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Phase I Pharmacokinetic Study of Tea Polyphenols following Single-dose Administration of Epigallocatechin Gallate and Polyphenon E¹

Arizona Cancer Center, The University of Arizona, Tucson, Arizona 85724 [H-H. S. C., Y. C., D. S. A., I. H., R. D., F. S.]; Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland 20892 [J. A. C.]; College of Pharmacy, Rutgers University, Piscataway, New Jersey 08854 [C. S. Y.]; and Mitsui Norin Co., Ltd., Shizuoka 426-01, Japan [Y. H.]

	Abstract

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Green tea has been shown to exhibit cancer-preventive activities in preclinical studies. Its principal active components include epigallocatechin gallate (EGCG), epigallocatechin (EGC), epicatechin (EC), and epicatechin gallate, of which EGCG is the most abundant and possesses the most potent antioxidative activity. We performed a Phase I pharmacokinetic study to determine the systemic availability of green tea catechins after single oral dose administration of EGCG and Polyphenon E (decaffeinated green tea catechin mixture). Twenty healthy subjects (five subjects/dose level) were randomly assigned to one of the dose levels (200, 400, 600, and 800 mg based on EGCG content). All subjects were randomly crossed-over to receive the two catechin formulations at the same dose level. Blood and urine samples were collected for up to 24 h after oral administration of the study medication. Tea catechin concentrations in plasma and urine samples were determined using high-performance liquid chromatography with the coulometric electrode array detection system. After EGCG versus Polyphenon E administration, the mean area under the plasma concentration-time curves (AUC) of unchanged EGCG were 22.5 versus 21.9, 35.4 versus 52.2, 101.9 versus 79.7, and 167.1 versus 161.4 min·µg/ml at the 200-, 400-, 600-, and 800-mg dose levels, respectively. EGC and EC were not detected in plasma after EGCG administration and were present at low/undetectable levels after Polyphenon E administration. High concentrations of EGC and EC glucuronide/sulfate conjugates were found in plasma and urine samples after Polyphenon E administration. There were no significant differences in the pharmacokinetic characteristics of EGCG between the two study medications. The AUC and maximum plasma concentration (C_max) of EGCG after the 800-mg dose of EGCG were found to be significantly higher than those after the 200- and 400-mg dose. The AUC and C_max of EGCG after the 800-mg dose of Polyphenon E were significantly higher than those after the three lower doses. We conclude that the two catechin formulations resulted in similar plasma EGCG levels. EGC and EC were present in the body after the Polyphenon E administration; however, they were present predominantly in conjugated forms. The systemic availability of EGCG increased at higher doses, possibly due to saturable presystemic elimination of orally administered green tea polyphenols.

	Introduction

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During the last decade, the relationship between tea consumption and cancer has been a subject of research interest for many investigators. Several recent studies have thoroughly reviewed and summarized epidemiological and experimental studies on tea and cancer prevention (1, 2, 3, 4, 5, 6) . Green tea, green tea extract, and one of the major green tea polyphenols, EGCG,³ have been shown to inhibit carcinogenesis induced by a wide variety of carcinogens in rodent cancer models. Cancer chemopreventive activity has been demonstrated in the following target organs: colon; duodenum; esophagus; forestomach; large intestine; liver; lung; mammary glands; and skin (1 , 2 , 4) . The preventive activity is believed to be due to the antioxidative and antiproliferative effects of tea polyphenols. The polyphenols may also inhibit carcinogenesis by suppressing the activation of carcinogens and trapping genotoxic agents. The principal polyphenols in green tea include EGCG, EGC, EC, and epicatechin gallate; of these, EGCG is the most abundant and possesses the most potent antioxidative activity (2) . At present, epidemiological evidence of the protective effect of tea consumption against the development of human cancers is not conclusive. This may be attributed to variables related to individual differences in tea preparation and consumption patterns and seasonal and geographic differences in tea production. Controlled prospective human intervention trials to evaluate the chemopreventive activity of ingestion of tea or tea components are clearly necessary.

Because it is not easy to change an individual’s dietary habits, ingesting purified green tea polyphenol products in oral formulations may be more acceptable for chronic use in individuals who do not customarily consume green tea. We have performed a Phase I pharmacokinetic study to determine the systemic availability of tea polyphenols after a single oral dose administration of purified tea polyphenol products and the effects of dose and polyphenol formulation on the pharmacokinetics of EGCG and other tea catechins.

