# Drug-Food Interactions with a Focus on Mediterranean Diet
## 2 Pharmacological Mechanisms of Drug-Food Interactions
### Pharmacokine Drug-Food Interactions (PK-DFIs)
#### 2.1.3 Metabolism  
Metabolic transformation of drugs occurs through a series of pathways in the liver and is divided in two phases (phase I and phase II) (Figure 2). Phase I reactions encompass the formation, or the modification of a functional group through oxidation, reduction, or hydrolysis while phase II are conjugation reactions. Cytochromes P450 (CYPs) are responsible for 80% of the total phase I oxidation reactions [84]. Of the total 18 CYP families described in humans, the first three participate the most in drug metabolism. Variations in CYP genes among individuals results in phenotypes of different metabolic activity and usually classifying them as ultra-rapid, extensive, intermediate, and poor metabolizers [85; 86; 87]. CYP2D6 is the most recognized example regarding inter-individual and inter-population variability regarding phenotypes [88]. Pharmacogenetic testing for CYP2D6 has become an important clinical aspect of personalized therapy, especially since it is responsible for the metabolism of 20-25% of drugs such as CNS and cardiovascular medications [87; 88]. This unique characteristic of CYP2D6 often makes it a focus point for potential drug interactions, including DFIs. CYP3A subfamily is the most abundant isoenzyme that plays role in drugs pharmacokinetics. CYP3A isoenzymes (CYP3A4 and CYP3A5) are expressed in the small intestine and the liver, and their metabolic activity accounts for 70-75% of drug metabolism [86]. Over the previous years it has become evident that CYP3A4 and P-gp play complementary roles for absorption, disposition, and metabolism processes. Hence, in many cases, interaction mechanisms for drugs often include both biological pathways of transport and metabolism [89]. The roles of food products in drug metabolism have been extensively evaluated [51]. St John's Wort (SJW) is a well-known example of DS involved in drug interactions through CYP3A4 and P-g. SJW has been promoted as a well-documented natural antidepressant supplement after long term use [90]. SJW's constituents (mainly hyperforin) can initially inhibit and subsequently induce the expression of CYP3A in the liver as well as induce the expression of P-pg [91; 92]. The overall effect is an initial increase in drug exposure but the later induction of P-gp and CYP3A leads in reduced and sub-therapeutic concentration of CYP3A and P-gp substrates. The impact of SJW on P-gp and CYP3A is correlated with the hyperforin content in the product [93]. As of today there are several drug categories reported to interact with SJW such as anticancer drugs (i.e., imatinib, irinotecan, docetaxel), HIV drugs (i.e., indinavir), immunosuppressive (cyclosporine, tacrolimus), anticoagulants (i.e., coumarin analogues), cardiovascular medications and lipid modifying agents (i.e., digoxin, statins etc. ), antipeipletics (i.e., carbamazepine), and oral contraceptives (i.e., levonorgestrel etc.) [92]. Hence, SJW, although promoted as a good natural antidepressant, needs special precautions when it is used form patients under therapies with NTI drugs [94]. Other important CYP enzymes are the CYP1A1 and CYP1A2, CYP2C9 and CYP2C19 that also metabolize a wide number of drugs. Polycyclic aromatic hydrocarbons (PAHs) present in tobacco are bio-transformed by CYP1A1 and CYP1A2 to oxy-derivatives, which can bind to DNA and initiate carcinogenesis. Tobacco can also induce CYP1A1 and CYP1A2 expression and modulate the systemic concentration of drugs that are substrates for these enzymes [95]. Isothiocyanates and other natural occurring polyphenols that are present in several vegetables have been shown to reduce the CYP1A enzyme activity, thus limiting the effect of PAHs [96]. CYP2C9 participates in the metabolism of coumarin anticoagulants (i.e., warfarin and acenocoumarol), thus is a site of potential interactions for anticoagulation treatment. A known case is that of gingko biloba, where gingkolic acid I and II can inhibit CYP2C9, however the interaction is negligible [97; 98].