## 5 De Novo Synthesis of EGCG and Methods of Isolation
Noteworthy is also the publication of recent studies confirming the legitimacy of continuous efforts for the development of treatments combining EGCG and doxorubicin [69], sunitinib [70], or 5-fluorouracilacil [71]. Other research demonstrated the ability of polyphenols and clofarabine combinations in the promotion of cancer cell death. Not only that but the reactivation of DNA methylation-silenced tumor suppressor genes in breast cancer cells with different invasive potential was also observed [72]. What is essential is that EGCG inhibited telomerase expression significantly and enhanced the effect of cisplatin and tamoxifen in both 1321N1 and U87-MG cells. In addition, EGCG may sensitize glioma cells to cisplatin and tamoxifen [73]. Meanwhile, data from several animal and clinical studies brought new light to the explanation of interactions between EGCG and commonly used drugs (Table 1). Putative pharmacokinetic mechanisms concern the inhibiting effect of EGCG on the organic anion transporting polypeptides (OATPs) [74; 75], CYP3A4-mediated metabolism and P-glycoprotein mediated efflux [23; 76; 77; 78; 79; 80]. Despite presented reports describing numerous EGCG interactions that could lead to increased bioavailability of some APIs e.g., statins or calcium channel blockers, additional studies have indicated that the concomitant use of EGCG does not necessarily cause therapeutic benefits for the patient. For example, [PERSON] et al. [81] studied the effect of concomitant administration of green tea extracts (GTE) and digoxin. Although the mechanism of observed effects was not identified, the authors concluded that GTE might significantly reduce the systemic exposure of digoxin. Taking into account the narrow therapeutic index of digoxin, possible fluctuations in its concentration in blood should be avoided. Noteworthy, [PERSON] et al. [82] found that EGCG can also reduce the bioavailability of orally administered folic acid, although AUC and C\({}_{\text{max}}\) differences did not reach statistical significance. In another study, the absorption of epi-isomers of EGCG in plasma was found to be more favorable than their non-epi-isomer counterparts. EGCG had the highest level of exposure (AUC) and the highest C\({}_{\text{max}}\) in the fetus, implying it may have potential for in utero antioxidant protection [83]. In a case study of a 44-year-old man who was receiving warfarin because of a mechanical valve replacement, regularly drinking between a half and one gallon (1.9-3.9 L) of green tea per day, caused a significant decrease in the international normalized ratio (INR) values. Changes in other factors, such as diet, medications, or diseases, which could potentially affect INR values were excluded. As only green tea drinking was stopped, the INR values mostly returned to the therapeutic level [84]. Plasma ECG and EGCG concentrations are reliable biomarkers for green tea consumption at the population level [85]. EGCG alone or combined with rosiglitzazone was found to increase the phosphorylation of Akt$473, leading to the increase of glucose uptake into C2C12 cells. The authors concluded that EGCG alone or in combination with rosiglitzazone could exhibit some therapeutic effects for the prevention or treatment of type 2 diabetes due to its substantial effect on the increase of phosphorylation of Akt$473 and the subsequent glucose uptake into the cells [86].