. This diet, however, varies across at least 16 countries bordering the Mediterranean Sea. Cultural, ethnic, religious, economic and agricultural differences in these regions account for variations in dietary patterns, which are widely characterized by the following: daily consumption of fruits, vegetables, whole grain breads, non-refined cere‐ als, olive oil, and dairy products; moderate weekly consumption of fish, poultry, nuts, pota‐ toes, and eggs; low monthly consumption of red meat, and daily moderate wine consumption [163]. Increasing evidence suggests that a Mediterranean-style diet rich in fruits, vegetables, nuts, fish and oils with monounsaturated fat and low in meat promotes cardiovascular health and aids cancer prevention because of its positive effects on lipid pro‐ file, endothelial function, vascular inflammation, insulin resistance, and its antioxidant properties [164,165].

Vegetarians, on the other hand, exhibit a wide diversity of dietary practices often described by what is omitted from their diet. When a vegetarian diet is appropriately planned and in‐ cludes fortified foods, it can be nutritionally suitable for adults and children and can promote health and lower the risk of major chronic diseases [166]. A vegetarian diet usually provides a low intake of saturated fat and cholesterol and a high intake of dietary fiber and many healthpromoting phytochemicals. This is achieved by an increased consumption of fruits, vegeta‐ bles, whole-grains, legumes, nuts, and various soy products. As a result of these factors, vegetarians typically have a lower body mass index, low-density lipoprotein cholesterol lev‐ els, and lower blood pressure; a reduced ischemic heart disease death rate; and decreased in‐ cidence of hypertension, stroke, type 2 diabetes, and certain cancers that are more common among non-vegetarians [167]. The vegan dietary category may be more comparable across countries and cultures because avoiding all animal products leaves little choice but to include large quantities of vegetables, fruit, nuts, and grains for nutritional adequacy. Admittedly, vegetable and fruit variety may also vary widely according to location [168].

Due to their high content of fruits and vegetables, all these diets contain a large propor‐ tion of antioxidant vitamins, flavonoids, and polyphenols [169]. Phenolic compounds may help protect the gastrointestinal tract against damage by reactive species present in foods or generated within the stomach and intestines. However, they may be beneficial in the gut in correct amounts. The overall health benefits of polyphenols are uncertain, and con‐ sumption of large quantities of them in fortified foods or supplements should not yet be encouraged [170].

polyphenols have been shown to interact with ABC drug transporters involved in drug re‐

**6. Drug-food interaction in specific diets with high content of fruits and**

Weight-reduction diets, vegetarian diets, hospitalization, or post-operative regimes all lead to dietary modifications. These diets are often maintained for long periods of time and are likely to result in metabolic changes due to subsequently administered drugs or exposure to environmental chemicals. Several epidemiologic, clinical, and experimental studies have es‐ tablished that certain types of diet may have beneficial effects on health. For example, the traditional Mediterranean diet has been shown to reduce overall mortality and coronary heart disease events [162]. This diet, however, varies across at least 16 countries bordering the Mediterranean Sea. Cultural, ethnic, religious, economic and agricultural differences in these regions account for variations in dietary patterns, which are widely characterized by the following: daily consumption of fruits, vegetables, whole grain breads, non-refined cere‐ als, olive oil, and dairy products; moderate weekly consumption of fish, poultry, nuts, pota‐ toes, and eggs; low monthly consumption of red meat, and daily moderate wine consumption [163]. Increasing evidence suggests that a Mediterranean-style diet rich in fruits, vegetables, nuts, fish and oils with monounsaturated fat and low in meat promotes cardiovascular health and aids cancer prevention because of its positive effects on lipid pro‐ file, endothelial function, vascular inflammation, insulin resistance, and its antioxidant

