Several human pharmacokinetic studies of tea catechins have been performed by us and other investigators. An early study by Yang et al. [7
] determined the blood and urine levels of tea catechins after ingestion of different amounts of decaffeinated green tea extract (DGT) by human volunteers. In this study, one gram of the DGT contained 73 mg EGCG, 68 mg EGC, 22 mg ECG, and 25 mg EC. After consumption of 1.5 g of DGT, the catechins in human plasma reached peak levels in 1.5 to 2.5 hours. The average peak plasma concentration (Cmax) of EGCG, EGC, and EC was 0.71, 1.8, 0.65 μM, respectively. When the dosage was increased from 1.5 to 3.0 g, the Cmax values increased 2.7 to 3.4 fold. However, increasing the dose to 4.5 g didn't increase the Cmax values significantly. It is likely that constituents in the green tea extract were not completely dissolved in the gastrointestinal fluid when the dose was increased to 4.5 g. Terminal half-lives of EGCG, EGC, and EC after oral administration of 1.5 to 4.5g of DGT were 4.9 to 5.5, 2.5 to 2.8, and 3.2 to 5.7 h, respectively. It should be noted that the tea catechin levels reported in this study were expressed as the sum of unchanged and conjugated catechins and the pharmacokinetic parameters were derived based on these hybrid values.
We conducted a clinical pharmacokinetic study of tea catechins following single-dose administration of EGCG or Polyphenon E [8
]. Polyphenon E is a defined and decaffeinated green tea catechin extract that contains 80–98% total catechins with EGCG as the main component accounting for 50–75% of the material. Each Polyphenon E capsule used for this study contained 200 mg EGCG, 37 mg EGC, 31 mg EC, and other green tea constituents. We found that, in equivalent EGCG doses, both formulations resulted in similar pharmacokinetics of EGCG. The average Cmax of unchanged EGCG were 0.16, 0.24, 0.37, 0.96 μM after 200, 400, 600, and 800 mg dose of EGCG, respectively. The average Cmax of unchanged EGCG were 0.16, 0.27, 0.36, 0.82 μM after Polyphenon E administration at doses that contained 200, 400, 600, and 800 mg EGCG, respectively. illustrates the peak plasma tea catechin concentration following a single dose administration of 800 mg EGCG or Polyphenon E that contained 800 mg EGCG. Following EGCG administration, only EGCG was detected in human plasma. EGCG levels did not change significantly after the plasma samples were treated with deconjugating enzymes (β-glucuronidase/sulfatase), suggesting that EGCG is present in plasma mostly as the unchanged form. After Polyphenon E administration, EGCG levels were detected in human plasma, while unchanged EGC and EC levels were low or undetectable. After the samples have been treated with deconjugating enzymes, EGCG levels did not change much, whereas EGC and EC levels increased substantially. Similar observation was also reported in the study performed by Lee et al. [9
]. In their study, healthy human subjects were instructed to drink green tea in warm water containing 200 mg EGCG, 154 mg EGC, and 45 mg EC. Large percent of EGCG (77%) was present in the unchanged form, whereas 31% of EGC and 21% of EC were in the unchanged form at one hour after tea consumption.
Figure 2 Peak plasma tea catechin concentrations following a single dose administration of 800 mg EGCG (A) or Polyphenon E containing 800 mg EGCG, 148 mg EGC, 128 mg EC, and other green tea polyphenols (B) . Black bars are data obtained from plasma samples (more ...)
In our follow up study, we determined the pharmacokinetics of green tea catechins following 4 weeks of daily EGCG or Polyphenon E administration [10
]. The study participants received 800 mg EGCG once/day, 400 mg EGCG twice/day, 800 mg EGCG as Polyphenon E once/day, or 400 mg EGCG as Polyphenon E twice/day. We found that there was a greater than 60% increase in the area under the plasma EGCG concentration-time curve (a measurement of systemic availability) after 4 weeks of EGCG or Polyphenon E treatment at a dosing schedule of 800 mg once daily. The observed increase in the systemic exposure of EGCG is not related to drug accumulation after repeated dosing, because the AUC calculation has corrected for this factor. No significant changes were observed in the pharmacokinetics of EGCG after repeated green tea catechin treatment at a regimen of 400 mg twice daily. The mechanism(s) responsible for the observed increase in the systemic exposure of EGCG after repeating dosing at a high daily bolus dose remain(s) to be studied. Reduction in non-enzymatic degradation, saturation of pre-systemic Phase II metabolism, and/or inhibition in intestinal flora metabolism are plausible contributing mechanisms. It is not known whether ingestion of green tea catechins at a high daily bolus dose for greater than 4 weeks will result in further enhancement in the systemic bioavailability of EGCG.