	Materials and Methods

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Study Drugs.
Bulk EGCG and Polyphenon E were supplied to the Chemoprevention Agent Development Research Group, National Cancer Institute (Bethesda, MD) from the Food Research Laboratories, Mitsui Norin Co., Ltd., (Fujieda City, Japan). EGCG and Polyphenon E formulated in capsules were supplied by the Chemoprevention Agent Development Research Group, National Cancer Institute. On average, each EGCG capsule contained 200 mg of EGCG, and each Polyphenon E capsule contained 200 mg of EGCG, 37 mg of EGC, 31 mg of EC, and other tea polyphenols. Caffeine was not present in either formulation. The study medications were stored at room temperature, protected from environmental extremes.

Participants.
Twenty healthy male and female subjects 30 years of age were recruited to participate in the study. To be eligible, the participants were required to be able to give informed consent, to have a performance status of 0–1 (as determined by the Southwest Oncology Group Performance Status Criteria), and to have normal liver and renal function. Individuals with performance status of 0–1 are fully active or restricted only in physically strenuous activity. Participants were excluded if they were pregnant, had had cancers of any types within the past 5 years, had severe metabolic disorders or other life-threatening acute or chronic diseases, had weight loss of >10% in the 6 months preceding study entry, and had a prior history of gastric ulcer. The study was approved by the University of Arizona Human Subjects Committee. Written informed consent was obtained from all participants.

Study Design.
All study participants were required to refrain from the ingestion of tea or tea products for 7 days before the first pharmacokinetic study and until the end of the second pharmacokinetic study. Study participants (five subjects/dose level) were randomly assigned to a dose level (200, 400, 600, or 800 mg based on EGCG content). All subjects were randomly crossed-over to receive the two polyphenol formulations at the same dose level, with a 2-week wash-out period. The diet of the subjects was not standardized or controlled before the study.

The day before the pharmacokinetic study, study participants were instructed to fast after midnight except for drinking water. On the pharmacokinetic study day, study subjects skipped breakfast and took no over the counter medications, vitamins, or health food products. Study participants came to the clinic in the early morning (6–8 a.m.) and were provided with one to two bagels for breakfast. Immediately after or during breakfast, study subjects swallowed one of the tea polyphenol formulations at the assigned dose level with a glass of water. Study subjects were allowed unlimited water intake throughout the study day. Other drinks were not allowed. Blood samples (5–7 ml each) were collected before the administration of the study medication and at time points 0.5, 1, 2, 4, 6, 8, and 24 h after drug administration. Study subjects self-collected urine before dosing and at three intervals during the 24-h period after dosing (0–4, 4–8, and 8–24 h). After the 4 h blood collection, a vegetarian or turkey bagel sandwich was provided to the study subjects.

Sample Collection and Processing.
Once collected, blood samples were kept in the refrigerator and centrifuged at 4°C within 2 h of collection. After centrifugation, 1 ml of plasma was aliquoted into cryotubes containing 20 µl of ascorbate-EDTA solution [0.4 M NaH₂PO₄ buffer containing 20% ascorbic acid and 0.1% EDTA (pH 3.6)]. The samples were stored at -80°C until analysis. Before each urine collection period, 5 ml of ascorbate-EDTA solution were added to the urine collection containers, which were kept in a cooler containing frozen ice-packs. At the end of the urine collection, urine volume was recorded, and an aliquot of 15 ml was transferred into a storage tube that contained 20 mg of ascorbic acid and 0.5 mg of EDTA. The pH of the urine samples was adjusted to 6.8 with 10% NaOH, and an aliquot was stored at -80°C until analysis.

Tea Polyphenol Concentration Measurements.
EGCG, EC, and EGC concentrations in plasma and urine samples were determined within 1 month of collection using a previously published HPLC procedure (7) . Briefly, for determination of the unchanged tea polyphenols in plasma, lipid soluble components in plasma were removed with a methylene chloride extraction. The remaining aqueous phase was extracted with ethyl acetate. The ethyl acetate fraction was collected, mixed with a small volume of 0.1% ascorbic acid, and dried by vacuum centrifugation. The dried sample was redissolved in an aliquot of 15% acetonitrile aqueous solution. The reconstituted sample was centrifuged at 16,000 x g for 10 min, and an aliquot of the sample was injected onto HPLC. For determination of the glucuronic acid/sulfate conjugates of tea polyphenols in plasma, the samples were mixed with an aliquot of ascorbate-EDTA solution and a mixture of ß-glucuronidase and sulfatase (to convert the conjugates to the unchanged form). The resulting mixture was incubated at 37°C for 45 min. Blank plasma spiked with polyphenol standards was incubated with a similar mixture at 37°C for 23 min (half of the incubation time of the sample). The reaction was stopped by adding methylene chloride and water and extracted as described for the unchanged polyphenols. Differences between the polyphenol concentrations determined before and after enzyme hydrolysis allowed the estimation of the concentrations of the conjugated polyphenols. The extraction procedures for the urine samples were similar to those for the plasma samples, except that the urine samples were not subjected to the clean-up procedures with methylene chloride. For each analytical run, a standard curve was prepared in the appropriate matrix and used to determine the tea polyphenol concentration. Quality control samples were prepared and analyzed along with the authentic samples. The whole batch of samples was reprocessed and reanalyzed if the variation of the quality control samples was greater than 15% of the expected values.

