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Nutrient Metabolism

Epigallocatechin-3-Gallate Is Absorbed but Extensively Glucuronidated Following Oral Administration to Mice^1,2

Departments of Chemical Biology and ^* Pharmacy Practice and Administration, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854

²To whom correspondence and reprint requests should be addressed. E-mail: csyang{at}rci.rutgers.edu.

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Epigallocatechin-3-gallate (EGCG), the most abundant catechin in green tea (Camellia sinensis), has shown cancer preventive activity in animal models. The bioavailability of EGCG in the most commonly used animal species, mice, is poorly understood. Moreover, the pharmacokinetic parameters of EGCG have not been reported previously in mice. Here we report that after administration of EGCG intravenously at 21.8 µmol/kg or intragastrically at 163.8 µmol/kg, the peak plasma levels of EGCG in male CF-1 mice were 2.7 ± 0.7 and 0.28 ± 0.08 µmol/L, respectively. EGCG was present mainly (50–90%) as the glucuronide. The plasma bioavailability of EGCG after intragastric administration was higher than previously reported in rats (26.5 ± 7.5% vs. 1.6 ± 0.6%). The conjugated EGCG displayed a shorter t_1/2 (82.8–211.5 vs 804.9–1102.3 min) than unconjugated EGCG (P < 0.01, Student’s t test). EGCG was present in the unconjugated form in the lung, prostate and other tissues at levels of 0.31–3.56 nmol/g after intravenous administration. Although intragastric administration resulted in lower levels in most tissues compared with intravenous administration (e.g., 0.006 ± 0.004 vs. 2.66 ± 1.0 nmol/g in the lung), the levels in the small intestine and colon were high at 45.2 ± 13.5 and 7.86 ± 2.4 nmol/g, respectively. This is the first report of the pharmacokinetic parameters of EGCG in mice. Such information provides a basis for understanding the bioavailability of EGCG in mice and should aid in understanding the cancer preventive activity of EGCG.

KEY WORDS: • epigallocatechin-3-gallate • pharmacokinetics • green tea • mice

Epigallocatechin-3-gallate (EGCG)² is the most abundant catechin found in green tea (Camellia sinensis, Theaceae) (Fig. 1) (1). Many studies with animal models have shown that green tea and EGCG inhibit carcinogenesis of the skin, lung, oral cavity, esophagus, intestine, colon, prostate and other organs (2). Although induction of apoptosis and inhibition of tumor cell growth were demonstrated in some animal models, the mechanism(s) of action of EGCG remain unclear (3,4). Numerous potential mechanisms have been proposed on the basis of experiments with human cancer cell lines including antioxidative activity, inhibition of epidermal growth factor signaling, inhibition of the proteasome, inhibition of activator protein-1 and nuclear factor-B–mediated transcription, and others (5–9). Most of these effects require concentrations of EGCG from 1 to 100 µmol/L, concentrations that exceed those found in human or rodent plasma after ingestion of green tea or pure EGCG (10). A more complete understanding of EGCG bioavailability may aid in relating observations made in vitro to those in vivo.

View larger version (19K): [in this window] [in a new window]   FIGURE 1 Results of HPLC analysis of epigallocatechin-3-gallate (EGCG) are shown in a representative chromatogram of (A) a standard solution of 100 µg/L epigallocatechin (EGC), epicatechin (EC), EGCG and epicatechin-3-gallate (ECG), (B) free and (C) total EGCG extracted from mouse plasma 50 min after intragastric dosing with 163.8 µmol/kg.

Data concerning the tissue distribution of EGCG are also limited. Previous work by our laboratory characterized the kinetics of EGCG in the liver, lung, intestine and kidney of rats after intravenous administration of decaffeinated green tea (11). We reported the tissue levels of EGCG, EGC, and EC in rats, as well as the liver and lung levels in mice, after administration of green tea as the sole source of drinking fluid (13). Suganuma et al. (17) reported that radioactivity was detected in several organs, including the prostate and brain, after intragastric administration of [³H]-EGCG, but the authors did not determine whether this was due to EGCG or some metabolite. No studies of the kinetics of EGCG in mouse tissues have been reported previously.