We further conducted a study to determine the effect of dose and dosing condition on the oral bioavailability of green tea catechins after single-dose administration of Polyphenon E in humans [11
]. The study evaluated the pharmacokinetics of tea catechins at three different Polyphenon E doses (400, 800, and 1,200 mg based on the EGCG content) and under both fed and fasting conditions. summarizes the effect of dose and dosing condition on the peak plasma tea catechin concentrations. The area under the plasma concentration time curve exhibited changes by the dose and dosing condition similar to that of the peak plasma level. Consistent with previous findings [8
], gallated catechins, EGCG and ECG, were present in plasma mostly as the unchanged form, whereas nongallated catechins, EGC and EC, were mostly present as the glucuronide and sulfate conjugates. There was a 3–5 fold increase in plasma levels of EGCG and ECG when Polyphenon E was taken on an empty stomach after an overnight fast than when taken with food. Taking Polyphenon E on an empty stomach after an overnight fast did not have a significant effect on the plasma levels of total (unchanged plus glucuronide and sulfate conjugates) EGC, but resulted in lower plasma levels of total EC. The data also showed that there was a more than proportional increase in the peak plasma levels of EGCG and ECG as the dose level was increased. In addition, the dose normalized plasma levels of unchanged EGCG and ECG were higher than that of unchanged EGC and EC under both dosing conditions. The dose normalized plasma levels of total EGC and EC were higher than that of total EGCG and ECG under fed condition, but were at similar levels under fasting condition. The study suggested that the systemic bioavailability of tea catechins are affected by dose and dosing condition. The mechanism(s) responsible for the observed changes remain(s) to be studied. Saturation of pre-systemic metabolism at higher doses, depletion of Phase II enzymes/cofactors after an overnight fast, and/or disparity in gastric stability, dissolution rate, and food interaction under different dosing conditions are potential contributing factors. It is worth noting that taking Polyphenon E on an empty stomach at higher doses is associated with a higher incidence of gastric discomfort.
Table 2 Average peak plasma concentrations of green tea catechins after single-dose administration of three different Polyphenon E doses (2, 4, and 6 capsules; each capsule contained 200 mg EGCG, 48.5 mg EGC, 34.2 mg EC, and 20 mg ECG) under both fed and fasting (more ...)
Henning et al. compared the pharmacokinetics of green tea catechins after consumption of green tea, black tea, or a decaffeinated green tea extract in humans [12
]. Each preparation was administered at levels that provided similar amounts of EGCG. Standardization of the EGCG content in the tea preparations affected the contents of the other tea constituents. They found that peak plasma catechin concentrations were achieved at 1.2–1.5 hrs when consumed as black or green tea beverage. The peak plasma levels were achieved at 2.5–2.8 hrs when administered as a green tea supplement in oral capsules, probably due to the delay in disintegration/dissolution of the oral capsules. Despite of the delay in oral absorption when administered as oral capsules, higher catechin peak levels were observed compared with when consumed as black or green tea beverage. This observation suggests that other components in green or black tea beverage may decrease the extent of tea catechin absorption. It is also plausible that subjects can more rapidly swallow the capsules and thus be getting a bolus dose whereas drinking tea beverage takes more time and thus representing a slower infusion.
Little information is available on the pharmacokinetics of black tea polyphenols. A pilot study showed that the peak plasma theaflavins concentration was only 2–7 nM after consuming 700 mg mixed theaflavins (equivalent to about 30 cups of black tea) [13
]. The very low systemic bioavailability of theaflavins after oral ingestion may be attributed to their large molecular structures. The pharmacokinetics of thearubigins has not been studied because this class of compounds is still largely uncharacterized.
Collectively, the available data showed that tea catechins are absorbed and eliminated rapidly in humans. Peak plasma concentrations were achieved between 1–3 hrs after oral administration and reached total catechin concentrations in the sub- or low μM range. With a half-life of 2–4 hrs, the parent catechins do not appear to accumulate in the systemic circulation.