The HPLC system consisted of an ESA Model 540 refrigerated autosampler, an ESA Model 582 two-pump solvent delivery system, an ESA 5600 coulochem electrode array system, and a Supelcosil C18 reversed-phase column (150 x 4.6 mm; particle size, 5 µm; Supelco Inc., Bellefonte, PA). The autosampler and column temperatures were maintained at 6°C and 35°C, respectively. Buffer A consisted of 30 mM NaH₂PO₄ buffer, acetonitrile, and tetrahydrofuran in a volume ratio of 98.13:1.75:0.12 (pH 3.35). Buffer B consisted of 15 mM NaH₂PO₄ buffer, acetonitrile, and tetrahydrofuran in a volume ratio of 41.5:58.5:12.5 (pH 3.45). The flow rate was maintained at 1 ml/min. The column was eluted at 96% buffer A and 4% buffer B from 0–7 min, and then the linear gradient was changed progressively to 17% buffer B at 25 min, 28% buffer B at 31 min, 33% buffer B at 37 min, and 98% buffer B at 38 min. It was maintained at 98% buffer B from 38–43 min and finally changed back to 4% buffer B at 44 min for the analysis of the next sample. The eluent was monitored by the coulochem electrode array system with potential settings at -90, -10, 70, and 150 mV, and four chromatograms were obtained simultaneously.

Data Analysis.
The following pharmacokinetic parameters of unchanged EGCG were estimated using the WINNONLIN program with the model-independent approach (8) : time to reach maximum plasma concentration (T_max); maximum plasma concentration (C_max); AUC; clearance/bioavailability (CL/F); volume of distribution/bioavailability (V_d/F); terminal elimination half-life (t_1/2); and terminal elimination rate constant (_n). The AUC, T_max, and C_max of total (unchanged and glucuronic acid/sulfate conjugates) EGC, EC, and EGCG were also estimated using the WINNONLIN program with the mode-independent approach. The amount of tea polyphenol excreted into the urine was estimated by the product of the polyphenol concentration in the urine and urine volume.

Pharmacokinetic parameters were compared among different dose levels for the same catechin formulation using ANOVA. Bonferroni’s t test was used for the pairwise multiple comparisons. Pharmacokinetic measurements of EGCG between the two catechin formulations were compared by a paired t test.

	Results

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Table 1 presents the demographic data of the study participants. A total of 20 subjects (5 subjects/dose level) completed the study. Because of the small number of male participants, we did not have a completely balanced male:female subject ratio among the dose levels. There were no significant differences in other demographic characteristics of the participants among the four dose groups.

View larger version (20K): [in this window] [in a new window]   Fig. 1. Average plasma EGCG concentration versus time profiles after oral administration of EGCG or Polyphenon E at different dose levels. a, EGCG formulation; b, Polyphenon E formulation. Each point represents the average of five subjects, and the cross-vertical bars represent 1 SD of the mean. •, 200 mg; , 400 mg; , 600 mg; , 800 mg.

View larger version (17K): [in this window] [in a new window]   Fig. 2. Average plasma tea polyphenol concentration versus time profiles after a 600-mg dose of EGCG. a, data obtained from plasma samples without glucuronidase/sulfatase treatment. b, data obtained from plasma samples treated with glucuronidase/sulfatase. Each point represents the average of five subjects, and the cross-vertical bars represent 1 SD of the mean. •, EGCG.

View larger version (17K): [in this window] [in a new window]   Fig. 3. Average plasma tea polyphenol concentration versus time profiles after a 600-mg dose of Polyphenon E. a, data obtained from plasma samples without glucuronidase/sulfatase treatment. b, data obtained from plasma samples treated with glucuronidase/sulfatase. Each point represents the average of five subjects, and the cross-vertical bars represent 1 SD of the mean. •, EGCG; , EGC; , EC.

