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

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 mechanismbased inactivators of CYP450. The major furanocoumarin present in grapefruit is bergamot‐ tin, which demonstrated a time- and concentration-dependent inactivation of CYP enzymes *in vitro* [49]*.* One interesting characteristic of this interaction is that grapefruit juice does not need to be taken simultaneously with the medication in order to produce the interaction. The bioavailability of drugs has been reported to be doubled by grapefruit juice, even when taken 12 h after ingestion. Colored grapefruit juice and white grapefruit juice are equally ef‐ fective in producing drug interactions.

transporters by P-gp, which could enhance the bioavailability of drugs and thus lead to an

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

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

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It has also been observed that components of orange juice -naringin in particular- are *in vitro* inhibitors of OATP transport activity [70]. Dresser et al., have previously reported that or‐ ange juice inhibits the function of human OATP-A (OATP1A2, gene symbol *SLC21A3/ SLCO1A2*) *in vitro* [29]. OATP-A, however, is predominantly expressed in the brain, but not in the intestine. On the other hand, Satoh et al. reported that OATP-B-mediated uptake of glibenclamide as well as estrone-3-sulfate was significantly inhibited by 5% orange juice [53]. Orange juice might reduce the intestinal absorption of substrates of OATP-B (e.g., di‐ goxin, benzylpenicillin, and hormone conjugates), resulting in a decrease in concentration in

Previous studies in humans using fexofenadine as a probe showed that oral coadministra‐ tion with orange juice decreased the oral bioavailability of fexofenadine [63]. Orange juice and its constituents were shown to interact with members of the OATP transporter family by reducing their activities. The functional consequences of such an interaction are reflect‐ ed in a significant reduction in the oral bioavailability of fexofenadine, possibly by prefer‐ ential direct inhibition of intestinal OATP activity. Other reports indicate that orange juice slightly reduced the absorption of ciprofloxacin, levofloxacin and celiprolol [65] A study of an interaction between orange juice and pravastatin showed an increase in AUC [54].Orange juice also moderately reduces the bioavailability of atenolol, which may neces‐

Early studies demonstrated the influence of tangeretin, a flavonoid found in high levels in tangerine juice, on drug metabolizing liver enzymes. It was demonstrated that tangeretin in‐ hibits P450 1A2 and P450 3A4 activity in human liver microsomes [73]. Tangeretin is a po‐ tent regioselective stimulator of midazolam 1'-hydroxylation by human liver microsomes CYP3A4. Although, clinical studies have shown no influence on midazolam pharmacokinet‐ ics *in vivo,* further studies are needed to evaluate its effects on other drugs [74]. Diosmin is one of the main components of citrus fruits, such as tangerine. Diosmin may increase the ab‐ sorption or bioavailability of co-administered drugs able to serve as P-gp substrates. As a

Grapes are one of the most valued conventional fruits worldwide. The grape is considered a source of unique and potentially useful medicinal natural products; they are also used in the manufacturing of various industrial products [75,76](Yadav and others 2009; Vislocky and Fernandez 2010). The main biologically active and well-characterized constituent from the grape is resveratrol, which is known for various medicinal properties in treating human dis‐ eases [75](Yadav and others 2009). Resveratrol was shown to be an irreversible (mechanismbased) inhibitor of CYP3A4 and a non-competitive reversible inhibitor for CYP2E1 in

increase in the risk of adverse events [52].

sitate a dose adjustment [71,72].

**5.3. Tangerine (***Citrus reticulata***)**

**5.4. Grapes (***Vitis vinifera***)**

result, some caution may be required with its clinical use [52].

the blood.