2.1 Oral Absorption and Bioavailability
Most of the absorption and oral bioavailability studies of green tea catechins were performed in laboratory animals. Chen et al. [14
] compared the plasma pharmacokinetics of EGCG in rats after intravenous (10 mg/kg) and oral (75 mg/kg) dosing and found that the oral bioavailability of EGCG was 1.6%. In this study, DGT containing 73, 68, and 27 mg/g of EGCG, EGC, and EC, respectively, was also administered to rats via intravenous (25 mg/kg) and oral (200 mg/kg) routes. The oral bioavailability was found to be 0.1%, 13.7%, and 31.2% for EGCG, EGC, and EC, respectively, following DGT administration. The authors suggested that the difference in oral bioavailability of EGCG after pure EGCG and DGT administration is due to the effect of other components in DGT on the oral absorption of EGCG. However, the dose normalized systemic exposure of EGCG was different between intravenous dosing of pure EGCG and DGT. This study determined the oral bioavailability based on the combined unchanged and conjugated catechin concentrations which could have complicated the interpretation of the bioavailability data because more conjugated metabolites could be formed during pre-systemic first-pass metabolism after oral catechin administration. Lambert et al. determined the pharmacokinetics of EGCG in mice after oral and intravenous dosing [15
]. The oral bioavailability of unchanged EGCG was found to be 15.8%. We compared the systemic exposure of EGCG in rats after intravenous and intraportal administration and found that the area under the plasma concentration-time curve of EGCG was similar between the two routes of administration, suggesting that tea catechins do not undergo significant pre-systemic hepatic metabolism [16
]. Consistently, when EGCG was administered at a dose of 100 mg/kg to rats by intraperitoneal injection, much higher dose normalized plasma concentrations of free EGCG were observed [17
]. These studies suggest that pre-systemic loss/metabolism within the GI tract may contribute more significantly to the low oral bioavailability of green tea catechins.
Recent clinical studies have examined tea catechin absorption in the small intestine in individuals with an ileostomy. Auger et al. [18
] determined the tea catechin levels in ileal fluid collected for 24 hrs after ingestion of 200 mg of Polyphenon E. They showed that the average recovery was 27% for the nongallated catechins, EC and EGC, and was 59% for the gallated catechins, EGCG and ECG, in the ileal fluid. Stalmach et al. [19
] found similar levels of recovery for the parent catechins in the ileal fluid after green tea consumption. In vitro
studies in gastric juice and ileal fluid indicated that tea catechins are stable in these fluid over a 4 h period at 37°C [18
]. Therefore, the recoveries in ileal fluid imply that nongallated catechins are absorbed from the small intestine more efficiently than their gallated analogs. The data also indicate that in healthy humans with an intact colon, substantial quantities of the green tea catechins would pass from the small intestine to the large intestine, where they will subject to breakdown by colonic bacteria.
Tea catechins have been shown to undergo extensive biotransformation via methylation, sulfation, and glucuronidation reactions. Multiple tea catechin metabolites were detected in human plasma and urine after oral green tea or green tea extract administration. Glucuronides/sulfates of EGCG, EGC, and EC were detected in plasma and that of EGC and EC were present in urine after oral ingestion of DGT or green tea catechins in humans [8
]. After oral administration of DGT, the major metabolites appeared in human urine included not only the glucuronides and sulfates of EGC and EC but also the O-methyl-EGC-O-glucuronides/sulfates and O-methyl-EC-O-sulfates [21
]. The methylated EGC conjugates were also detected in human plasma after oral DGT administration [22
]. However, no methylated EGC was detected either in plasma or urine in another clinical study [23
In addition to Phase II metabolites, metabolites that derive from microflora mediated catabolic processes have been identified in human plasma and urine. Earlier studies have identified 5-(3′, 4′, 5′-trihydroxyphenyl)-γ-valerolactone (M4) and 5-(3', 4'-dihydroxyphenyl)-γ-valerolactone (M6) as catechin-derived microflora metabolites [24
]. These were found to be present in the conjugated form. M4 and small amounts of M6 were detected and only M6 was detected in human urine after pure EGC or EC oral administration, respectively. The study results suggest that these metabolites are produced by intestinal microorganisms, with EGC and EC as the precursors of M4 and M6, respectively, and subsequently absorbed into the systemic blood and excreted in the urine. The urinary recovery of these two metabolites accounted for 6–39% of the ingested EGC and EC. After oral administration in rats, EGCG has been shown to be metabolized by intestinal microflora to form EGC and 5-(3',5'-dihydroxyphenyl)-γ-valerolactone [25
]. However, when EGCG was administered orally in humans, EGC was not found in blood or urine [8
Recently, HPLC with multi-stage mass spectrometry detection has been utilized to facilitate the identification of a range of additional metabolites. Stalmach et al. [26
