5. Distribution

methylated EGC conjugates were detected in human plasma after oral GTE administration [55],

A large amount of catechins were further catabolized by microflora in the colon, reabsorbed into plasma, and eliminated through urine. Major catechins catabolites were phenylvaleric

> , 4<sup>0</sup> , 5<sup>0</sup>

and shortened to C6-C1 phenolic and aromatic acids, and then reabsorbed to enter the circulation and excreted into urine. These small phenolic acids can be conjugated to valerolactone-


of metabolites was about 6–39% of the ingested EGC and EC [59]. Elevated hippuric acid (N-benzoylglycine) in excretion after green tea consumption by healthy volunteers comparing

Owing to extensive metabolism, a wide variety of metabolites of catechins were found in the plasma and urine after green tea consumption [61]. Ten metabolites, in the form of O-methylated, sulfated, and glucuronide conjugates of EC and EGC, were identified in human plasma, where only low levels, 55 and 25 nM, of intact EGCG and ECG were present. The phase II catechin metabolites in urine were about 8% of the total catechin intake. Ileal fluid from ileostomist fed with catechins contained about 33% parent compounds and 37% of 23 catechins conjugates, similar to healthy subjects [62]. About 70% of the ingested catechins that were found as naïve catechins and conjugated metabolites, indicated that catechins were mainly metabolized after glucuronidation, sulfation and methylation, and were effluxed back into the lumen without extensive catabolism in the intestine. These compounds entered into the colon and were subsequently hydrolyzed by resident microflora to remove the conjugated moieties, releasing the aglycones and further catabolized into low molecular weight phenolic acids by ring fission. Consequently, substantial amount of the gallated catechins (47% of input dose) were detected in ileal fluid, and small amount of phenolic acids, pyrocatechol and pyrogallol derived from the gallic acid moiety, were detected in human urine after green tea consumption [63]. Other catabolites, 4-hydroxybenzoic acid, 5-(3,4,5-trihydroxyphenyl)-γvaleric acid, 3-(3-hydroxyphenyl)-3-hydroxypropionic acid, hippuric acid, 3-methoxy-4 hydroxyphenylacetic acid, and 4-hydroxyphenylacetic acid, were also found in urine. These phenolic acid catabolites account to about 40% of the intake, and would account for the major biological activity of catechins instead of the low bioavailability of the parent compounds.

The efficiency of microbial metabolism on catechins was well reported in a GTE study on cows [64]. Different doses of GTE was applied intraruminally (10 and 50 mg/kg) and duodenally (10, 20 and 30 mg/kg BW) to dairy cows. No catechin could be found in the plasma for both doses after intraruminal administration. However, plasma concentrations of EC, EGC, and EGCG were increased on increasing dosage after intraduodenal administration. It demonstrated the high metabolism efficiency of ruminal microorganisms under intraruminal administration.




but the metabolites were not found in plasma in the other study [56].

24 Pharmacokinetics and Adverse Effects of Drugs - Mechanisms and Risks Factors

,50

to ileostomist also indicated extensive catabolism of catechins in the colon [60].

acid and phenylvalerolactones, such as 5-(3<sup>0</sup>

and 5-(3<sup>0</sup>

30

, 4<sup>0</sup>

was metabolized to EGC and 5-(3<sup>0</sup>

4.2. Microbial metabolism

Most distribution studies were conducted in rodents. In one study, green tea polyphenols (0.6%) were given to rats for 8 days. Total (conjugated and free) EGC and EC levels were found in the bladder, large intestine, kidney, lung, and esophagus at 2–3, 1–3, 1–2, 0.5–1, 0.5–0.7 micromole levels, respectively. However, they were almost undetectable in spleen, liver, thyroid, and heart [70]. The total EGCG levels in large intestine, esophagus, and bladder were 1.1, 0.61, and 0.44 micromoles while kidney, prostate, spleen, liver, and lung were undetected. In a 12-day study in mice, Tmax of tea catechins in the lung and liver occurred on Day 4, but the level was decreased from then on. Catechin concentrations in the lung were always higher than that in the liver [67]. In an EGCG study on rats at 500 mg/kg orally, the Cmax of EGCG in the small intestine mucosa, colon mucosa, liver, plasma, and brain were 565, 69, 48, 12, and 0.5 μmol/L, respectively [68]. It appears the level of distribution is related to the extent of catechins contact to the tissues.