	Discussion

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In our study, the EGCG and Polyphenon E formulations containing the same amount of EGCG resulted in similar plasma EGCG levels. This is likely to be attributable to the fact that EGCG was the major component in the Polyphenon E formulation (EGCG:EGC:EC ratio of 20:3.7:3.1). EGC and EC were detected in plasma and urine samples after Polyphenon E administration, predominantly as glucuronic acid/sulfate conjugates. It is not known whether the tea catechin conjugates possess any biological activities. In a recent study (9) , the glucuronic acid/sulfate conjugates of catechins were shown to have the same electrochemical behavior as the parent drug across different electrode potentials. Considering that the oxidation potential of chemicals may represent their antioxidant capacity, the electrochemical behavior of the conjugates suggests that they are effective antioxidants. Nevertheless, because the glucuronic acid/sulfate conjugates are generally more hydrophilic than the parent compound, the tissue distributions of these metabolites are likely to be more limited than those of the parent catechins. Therefore, it is not known whether the glucuronic acid/sulfate conjugates of tea catechins will be pharmacologically relevant in target tissues. Based on the plasma polyphenol levels, the EGCG and Polyphenon E formulations should have similar pharmacological responses if the conjugates do not contribute to the activities. Otherwise, the Polyphenon E formulation should be more potent because of the presence of high plasma levels of EGC and EC conjugates.

Fig. 4 shows the relationship between the AUC of unchanged EGCG and the tea polyphenol dose ingested. The AUC of EGCG showed less than proportional increases at the three lower doses and more than proportional increases as the dose was increased to 800 mg. This phenomenon is consistent with that observed for chemicals undergoing extensive presystemic elimination. Because the presystemic elimination is saturated at higher doses, the extents of the unchanged form available in the systemic circulation are increased. In a previous clinical study using reconstituted green tea beverages (10) , the C_max of EGCG increased approximately 2–3-fold when the dose of green tea solids was increased from 1.5 to 3.0 grams, but increasing the dose to 4.5 grams did not increase the C_max values significantly. These findings differed from our current observation. In the previous study, EGCG is not the major component in the green tea solids, with EGC content similar to that of EGCG. The presence of other tea polyphenols in significant quantities might affect the absorption and disposition of EGCG (10) . Furthermore, the tea polyphenol concentrations were reported as the sum of unchanged and conjugated forms in the previous study (10) , although the kinetic disposition of the conjugates can be very different from that of the parent catechins.

View larger version (12K): [in this window] [in a new window]   Fig. 4. The relationship between the AUC of the unchanged EGCG and the tea polyphenol dose ingested. a, EGCG formulation. b, Polyphenon E formulation. Within each dose level, five different symbols were used to identify data derived from different subjects, and the same symbol was used to represent data obtained from the same subject receiving EGCG and Polyphenon E.

It is worth noting that although the EGC or EC content in the Polyphenon E formulation was less than 20% of that of EGCG, the AUCs of total (unchanged and conjugated) EGC or EC were 36–170% of total EGCG. If a nonspecific assay were used, we might have concluded that orally administered EGC and EC were more bioavailable than EGCG. However, total EGC or EC consisted mostly of conjugated forms, whereas total EGCG was constituted mostly of the unchanged form. Having specifically determined the unchanged tea polyphenol concentrations and compared the dose-adjusted AUC of the unchanged forms, we found EGCG to be more bioavailable than EGC and EC.

Throughout the study, we recorded all side effects experienced by our study subjects. Both tea polyphenol formulations administered as a single oral dose over the dose range studied were well tolerated by the study participants. The highest dose used was equivalent to consuming up to 8 cups of green tea at once. Some subjects experienced mild headache and fatigue, possibly related to the study products. These adverse events could also have been consequences of the procedures and restrictions that the subjects encountered on the pharmacokinetic study days (such as refraining from beverages containing caffeine).

We conclude that both tea polyphenol formulations administered as a single oral dose over the dose range studied were well tolerated by the study participants. Oral administration of EGCG and Polyphenon E at the same dose level (based on EGCG content) resulted in similar plasma EGCG levels. From the economical standpoint in chemoprevention, these results are encouraging because it would be less expensive to produce the Polyphenon E formulation than the pure EGCG formulation. Orally ingested tea polyphenols undergo extensive and saturable presystemic elimination and have large intersubject variations in systemic availability. Additional studies are needed to address factors affecting the systemic availability of tea polyphenols. Future clinical studies are planned to determine the safety, pharmacokinetics, and pharmacological activity of tea polyphenols after chronic EGCG/Polyphenon E treatment.