] analyzed the catechin metabolite levels in plasma and urine collected over 24 hours after consuming 500 ml Choladi green tea (consisting of 78.6 mg EGC, 105.3 mg EGCG, 16.8 mg EC, 21.7 mg ECG). A total 10 metabolites, in the form of O-methylated, sulfated, and glucuronide conjugates of EC and EGC, with 29-126 nM peak plasma concentrations, were identified in human plasma. Unchanged EGCG and ECG were also detected with respective peak plasma values of 55 and 25 nM. Fifteen metabolites of EC and EGC were detected in urine, in the form of O-methylated, sulfated, and glucuronide conjugates, but EGCG and ECG were not detected in urine. The overall urinary excretion of the Phase II catechin metabolites accounted for about 8% of the total catechin intake. A follow up green tea feeding study by the same research group was carried out using human volunteers with an ileostomy [19
]. The ileal fluid contained around 70% of the ingested catechins in the form of the parent compounds (33%) and 23 metabolites (37%). The main metabolites effluxed back into the lumen of the small intestine were sulfates and methyl sulfates of EC and EGC. This indicates that in subjects with a functioning colon, substantial quantities of catechins pass from the small intestine to the large intestine. Once the catechins enter into the colon, the microflora are capable of hydrolyzing and removing conjugated moieties, such as glucuronides and sulfates. The released aglycones can be catabolized to ring fission products and low molecular weight phenolic acids. Roowi et al. determined the urinary excretion of phenolic acid catabolites after green tea consumption [27
]. Two low molecular weight phenolic acids, pyrocatechol and pyrogallol, believed to be derived from the gallic acid moiety of the gallated catechins, were detected in human urine after green tea consumption. The combined amount of pyrocatechol and pyrogallol detected in urine is equivalent to 47% of the gallated catechins detected in ileal fluid [19
]. Other urinary catabolites, excreted in significantly higher amounts after green tea consumption are 5-(3,4,5-trihydroxyphenyl)-γvaleric acid, 3-(3-hydroxyphenyl)-3-hydroxypropionic acid, and 4-hydroxybenzoic acid. Additional potential catabolites include 3-methoxy-4-hydroxyphenylacetic acid, 4-hydroxyphenylacetic acid, and hippuric acid. Quantitatively, the phenolic acid catabolites may account for 40% of the catechin intake, pointing to the importance of the colonic absorption in the overall bioavailability. In addition, these catabolites could contribute to the chemopreventive activity.
2.3 Tissue Distribution
Tissue distribution of tea catechins has been mostly studied in laboratory animals. Tissue distribution of EGCG was determined in rats 1 hour after a single oral dose of EGCG at 500 mg/kg. The highest level of unchanged EGCG was found in the small intestine mucosa (565 μM), followed by colon mucosa (69 μM), liver (48 μM), plasma (12 μM), and brain (0.5 μM) [28
]. Tea catechin tissue distribution was also determined in rats when 0.6% of GTP was dosed for 8 days [29
]. In this study, tea catechin concentrations were presented as the total of unchanged and conjugated tea catechin levels. Substantial amounts of EGC and EC were found in the bladder (2–3 μM), large intestine (1–3 μM), kidney (1–2 μM), lung (0.5–1 μM), and esophagus (0.5–0.7 μM). Levels of EGC and EC were low in the spleen, liver, thyroid, and heart. The amount of EGCG was higher in large intestine (1.1 μM), esophagus (0.61 μM), and bladder (0.44 μM) and lower in kidney, prostate, spleen, liver, and lung. Tea catechin liver and lung distribution was also determined in mice when 0.6% of GTP was dosed for 12 days [29
]. The concentration of EGCG was higher than EGC and EC in the lung, whereas EGC was slightly higher than EGCG in the liver. However, at any time, tea catechin concentrations in the lung were higher than those in the liver. In both tissues, tea catechins peaked on Day 4 and then declined to Day 12.
Studies on the tissue distribution of tea catechins in humans are limited. Henning et al. [30
] conducted the first clinical study to determine the tea catechin levels in prostate tissue. In this study, men scheduled to undergo prostatectomy were assigned to consume 5 cups of green tea, black tea, or a caffeine-matched soda each day for 5 days prior to surgery. The four major tea catechins were detected in the prostate tissue after green tea or black tea consumption with mean concentrations ranging from 21 to 107 pmol/g tissue. A follow up study by the same group showed that 4”-O-methyl EGCG was present in the prostate tissue in amounts similar to that of EGCG [31
]. EGCG has been shown previously to convert to 4”-O-methyl EGCG and 4’, 4”-dimethyl EGCG by liver cytosolic catechol O-methyltransferase [32
]. However, only trace amounts of 4”-O-methyl EGCG were detected in human plasma after green tea consumption in a reported study [33
] and in our unpublished data, suggesting that 4”-O-methyl EGCG detected in the human prostate may derive from methylation of EGCG in the target tissue. Consistent with this hypothesis, Henning’s group was able to show that LNCaP prostate cancer cells were able to methylate EGCG to 4”-O-methyl EGCG [31
]. Nevertheless, 4”-O-methyl EGCG has reduced activity in inhibiting cell proliferation and NF-κB activation and in inducing apoptosis when compared to the parent catechin. Therefore, genetic polymorphisms of catechol O-methyltransferase may affect the methylation status of EGCG and subsequently modulate its preventive effect on prostate cancer and possibly other cancers. Further studies on the tissue disposition of tea catechins and catechin-derived metabolites are warranted to delineate the moieties responsible for target tissue activities.