To our knowledge, studies of the biotransformation of pure EGCG in mice have not been reported nor have studies of the plasma and tissue pharmacokinetics of single-dose EGCG in mice been reported. Given the paucity of data concerning the distribution, biotransformation and elimination of pure EGCG in mice, the potential similarities between mice and humans in terms of EGCG biotransformation (based on in vitro data) and the importance of the mouse as a model to study carcinogenesis, we elected to characterize the pharmacokinetics of EGCG in mice after either intravenous or intragastric administration of a single dose of pure EGCG. Herein, we describe the plasma and tissue pharmacokinetic parameters of EGCG, the levels of EGCG in the urine and feces and the relative amount of free vs. total EGCG in plasma, tissues and excretia.

	MATERIALS AND METHODS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Chemicals.

EGCG (100% pure) was provided by Unilever-Bestfoods (Englewood Cliffs, NJ). ß-D-Glucuronidase (G-7896, EC 3.2.1.31, from Escherichia coli with 9 x 10⁶ U/g solid) and sulfatase (S-9754, EC 3.1.6.1, from Abalone entrails with 2.3 x 10⁵ U/g solid) were purchased from Sigma Chemical (St. Louis, MO). All other reagents were of the highest grade commercially available. Dosing solutions of EGCG were prepared in 0.154 mol/L NaCl. For analytical purposes, a standard stock solution of EGCG, epigallocatechin (EGC), epicatechin (EC) and epicatechin-3-gallate (ECG) (10 mg/L each) was prepared in 11.4 mmol/L ascorbic acid/0.13 mmol/L EDTA (pH 3.8) and stored at -80°C.

Mice.

Male CF-1 mice (30–35 g) were purchased from Charles River Laboratories (Wilmington, MA) and allowed to acclimate for at least 1 wk before the start of the experiment. The mice were housed 10 per cage, and maintained in air-conditioned quarters with a room temperature of 20 ± 2°C, relative humidity of 50 ± 10%, and an alternating 12-h light:dark cycle. Mice consumed Purina Rodent Chow 5001 (Research Diets, New Brunswick, NJ) and water ad libitum. Animals were deprived of food for 12 h before the experiment.

Sample collection.

The pharmacokinetic parameters of EGCG were determined after either intravenous (i.v.) or intragastric (i.g.) administration of EGCG to male CF-1 mice. For i.v. experiments, mice (n = 6/group) were given a single dose of 21.8 µmol/kg EGCG and killed at 5, 20, 60, 120, 300 or 720 min after injection. A dose of 163.8 µmol/kg EGCG was used for i.g. experiments and mice (n = 6/group) were killed at 20, 50, 90, 180, 300 and 720 min.

For both treatments, blood was collected from anesthetized mice by cardiac puncture, and plasma was isolated by centrifugation at 500 x g for 15 min. Plasma was combined with 0.1 volume of 1.14 mol/L ascorbic acid and stored at -80°C for later analysis. Urine was collected after spontaneous voiding upon killing and combined with 0.1 volume of 1.14 mol/L ascorbic acid. Feces was collected from the interior of the colon after dissection. The lungs, liver, spleen, kidneys, colon, small intestine, prostate and brain were collected, washed in 0.154 mol/L NaCl and frozen at -80°C for later analysis.

Quantification of EGCG and metabolites.

Plasma and urine levels of EGCG and its metabolites were analyzed as reported previously (11). Fecal samples were diluted 1:10 in 114.0 mmol/L ascorbic acid and sonicated. A 20-µL aliquot was then hydrolyzed with ß-glucuronidase/sulfatase as described previously (11). After hydrolysis, the sample was extracted twice with ethyl acetate. The organic phase was dried under vacuum, resuspended in 10% aqueous acetonitrile, and analyzed by HPLC with electrochemical detection (ECD). Duplicate samples of feces, urine, and plasma were prepared without sulfatase/ß–glucuronidase treatment to determine the unconjugated fraction of EGCG and its metabolites.