Vegetarians, on the other hand, exhibit a wide diversity of dietary practices often described by what is omitted from their diet. When a vegetarian diet is appropriately planned and in‐ cludes fortified foods, it can be nutritionally suitable for adults and children and can promote health and lower the risk of major chronic diseases [166]. A vegetarian diet usually provides a low intake of saturated fat and cholesterol and a high intake of dietary fiber and many healthpromoting phytochemicals. This is achieved by an increased consumption of fruits, vegeta‐ bles, whole-grains, legumes, nuts, and various soy products. As a result of these factors, vegetarians typically have a lower body mass index, low-density lipoprotein cholesterol lev‐ els, and lower blood pressure; a reduced ischemic heart disease death rate; and decreased in‐ cidence of hypertension, stroke, type 2 diabetes, and certain cancers that are more common among non-vegetarians [167]. The vegan dietary category may be more comparable across countries and cultures because avoiding all animal products leaves little choice but to include large quantities of vegetables, fruit, nuts, and grains for nutritional adequacy. Admittedly,

Due to their high content of fruits and vegetables, all these diets contain a large propor‐ tion of antioxidant vitamins, flavonoids, and polyphenols [169]. Phenolic compounds may help protect the gastrointestinal tract against damage by reactive species present in foods or generated within the stomach and intestines. However, they may be beneficial in the

vegetable and fruit variety may also vary widely according to location [168].

sistance and drug absorption, distribution and excretion [32].

**vegetables**

18 Drug Discovery

properties [164,165].

Flavonoids have been known as plant pigments for over a century and belong to a vast group of phenolic compounds that are widely distributed in all foods of plant origin. Un‐ fortunately, the potentially toxic effects of excessive flavonoid intake are largely ignored. At higher doses, flavonoids may act as mutagens, pro-oxidants that generate free radicals, and as inhibitors of key enzymes involved in hormone metabolism [171]. It has been shown that phenol ring-containing flavonoids yield cytotoxic phenoxyl radicals upon oxidation by per‐ oxidases; co-oxidize unsaturated lipids, GSH, NADH, ascorbate, and nucleic acids; and cause ROS formation and mitochondrial toxicity [172]. In high doses, the adverse effects of flavonoids may outweigh their beneficial ones, and caution should be exercised when in‐ gesting them at levels above those which would be obtained from a typical vegetarian diet [173]. Moreover, it is possible that people ingesting a vegetarian or Mediterranean diet may be taking medication and thus have drug-food interaction.

Inhibition of CYP enzymes, which are necessary for carcinogen activation, is a beneficial chemopreventive property of various flavonoids but may be a potential toxic property in flavonoid-drug interactions. Inhibition of CYP activities by flavonoids has been extensively studied because of their potential use as blocking agents during the initial stage of carcino‐ genesis [174]. The general conclusion after an analysis of available data on CYP-flavonoid interactions is that flavonoids possessing hydroxyl groups inhibit CYP activity, whereas those lacking hydroxyl groups may induce the metabolizing enzyme [175]. Flavonoids can either inhibit or induce human CYP enzymes depending on their structure, concentration, or experimental conditions [176]. The interaction of flavonoids with CYP3A4, the predominant human hepatic and intestinal CYP responsible for metabolizing 50% of therapeutic agents as well as the activation of some carcinogens, is of particular interest [177].

The simultaneous administration of flavonoids present in fruits or vegetables and clinically used drugs may cause flavonoid-drug interactions by modulating the pharmacokinetics of certain drugs, which results in an increase in their toxicity or a decline in their therapeutic effect, depending on the flavonoid structure [178]. Additional reasons for concern regarding mega flavonoid supplements include potential flavonoid-drug interactions, since flavonoids have been shown to both induce and inhibit drug-metabolizing enzymes [38, 39]. Further re‐ search regarding the potential toxicities associated with flavonoids and other dietary phe‐ nolics is required if these plant-derived products are to be used as therapy.

It is a fact that diets based on fruits and vegetables may have a variety of phytochemicals, as was mentioned earlier, so the possibility of developing a drug-food interaction is high. While dietary polyphenols may be beneficial in the correct amount, but too much may not be good and combining them with medication should be avoided.