This inhibitory interaction should be kept in mind when prescribing drugs metabolized by CYP3A4. Examples of drugs affected by grapefruit or its components include: calcium chan‐ nel antagonists such as felodipine, nisoldipine, amlodipines, verapamil, and diltiazem [57]; central nervous system modulators, including diazepam, triazolam, midazolam, alprazolam, carbamazepine, buspurone and sertraline [58]; HMG-CoA reductase inhibitors, such as sim‐ vastatin, lovastatin, atorvastatin, and pravastatin [59]; immunosuppressants such as cyclo‐ sporine [60]; anti-virals such as saquinavir [61]; a phosphodiesterases-5 inhibitor such as sildenafil [62]; antihistamines, including as terfenadine and fexofenadine [63]; antiarhyth‐ mics such as amiodarone [62]; and antibiotics such as eritromicine [64].

Epidemiologic studies reveal that approximately 2% of the population in the United States consumes at least one glass of regular strength grapefruit juice per day. This becomes perti‐ nent if we consider that many people suffer from chronic metabolic diseases (including hy‐ pertension, hyperlipidemia, and cardiovascular diseases) and receive calcium channel antagonis therapy and HMG-CoA reductase inhibitors. Patients with mental disorders also chronically receive central nervous system modulators. In the case of many drugs, an in‐ crease in serum drug concentration has been associated with increased frequency of dosedependent adverse effects [65-67]. In light of the wide ranging effects of grapefruit juice on the pharmacokinetics of various drugs, physicians need to be aware of these interactions and should make an attempt to warn and educate patients regarding the potential conse‐ quences of concomitant ingestion of these agents.

#### **5.2. Orange (***Citrus sinensis***)**

Consumption of most types of orange juice does not appear to alter CYP3A4 activity *in vivo* [55]. However, orange juice made from Seville oranges appears to be somewhat similar to grapefruit juice and can affect the pharmacokinetics of CYP3A4 substrates [68]. It has been previously shown that consumption of a single 240 mL serving of Sevilla orange juice result‐ ed in a 76% increase in felodipine exposure, comparable to what is observed after grapefruit juice consumption [11]. Presumably, the mechanism of this effect is similar to that of grape‐ fruit juice-mediated interactions, because Sevilla orange contains significant concentrations of flavonoids, mainly bergamottin and 6´,7´-dihydroxybergamottin [69]. Orange juice has al‐ so been shown to exert inhibitory effects on P-glycoprotein (P-gp)-mediated drug efflux. Ta‐ kanaga and others showed that 3,3′,4′,5,6,7,8-heptamethoxyflavon and tangeretin were the major P-gp inhibitors present in orange juice and showed that another component, nobiletin, was also a P-gp inhibitor [55]. Therefore, the intake of orange juice might inhibit the efflux transporters by P-gp, which could enhance the bioavailability of drugs and thus lead to an increase in the risk of adverse events [52].

It has also been observed that components of orange juice -naringin in particular- are *in vitro* inhibitors of OATP transport activity [70]. Dresser et al., have previously reported that or‐ ange juice inhibits the function of human OATP-A (OATP1A2, gene symbol *SLC21A3/ SLCO1A2*) *in vitro* [29]. OATP-A, however, is predominantly expressed in the brain, but not in the intestine. On the other hand, Satoh et al. reported that OATP-B-mediated uptake of glibenclamide as well as estrone-3-sulfate was significantly inhibited by 5% orange juice [53]. Orange juice might reduce the intestinal absorption of substrates of OATP-B (e.g., di‐ goxin, benzylpenicillin, and hormone conjugates), resulting in a decrease in concentration in the blood.

Previous studies in humans using fexofenadine as a probe showed that oral coadministra‐ tion with orange juice decreased the oral bioavailability of fexofenadine [63]. Orange juice and its constituents were shown to interact with members of the OATP transporter family by reducing their activities. The functional consequences of such an interaction are reflect‐ ed in a significant reduction in the oral bioavailability of fexofenadine, possibly by prefer‐ ential direct inhibition of intestinal OATP activity. Other reports indicate that orange juice slightly reduced the absorption of ciprofloxacin, levofloxacin and celiprolol [65] A study of an interaction between orange juice and pravastatin showed an increase in AUC [54].Orange juice also moderately reduces the bioavailability of atenolol, which may neces‐ sitate a dose adjustment [71,72].