Tissue samples were homogenized in 4 volumes of ice-cold 114.0 mmol/L ascorbic acid using a mechanical dounce homogenizer and mixed with an equal volume of 0.4 mol/L sodium phosphate buffer (pH = 6.8) and water to give a total volume of 0.5 mL. For analysis of total EGCG, 1 U of sulfatase and 250 U of ß-glucuronidase were added. Samples were incubated at 37°C for 45 min and then extracted, dried and resuspended in a manner similar to that for plasma. Samples were then analyzed by HPLC-ECD. Samples to determine the unconjugated fraction were prepared identically but without ß-glucuronidase/sulfatase treatment. The amount of EGCG glucuronide vs. EGCG sulfate in the plasma was determined by comparing the amount of unconjugated and total EGCG with the amount of EGCG in plasma after treatment with sulfatase in the presence of 1 mmol/L DL-saccharic acid-1,4-lactone (SAC), an inhibitor of ß-glucuronidase. Results obtained after this latter treatment represent the unconjugated plus sulfated EGCG.

Sample analysis.

EGCG levels were analyzed using an HPLC consisting of two ESA model 580 dual-piston pumps (Chelmsford, MA), a Waters Model 717plus refrigerated autosampler (Milford, MA) and an ESA 5500 coulochem electrode array system with the potentials set at -100, 100, 300 and 500 mV. Separation was achieved using previously described methods (11).

Pharmacokinetic analysis.

A best-fit curve was prepared for the plasma concentration of total EGCG as a function of time after either i.v. or i.g. administration using WinNonlin software (Pharsight, Mountain View, CA). Goodness of fit was assessed using the correlation coefficient (r²), the Akaike Information Criterion and the Schwartz Criterion. The exposure (area under the curve; AUC), half-life (t_1/2), maximum concentration (C_max), and time of maximum concentration (T_max) were determined by the program. Volume of distribution (V_d) was calculated by dividing the dose by the C_max. Clearance (CL) was determined by dividing the dose by the AUC. Values are means ± SD. Differences between means were assessed using Student’s t test and were considered significant at P < 0.05.

	RESULTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Quantification of EGCG by HPLC.

After administration of EGCG, a sharp peak with a retention time of 29 min was detected by HPLC (Fig. 1). The retention time and electrochemical spectrum were identical to authentic EGCG standards. No EGC, EC or ECG was observed in the samples analyzed. In a comparison of the EGCG concentration of sulfatase/glucuronidase-treated plasma (total EGCG) with that of untreated plasma (unconjugated EGCG), 50–90% of EGCG was present in the conjugated form in mouse plasma (Fig. 2). The relative proportion of unconjugated to total EGCG increased over time, suggesting that the conjugated metabolites were cleared from the plasma more quickly. Hydrolysis in the presence of 1 mmol/L SAC revealed that almost all of the conjugated EGCG was present as the glucuronide conjugates (data not shown).

View larger version (19K): [in this window] [in a new window]   FIGURE 2 Plasma levels of epigallocatechin-3-gallate (EGCG) in male CF-1 mice were determined by HPLC after a single dose of (A) 21.8 µmol/kg EGCG intravenously or (B) 163.8 µmol/kg EGCG intragastrically. Each point represents the mean ± SEM, n = 4–6; r2 > 0.95 for all curve fits.

