# Drug-Food Interactions with a Focus on Mediterranean Diet
## 3 Mediterranean Food Products and Potential DFIs
### Drug-Med Diet Interactions  
#### 3.2.1 Vegetables, Herbals, Olive Oil, Cereals, and Nuts  
The Med-D has its basis in foods of plant-origin with a wide variety of vegetables along with other herbals. It contains an extensive list of domestic and imported vegetables that reached the area through historical trading routes. The most common vegetables include artichokes, arugula, asparagus, beetroots, broccoli, brussel sprouts, cabbage, carrots, celery, collard greens, cucumbers, dandelion greens, eggplant, fennel, garlic leeks, lettuce, mushrooms, mustard greens, onions (all types), peas, peppers, potatoes, pumpkin, radishes, spinach, turnips, zucchini. Case reports and clinical data suggest that potential PK-DFIs can result from consumption of artichoke, broccoli, brussel sprouts, cabbage, cauliflower, and tomatoes [111; 112; 113]. A pharmacological mechanism can be attributed to the isothi-cyanate content (i.e., broccoli, cauliflower etc.) and their capability to modulate drugs' CYP-mediated metabolism or transport (ABC-transporters) [112]. Especially for CYP1A2, it has been shown through clinical trial that Brassica vegetables can induce CYP1A2 metabolic activity modulating caffeine's pharmacokinetics [114]. In addition, celery and other apiaceous vegetables (i.e., carrot, celery, dill, cilantro, parsnip, parsley etc.) can decrease cytochrome CYP1A2 activity as has been shown through several studies [112; 114]. Garlic components have shown inhibitory action for CYPs 2C, 2D, and 3A-mediated metabolism in vitro but in a later clinical pharmacokinetic study, long-term use of garlic caplets led to a significant decline in the plasma concentrations of saquinavir which is metabolized from CYP3A4 [115; 116]. Tomato juice was shown in vitro to contain mechanism-based and competitive inhibitor(s) of CYP3A4 [117; 118]. Cabbage and onion juices have also shown potential inhibiting activities on CYP3A4 in vitro [119]. Basil demonstrated in vitro potential reversible and time-dependent inhibition of CYP2B6 and CYP3A4 as well as esterase-mediated metabolism of rifampicin, but the concentrations were higher than the ones used in daily food consumption [120]. The significance of these potential PK-DFIs is currently unresolved and the level of evidence for most of the cases is low. The frequent consumption of these foods may contribute in an observed inter-individual variability within the treatment goals. A recent systematic review and meta-analysis of twenty-three dietary intervention trials in humans analyzed the effect of cruciferous vegetable-enriched diets on drug metabolism. The meta-analyses showed a significant effect on CYP1A2 and glutathione S-transferase-alpha (GSTa) [113]. Thus, healthcare advice is needed in case patients habitually consume excessive amounts of vegetables such as broccoli, brussel sprouts, cabbage, cauliflower, radish, and watercress and are under treatment with CYP1A2 substrates (i.e., clozapine, olanzapine, fluvoxamine, haloperidol, melatonin, rampleton, tizanidine, and theophylline). Regarding PD-DFIs, arugula, asparagus, bell peppers, broccoli, celery, collard greens, kale, onions and leeks, spinach, and chard due to their content of vitamin-K could modulate the INR for people treated with coumadin analogues such as warfarin or acenocoumarol. However, despite this, DFI represents a clinically significant case; it is estimated to be of moderate importance and has a low level of evidence with studies suggesting that a balanced consumption of vegetables does not interfere with INR in a clinically significant way [107; 108]. Concerning other potential PD-DFIs, anise and aniseed's essential oil (used to enhance the flavor of Greek Ouzo and mastic) in vivo enhanced the effects of CNS drugs (codeine, diazepam, midazolam, pentobarbital, imipramine and fluoxetine) in mice suggesting potential synergism and a clinically significant PD-DFI if it is used in extensive doses [121].