# Drug-Food Interactions with a Focus on Mediterranean Diet
## 2 Pharmacological Mechanisms of Drug-Food Interactions
### Pharmacokine Drug-Food Interactions (PK-DFIs)  
#### 2.1.1 Absorption  
Drug's absorption--for orally administered drugs--is determined by its physicochemical properties, formulation, the capability of transportation (active or passive) across epithelial cells in the gastro-intestinal (GI) tract and the administration during fasted/fed state (Figure 3) [52]. Any modulation of intestinal transit time can change the drug's bioavailability--the fraction that reaches systemic circulation--and alter its systemic concentration. This is very important for drugs with reduced aqueous solubility but sufficient permeability [53; 54]. Dietary compounds can modulate absorption either through biological activities or due to physicochemical mechanisms that change GI-environment, thus altering the biopharmaceutical properties of a drug formulation. For example, radial extract has been shown to stimulate GI motility in vitro through activation of muscarinic pathways [55]. Oat brans and fibers, although assisting in lowering cholesterol, also inhibit the intestinal absorption of statins, altering their PD properties, thus concurrent adminis  
Figure 1: Representation of pharmacological mechanisms of DFIs and their impact on clinical outcome. Figure 2: Graphical representation of food effect on the PK profile of a drug that leads in clinically significant DFIs (MEC maximum effective concentration, MIC: minimum effective concentration). tration and consumption is proposed to be avoided or limited [56; 57]. High-fat diets may lead in raised bile salt secretion which may increase the solubilization and absorption of lipophilic drugs such as anticancer drugs pazopanib, vemurafenib and lapatinib [58; 59]. Generally the impact of fasted/fed state seems to be an important factor for orally administered drugs and especially for drugs used in oncology [60; 61]. Thus, it is important relative information to be placed on drug labels since certain foods can change the pH in the stomach, alter the solubility, delay gastric emptying, change the stimulation of bile and blood flow, create unabsorbed chelate ligands, or change the gut microflora [50; 62]. Following dispersion and dissolution in the GI track, a drug molecule is transported across epithelial GI-cells to the portal vein through active transport. Drug carriers can be classified into two major superfamilies, (i) ATP-binding cassette (ABC) transporters with efflux activity and (ii) solute carrier (SLC) transporters with influx activity [63; 64; 65; 66; 67]. P-glycoprotein (P-gp) is the most well-known efflux carrier regulating the absorption of drugs (i.e., anticancer, immunosuppressiveants, cardiovascular and lipid-modifying agents, antivirals, antibiotics, antipeiletics). Additional efflux transporters are: (i) the breast cancer resistance protein (BCRP) alleged to prevent absorption of toxic compounds and regulate the absorption of chemotherapeutics, and drugs such as prazosin, glyburide, cintidine, sulfasalazine, rousvastatin etc. ; and (ii) the multidrug resistance-associated protein 2 (MRP2) that plays a role in the absorption of chemotherapeutic products [64; 66; 67]. Regarding influx transport, it is regulated by SLCs superfamily and includes a wide number of carriers such as organic anion transporters proteins (OATPs); organic cation transporters (OCTs); proton-dependent oligopeptide transporters (PEPTs); plasma membrane monoamine transporters (PMTs); and the monocarboxylate transporters (MCTs), all of which have been shown to play roles in drug transport across cell membranes [65; 67]. Constituents of food products and DS can influence transporter's activity [68; 69; 70; 71]. The efflux activity of P-gp has been shown in vitro to be inhibited from rosmearty extracts, orange juices, strawberry and apricot extracts, dietary fatty acids, mint extracts, and spices constituents found in black pepper (piperne), chili peppers (capsaicin), and sesame oil (sesamin) [72].