After i.v. administration of EGCG, plasma levels were determined as a function of time (Fig. 2). For both free and conjugated EGCG, these data were fit to a two-compartment model described by the following equation:

where + ß = K₁₂ + K₂₁ + K₁₀, · ß = K₂₁ · K₁₀, C is the concentration, D is the dose, V_d is the apparent volume of distribution, K₁₂ is the distribution rate constant from the central compartment to the peripheral compartment, K₁₀ is the rate constant associated with elimination from the central compartment, is the rate constant associated with the distribution phase of the concentration-time curve, ß is the rate constant associated with the elimination phase of the concentration-time curve, and t is the time. The r² were 0.99 and 0.99 for the fit of unconjugated and total EGCG plasma concentration-time curve, respectively. The C_max of total EGCG was 2.7 ± 0.7 µmol/L. The AUC and t_1/2ß of EGCG were 35.2 ± 9.5 (µmol · min)/L, and 211.5 ± 56.9 min, respectively. V_d and CL of EGCG were calculated as 8.0 ± 2.2 L/kg and 0.62 ± 0.17 L/(min · kg), respectively (Table 1). Unconjugated EGCG had a longer t_1/2ß (237.5 ± 34.7 min, P < 0.01) but similar CL [0.57 ± 0.1 L/(min · kg)] to total EGCG (Table 1).

where C is the concentration, Fis the absolute bioavailability, D is the dose, V_d is the volume of distribution, K₁₀ is the elimination rate constant, K_a is the absorption rate constant, and t is the time. F was determined by the following equation:

The r² were 0.96 and 0.95 for the fit of unconjugated and total EGCG plasma concentration-time curve, respectively. After i.g. dosing, F was 26.5 and 12.4% for total and unconjugated EGCG, respectively. Total EGCG reached a C_max = 0.28 ± 0.08 µmol/L at t = 89.8 ± 25.5 min. The AUC, t_1/2K10, V_d and CL were 69.9 ± 19.9 µmol/L. min, 82.8 ± 23.5 min, 152.9 ± 43.4 L/kg and 0.62 ± 0.17 L/(min. kg), respectively (Table 2). As with i.v. administration, the CL of unconjugated EGCG did not differ [0.45 ± 0.13 L/(min · kg)] but the terminal half-life was longer (t_1/2(K10) = 804.9 ± 239.1 min) than total EGCG. In contrast, the C_max (0.04 ± 0.01 vs. 0.28 ± 0.08 µmol/L, P < 0.01) and AUC [45.6 ± 13.5 vs. 69.9 ± 19.9 (µmol · min)/L] were lower than total EGCG (Table 1).

The levels of EGCG and its methylated metabolites were determined in urine and feces after either i.v. or i.g. administration. Urine could not be collected for all time points after i.v. dosing; the concentration range of EGCG was 1.1–4.4 µmol/L from 180–720 min. Fecal levels of EGCG at the time of killing were 1.1–21.8 nmol/g after i.v. administration. After i.g. administration, EGCG was detected in urine and feces at concentrations of 0.2–9.4 µmol/L and 100.0–1572.0 nmol/g, respectively. In urine, >90% of the EGCG was in the conjugated form, whereas in feces, nearly all was in the unconjugated form. In addition to the parent compound, several methylated metabolites were also observed in the feces (4''-O-methyl-EGCG and 4',4''-di-O-methyl-EGCG at 0.1–1.93 nmol/g) and urine (4''-O-methyl-EGCG at 0.2–6.4 µmol/L). Additionally, three other monomethylated EGCG metabolites were observed in the urine. The structure of these metabolites is currently being determined.

Tissue levels of EGCG.

The levels of free and total EGCG were determined in the lung, liver, spleen, prostate, small intestine, colon and kidney after i.v. treatment with 21.8 µmol/kg EGCG (Fig. 3). In all tissues analyzed, EGCG was largely in the unconjugated form. The highest levels were observed in the liver, lung and small intestine with C_max = 3.56 ± 0.80, 2.66 ± 1.0 and 2.40 ± 1.1 nmol/g, respectively (Table 2). Although the colon had a lower C_max (1.20 ± 0.30 µmol/g), it had a higher exposure [AUC_{0–720 min} = 325.3 ± 88.7 (nmol · min)/g] and a long half-life (224 ± 61.1 min). Levels in the prostate and the spleen were 0.31–0.83 nmol/g.