	Footnotes

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by Contract N01-CN-85179 from the National Cancer Institute.

² To whom requests for reprints should be addressed, at Arizona Cancer Center, The University of Arizona, Tucson, AZ 85724. Phone: (520) 626-3358; Fax: (520) 626-5348; E-mail: schow{at}azcc.arizona.edu

³ The abbreviations used are: EGCG, epigallocatechin gallate; EGC, epigallocatechin; EC, epicatechin; HPLC, high-performance liquid chromatography; AUC, area under the plasma concentration-time curves.

Received 7/19/00; revised 11/ 2/00; accepted 11/ 7/00.

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				D. S. Wheeler, J. D. Catravas, K. Odoms, A. Denenberg, V. Malhotra, and H. R. Wong Epigallocatechin-3-gallate, a Green Tea-Derived Polyphenol, Inhibits IL-1{beta}-Dependent Proinflammatory Signal Transduction in Cultured Respiratory Epithelial Cells J. Nutr., May 1, 2004; 134(5): 1039 - 1044. [Abstract] [Full Text] [PDF]

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				J. B. Vaidyanathan and T. Walle Cellular Uptake and Efflux of the Tea Flavonoid (-)Epicatechin-3-gallate in the Human Intestinal Cell Line Caco-2 J. Pharmacol. Exp. Ther., November 1, 2003; 307(2): 745 - 752. [Abstract] [Full Text] [PDF]

				J. D. Lambert and C. S. Yang Mechanisms of Cancer Prevention by Tea Constituents J. Nutr., October 1, 2003; 133(10): 3262S - 3267. [Abstract] [Full Text] [PDF]

				I. A. Hakim, R. B. Harris, S. Brown, H-H. S. Chow, S. Wiseman, S. Agarwal, and W. Talbot Effect of Increased Tea Consumption on Oxidative DNA Damage among Smokers: A Randomized Controlled Study J. Nutr., October 1, 2003; 133(10): 3303S - 3309. [Abstract] [Full Text] [PDF]

				H-H. S. Chow, Y. Cai, I. A. Hakim, J. A. Crowell, F. Shahi, C. A. Brooks, R. T. Dorr, Y. Hara, and D. S. Alberts Pharmacokinetics and Safety of Green Tea Polyphenols after Multiple-Dose Administration of Epigallocatechin Gallate and Polyphenon E in Healthy Individuals Clin. Cancer Res., August 1, 2003; 9(9): 3312 - 3319. [Abstract] [Full Text] [PDF]

				M. Masuda, M. Suzui, J. T. E. Lim, and I. B. Weinstein Epigallocatechin-3-gallate Inhibits Activation of HER-2/neu and Downstream Signaling Pathways in Human Head and Neck and Breast Carcinoma Cells Clin. Cancer Res., August 1, 2003; 9(9): 3486 - 3491. [Abstract] [Full Text] [PDF]

				H. Lu, X. Meng, C. Li, S. Sang, C. Patten, S. Sheng, J. Hong, N. Bai, B. Winnik, C.-T. Ho, et al. Glucuronides of Tea Catechins: Enzymology of Biosynthesis and Biological Activities Drug Metab. Dispos., April 1, 2003; 31(4): 452 - 461. [Abstract] [Full Text] [PDF]

				Y. Cai, N. D. Anavy, and H-H. S. Chow Contribution of Presystemic Hepatic Extraction to the Low Oral Bioavailability of Green Tea Catechins in Rats Drug Metab. Dispos., November 1, 2002; 30(11): 1246 - 1249. [Abstract] [Full Text] [PDF]

				M.-J. Lee, P. Maliakal, L. Chen, X. Meng, F. Y. Bondoc, S. Prabhu, G. Lambert, S. Mohr, and C. S. Yang Pharmacokinetics of Tea Catechins after Ingestion of Green Tea and (-)-Epigallocatechin-3-gallate by Humans: Formation of Different Metabolites and Individual Variability Cancer Epidemiol. Biomarkers Prev., October 1, 2002; 11(10): 1025 - 1032. [Abstract] [Full Text] [PDF]

J. B. Vaidyanathan and T. Walle Glucuronidation and Sulfation of the Tea Flavonoid (-)-Epicatechin by the Human and Rat Enzymes