Formulation of EGCG has become critical as purifi ed EGCG is considered to be too costly for clinical use and is poorly absorbed, and tolerance has become an issue because of the caffeine content (47, 82, 83). Investigators have used supplemental or synthetic forms of EGCG and other tea catechins to help characterize dose- response kinetics and other bio- logic effects and to promote the design and development of chemopreventive drug candi- dates based on EGCG.
A decaffeinated supplemental preparation of tea catechins, Polyphenon® E, developed by the Division of Cancer Prevention (DCP) Chemoprevention Branch at the National Can- cer Institute (NCI) and in conjunction with Mitsui Norin Co., Ltd., contains approximately 50% EGCG and 30% other catechins. In a phase I pharmacokinetic study of Polyphenon® E, 20 human subjects were given single- dose administration of 200, 400, 600, or 800 mg EGCG, with each capsule containing 200 mg of EGCG and 68 mg of other catechins. Peak plasma EGCG levels of 200 to 400 ng/ml (0.4– 0.8 μM) could be achieved after the admin- istration of these formulations at doses equivalent to the EGCG content in 8 to 16 cups of green tea (depending on the cup size) (53).
A subsequent in- depth study of the safety and plasma kinetics of multiple- dose adminis- tration of purifi ed EGCG and Polyphenon® E was performed. This study examined once- daily and twice- daily dosing regimens of EGCG and Polyphenon® E over a four- week period in 40 healthy volunteers (52). In this study, standardized, defi ned, and decaffeinated green tea polyphenol oral products in amounts similar to the EGCG content in 16 Japanese- style cups of green tea were consumed once daily or in divided doses twice daily (four cap- sules/day) for four weeks. EGCG intake at doses of 400 mg twice daily and 800 mg once daily established peak serum concentrations averaging 150 to 290 ng/mL. Peak concentra- tions were reached between 2.4 and 4.2 hours. Once- daily dosing of 800 mg resulted in approximately a 60% increase in the systemic exposure of free EGCG after chronic Poly- phenon® E administration. Purifi ed EGCG and Polyphenon® E were administered with food in these studies. All adverse events during the four- week period were rated as mild and overall were similar to placebo. Abdominal discomfort (19%) was the most frequent adverse event. Other side effects included headache (6%), excess gas (6%), and dizziness (6%) (52).
On the basis of the reported adverse events and clinical laboratory data in this trial, the study agents and dosing schedules have been found to be safe and well tolerated by the study subjects for at least one month. The reported adverse events were rated as mild events. The more common events include headache, stomachache, abdominal pain, and nausea, which have been reported in subjects receiving green tea polyphenol treatment as well as in sub- jects receiving placebo. There were no signifi cant changes in blood counts and blood chem- istry profi les after four weeks of green tea polyphenol treatment (52).
Fasting
As a signifi cant fraction of the orally administered green tea catechin is either not ab- sorbed or is eliminated presystemically, Chow et al. performed a randomized, single- dose,
crossover pharmacokinetic study of Polyphenon® E in 30 healthy individuals comparing dosing with food and under fasting conditions (84). In this study, taking Polyphenon® E at 400, 800, or 1200 mg on an empty stomach after an overnight fast resulted in a dramatic increase in the blood levels of free EGCG. Fasting peak concentrations occurred between 1.0 and 2.0 hours. AUC and Cmax were 2.3 to 3.5 times and 3.6 to 5.6 times higher, respec- tively, when taken on an empty stomach. Fasting doses were also generally well tolerated, with grade 1 or 2 nausea being the most frequent adverse effect, occurring in approxi- mately 36% of subjects. Other side effects included abdominal discomfort (10%), headache (10%), dyspepsia (3%), diarrhea (7%), gas (3%), and rash (3%). Results showed that greater oral bioavailability of free catechins can be achieved by taking Polyphenon® E on an empty stomach after an overnight fast. Polyphenon® E up to a dose that contains 800 mg EGCG is well tolerated when taken under the fasting condition. This dosing condition is also expected to optimize the biological effects of tea catechins (84).
Metabolism
After oral intake, EGCG undergoes extensive hepatic fi rst- pass metabolism including glucuronidation, sulfation, and methylation. In humans, EGCG is present mainly in the free form in plasma. EGCG is degallated to EGC. EGC is detected mainly as the glucuroni- dated form (57%– 71%) or sulfated form (23%– 36%), with only a small amount present as the free form (3%– 13%) (69). In addition to these conjugation reactions, EGCG and EGC undergo gut metabolism to form ring fi ssion products (69), which are then further broken down by gut fl ora to phenylacetic and phenylpropionoic acids (79). EGCG is not detected in the urine after ingestion (53, 69). These data suggest that EGCG is not excreted in the urine but transported to the liver for excretion into bile and feces.
In a study by Ullman et al., a complete set of plasma kinetic data for single oral doses of pure EGCG capsules (94% crystalline bulk EGCG, Roche Vitamins, Ltd.) in the dose range of 50 to 1600 mg was assessed under fasting conditions in 60 healthy volunteers (85). The plasma kinetic profi le of Roche bulk EGCG revealed a rapid absorption with a one- peak plasma concentration versus time course, followed by a distribution phase and an elimina- tion phase. A dose linearity can be assumed for rate and extent. Single oral doses of Roche bulk EGCG up to 1600 mg were very well tolerated in this study, and no clinical or biologi- cal adverse events occurred (85). Other clinical studies have assessed the drug interactions of EGCG with cytochrome P450 activity or long- term EGCG dosing. Two studies showed no signifi cant alteration in the disposition of medications primarily dependent on the CYP2D6 or CYP3A4 pathways of metabolism (86, 87).
Drug interactions may result from either pharmacokinetic or pharmacodynamic sources. Pharmacokinetic interactions can affect absorption, transport, distribution, metabolism, or elimination of a drug. Pharmacodynamic interactions alter the pharmacologic response to a drug but may not affect the drug’s body concentrations. Risk of drug interactions of EGCG may be decreased due to minimal interaction with major cytochrome P450 (CYP) isozymes. Four weeks of Polyphenon® E 800 mg once daily did not change the activities of CYP1A2, CYP2D6, and CYP2C9 but inhibited CYP3A4 activity by approximately 20% compared to baseline (p = 0.01) (84). This is not likely to be clinically relevant. Lack of signifi cant effect on CYP isozymes is benefi cial, because of the 22 currently FDA- approved agents for HIV treatment, 14 are substrates, inducers, or inhibitors of CYP en-
zymes. These results suggest that EGCG administration may be less likely to affect the pharmacokinetics of commonly used pharmaceutical drugs, in par tic u lar many of the available ARV agents; however, it could enhance the detoxifi cation of compounds that are signifi cantly glucuronidated. Of the available ARVs, at least fi ve are either primary sub- strates for UDP glucuronosyltransferases (UGT) or increase/inhibit UGT activity and thus may be a potential source for drug interactions. Effects of EGCG on drug transporters are currently unknown.