View larger version (23K): [in this window] [in a new window]   FIGURE 3 Tissue levels of epigallocatechin-3-gallate (EGCG) in male CF-1 mice in lung, liver, small intestine, colon, prostate and spleen (A) were determined after a single dose intravenous of 21.8 µmol/kg EGCG to male CF-1 mice. Levels of EGCG in the small intestine and colon (B) were determined after a intragastric single dose of 163.8 µmol/kg EGCG to male CF-1 mice. Each point represents the mean ± SEM, n = 4–6.

	DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

The levels of EGCG in the lung, liver, and small intestine (2.40–3.56 nmol/g) after i.v. administration did not differ from those found in the plasma. The levels in the prostate, colon and spleen were somewhat lower (0.87–2.18 nmol/g). After i.g. administration, high concentrations of EGCG were observed in the small intestine (46.2 ± 13.5 nmol/g) and colon (7.9 ± 2.4 nmol/g). Assuming that 1 g of tissue is equivalent to 1 mL, then the local concentrations of EGCG in the small intestine and the colon were quite high (46.2 and 7.9 µmol/L, respectively). These high concentrations are in the range of those used in cell culture experiments.

The biphasic nature of small intestinal EGCG levels was likely a result of the arrival of EGCG from multiple routes. The initial maximum (t = 50 min) was probably due to gastric emptying and the exposure of the enterocytes to high concentrations of EGCG in the intestinal contents. This idea is supported by the reported gastric emptying half-life (30 min) for mice (18). The subsequent decrease in EGCG concentration may be due to movement from the intestine into the colon and absorption of EGCG from the enterocytes into the portal circulation. Previous reports demonstrated that the transit time through the mouse small intestine is 40 min (19). The second maximum (t = 300 min) may represent the return of absorbed EGCG from the circulation as well as EGCG that was extracted from the blood by the liver and excreted in the bile. This maximum would be expected to be somewhat delayed compared with the plasma T_max. The T_max of EGCG in the colon (180 min) is delayed relative to the small intestine and the plasma, but is similar to the whole-gut transit time of liquids in mice (200 min). The arrival of EGCG via the blood probably occurs simultaneously, and it is currently not possible to determine the relative contribution of each route of exposure (19).

The levels of EGCG in other organs were lower than predicted on the basis of the bioavailability of EGCG in the plasma after i.g. administration. This may be the result of the order in which EGCG encounters organs after i.g. vs. i.v. dosing. After an i.g. dose, EGCG first encounters the small intestine and then the liver, both of which have high UDP-glucuronosyl-transferase activity (15). EGCG may therefore be largely conjugated before reaching other organs and, as a result, be excluded from those tissues. With i.v. administration, on the other hand, EGCG reaches all of the tissues in parallel after leaving the lung and is presumably in a less conjugated form (if only briefly). This would expose tissues to higher concentrations of free EGCG compared with i.g. administration. The free EGCG could more readily enter the tissues and result in rather high levels.

Interestingly, although EGCG is conjugated largely in the plasma, we showed here that EGCG is present in the tissues in the free form. To confirm that this was not due to endogenous ß-glucuronidase/sulfatase–mediated hydrolysis during tissue preparation, samples were prepared in the presence and absence of 1 mmol/L SAC. Treatment with SAC did not alter the ratio of free to total EGCG, confirming that EGCG is largely in the free form in the tissues after i.v. administration. The lack of conjugated EGCG is probably due to its exclusion from tissues. Our observations are in agreement with the widely held opinion that glucuronidation and sulfation are meant to limit the distribution of compounds and increase clearance.

Previously, we and others demonstrated that EGCG levels in feces are very high but levels in urine are much lower in rats and mice after administration of green tea polyphenols or EGCG as the sole source of drinking fluid, respectively (13,20). Here, we demonstrated that after i.v. or i.g. administration of EGCG, the levels of EGCG in feces were greater than those in urine. The fecal levels (0.65–6.5 nmol/g) after i.v. administration were twofold higher than those in urine (0.13–5.67 µmol/L), suggesting the greater importance of feces as a route of elimination. The fecal levels (57.9–1572.1 nmol/g) after i.g. administration were 150- to 400-fold higher than urine concentrations (0.11–9.39 µmol/L). The dramatic difference in fecal levels of EGCG after i.v. vs. i.g. administration probably represents the passage of unabsorbed EGCG through the intestine and out in the feces. Poor absorption of EGCG is expected on the basis of calculations of polar surface area (21).

