# Drug-Food Interactions with a Focus on Mediterranean Diet
## 3 Mediterranean Food Products and Potential DFIs
### Drug-Med Diet Interactions
#### 3.2.2 Fruits and Fruit Jucices  
The Mediterranean fruits are among the most famous and widely consumed food products globally. Apples, apricots, avocados, cherries, clementines, figs, grapefruits, grapes, melons, nectarines, oranges, peaches, pears, pomegranates, strawberries, tangerines are the most common ones that are consumed by people following the Med-D style. Regarding fruit jucies, the fermentable but unfermented product obtained from the edible part of the fruit and preserved fresh, they sometimes contain (due to the extraction process) different constituents or quantities from the original fruit. The most notorious DFI regarding fruits and/or fruit juice with medications is that of grapefruit and its juice (GF) [41; 131; 132; 133]. GF) constituents (i.e., furanocoumarins etc.) can inhibit CYP activity (mainly CYP3A) through mechanism-based inhibition as well as transporter proteins in the intestine and liver (i.e., P-gp) [131; 133; 134; 135; 136]. This can elevate drugs' bioavailability which, along with reduction in drugs' intrinsic clearance, can result in increased concentrations and potential side effects. Typical examples are the concomitant use of GFJ with: (i) Ca\({}^{2+}\) channel antagonists that result in low blood pressure; (ii) HMG-CoA reductase inhibitors that may lead to rhabdomyosis and renal impairment; and (iii) adverse pulmonary effects caused by amiodarone co-administration [41; 70; 131; 137]. Grapefruit as a plant belongs to the plant family of Rutaceae within the genus of Citrus fruits such as lemons, oranges, limes, tangerines fruits that are widely consumed. As a result, the frequent consumption of these products alerted the previous years the scientific community to the need to examine if DFIs could be further observed [138; 139; 140]. Until today, the most often described mechanism for potential DFIs are related with modulation of the activity of OATP transporters and CYPs metabolic activities [141; 142; 143]. Citrus fruits such as orange, lemon, pomelo, and lime have been assessed for potential DFIs and compared with GFJ. Pomelo juice increased the bioavailability of cyclosporine in an open-label crossover PK study probably due to inhibition of CYP3A4 and P-gp [144]. Orange juice reduced the bioavailability of alendronate and aliskiren [145; 146], whereas Seville orange juice interacts with felodipine in a similar way to GFJ [147]. Lime juice has been shown in vivo to increase (similarly to GFJ) the bioavailability and systemic concentrations of carbamazepine with a clinically significant risk for liver and kidney toxicity [148]. Although tangerine (fruit and juice) showed some effect in vitro on CYP3A4-mediated metabolism of midazolam, this was of no clinical significance [149]. Narirutin found in Citrus fruits has also been observed in vivo to inhibit OATP1A2 and OATP2B1 [150]. Regarding apple juice, there is evidence from in vitro, in vivo and clinical studies of inhibiting activity on OATPs and modulation of the PK profile of drugs such as foxofenadine, montelukast and aliskiren [142; 143; 146; 151]. It also contributed to a DFI with atenol in a dose-response relationship but with limited effect on the PD-profile of the drug [152]. Cranberry juice and its constituent avicularin inhibited uptake transporters OATP1A2 and AOATP2B1 in vitro [153]. In addition, in vitro data indicated inhibition of CYP-mediated metabolism (CYP2C9 and CYP3A4) similar to ketoconazole and fluconazole. The effect is mainly attributed to anthocyanins content but these compounds show poor bioavailability, thus in vitro data were not repeated in vivo or through clinical studies [154, 155, 156]. Pomegranate juice has demonstrated in vitro/in vivo inhibiting action against CYP2C9 and CYP3A4 but with no clinical impact based on the available clinical data [157]. Drug interactions with fruits, fruit juices or pulps can also be related with PD-DFIs, and especially for fruits that contain considerable amounts of potassium (K\({}^{+}\)).