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

based 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‐

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‐

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‐

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

mics such as amiodarone [62]; and antibiotics such as eritromicine [64].

quences of concomitant ingestion of these agents.

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

fective in producing drug interactions.

10 Drug Discovery

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