In addition to EGCG, we also measured the levels of 4''-O-methyl-EGCG and 4', 4''-di-O-methyl-EGCG in feces and 4''-O-methyl-EGCG and two other monomethylated EGCG derivatives in urine. Although EGCG and its methylated derivatives were found only as conjugates in urine, nearly all of the EGCG and methylated EGCG in feces were found in the free form. This difference is likely due to the cleavage of the glucuronide conjugates by microorganisms in the feces and/or intestinal glucuronidases. Preliminary results from our laboratory suggest that these compounds maintain some of the biological activity of EGCG, and as such, may contribute to the overall pool of biologically active molecules to which the colonic mucosa is exposed (14).

Comparison of the present data with that from previous studies of humans and rats indicates that humans and mice have similar (and higher) EGCG bioavailability than rats (10–12). If the AUC [30.8 ± 8.5, 69.9 ± 19.9, 28.0 ± 11.3 µmol · min)/L, for rats, mice, and humans, respectively] after oral dosing is normalized to the dose (4.7 x 10^-4, 0.98 x 10^-4 and 0.36 x 10^-4 µmol/kJ for rats, mice and humans, respectively) and one assumes that the relationship between AUC and dose is linear, then it becomes clear that humans and mice have a higher AUC (777.8 x 10³ ± 313.9 x 10³ and 713.3 x 10³ ± 203.1 x 10³, respectively) at a given dose than rats (80.9 x 10³ ± 18.1 x 10³). However, the high degree of conjugation of EGCG in mouse plasma differs from previous results in humans in which plasma EGCG was largely in the free form (10,12). This indicates that although humans and mice are similar in terms of phase II biotransformation enzyme activity, they differ in other ways that limit the amount of conjugated EGCG in humans but not in mice. Further studies are warranted to characterize these differences.

In summary, we reported here for the first time the pharmacokinetic parameters of EGCG in the mouse. These results point to the potential role of glucuronidation in affecting EGCG bioavailability and demonstrate important species differences among humans, rats and mice. Further, we confirmed the results of previous studies suggesting that the intestine represents a major barrier to the bioavailability of EGCG and that fecal excretion is the major route of elimination (23). These results provide a basis for future studies of the mechanisms that affect EGCG bioavailability. Further studies of the kinetics of low dose, chronic EGCG, in conjunction with appropriate in vivo markers of a particular mechanism(s), are required to delineate clearly the importance of various in vitro mechanisms in whole animals and in humans. The fundamental pharmacokinetic parameters reported here provide a basis for the design of these future experiments.

	FOOTNOTES

 
¹ Supported by National Institutes of Health Grant CA 88961.

³ Abbreviations used: AUC, area under the curve; , distribution rate constant; ß, elimination rate constant; C_max, maximum concentration; C, concentration; CL, clearance; D, dose; EC, epicatechin; ECD, electrochemical detection; ECG, epicatechin-3-gallate; EGC, epigallocatechin; EGCG, epigallocatechin-3-gallate; F, absolute bioavailability; i.g., intragastric; i.v., intravenous; K₁₀, rate constant for elimination from the central component; K₁₂, rate constant for distribution from the central compartment; K₂₁, rate constant for distribution to the central component; K_a, absorption rate constant; SAC, DL-saccharic acid-1,4-lactone; t_1/2, distribution half-life; t_1/2ß, elimination half-life; t_1/2K10, elimination half-life from the central compartment; T_max, time of maximum concentration; V_d, volume of distribution.

Manuscript received 30 July 2003. Initial review completed 19 August 2003. Revision accepted 31 August 2003.

	LITERATURE CITED

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 

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