Furthermore, we found that catechins can be distributed into various ocular tissues including aqueous humor, vitreous humor, choroid-sclera, retina, lens, and cornea. After feeding 550 mg/kg GTE to SD rats, the Cmax of GC and ECG can reach to more than 10 and 1 μmol/kg, respectively, in the choroid-sclera and retina and 1 μmol/kg in the lens [52] (Table 1). Levels of catechins disposed in the ocular tissue could reach the effective dose. In our studies, green tea extract can exert anti-oxidation, anti-inflammation and anti-apoptotic effects on the ocular tissues especially for retina [52, 53, 69]. However, doubled the dose of EGCG in another GTE resulted surge of EGCG deposing in the ocular tissues and caused the retina turning to


In a human study, green tea and black tea were given to patients 5 days prior to undergoing prostatectomy surgery. Four main catechins were found in the prostate tissue ranging from 21 to 107 pmol/g [74]. Similar amount of EGCG and 400-O-methyl EGCG were found in the prostate tissue in a following study [75]. Since only trace amounts of 400-O-methyl EGCG were present in human plasma after green tea consumption, it suggested that catechol O-methyltransferase was

Pharmacokinetics and Disposition of Green Tea Catechins

http://dx.doi.org/10.5772/intechopen.74190

27

Catechins are mainly cleared through urinary and biliary excretion. Non-galloylated catechins are mainly excreted in urine in the form of parent and conjugated compounds. Galloylate catechins are mainly excreted through biliary excretion to the colon. In one study, minor epi- or gallocatechin-O-sulfates were detected in urine, while aglycones, ECG and EGCG, were absent after green tea consumption [68]. No conjugates of ECG and EGCG were detected in urine suggesting the gallate derivatives did not undergo phase II metabolism. The flavan-3-ol metabolites excreted were equivalent to 8.1% of ingested green tea flavan-3-ols [68]. Other studies found catechin metabolites accounted for 28.5% of intake, whereas gallocatechin metabolites accounted for 11.4% of the ingested (�)-epigallocatechin and (+)-gallocatechin [77]. EGCG cannot be detected in urine showing its elimination is not renal. On the other hand, EGCG may be degalloylated to other catechins in the liver after absorption through small intestine, subsequently metabolized and eliminated into urine resulting EGCG absent in there. However, EGCG and its metabolites could not be found in ileostomists urine suggested EGCG was not eliminated through the internal degalloylation process [78] because EGCG could be absorbed through colon and eliminated directly into urine. In addition, the half-lives of non-gallated catechins, EGC and EC, were shorter than gallated catechins, EGCG and ECg [31]. It may be because the more hydrophobic gallated catechins bind stronger to serum proteins and exist in non-conjugated free form that is not favorable for renal excretion [79, 80]. On the other hand, oral administration of catechins in rats found relative amounts of EC, EGCG, and ECG, respectively, at 4.72, 0.17, and 0.25% in urine and 11.0, 7.89, and 5.80% in feces [81]. In an isotope tracing study in rats, about 77% of the total radioactivity was present in bile but only 2.0% in the urine after intravenous

H]-EGCG [82]. These evidences suggested that the galloyl catechin are

In our study on GTE, Sunphenon, the elimination rates of catechins in retina and choroidsclera were in general higher than the humors and plasma. The elimination rate was from 0.19 h�<sup>1</sup> for GC to 2.4 h�<sup>1</sup> in the retina, while the rate was from 0.04 for EGC to 0.24 for ECG in vitreous humor in SD rats [52]. However, when the dose of EGCG was doubled in another GTE, Theaphenon® E, we found the elimination rates of all catechins in the ocular tissues, particularly the retina, lower than the plasma [53] (Table 2). It appeared that some active elimination or metabolic mechanisms in ocular tissues facilitated the elimination. The elimination mechanism actively removed the catechins in the ocular tissues, but the mechanism was suppressed by the increased EGCG concentration. On the other hand, in our rat fetus study,

present in prostate to methylate EGCG [76].

6. Elimination

administration of [4-3

excreted through the bile and eliminated through the feces.

Adapted from Chu et.al. [52].

\* Indicates that the catechin(s) has significant higher (p < 0.05, n = 6) level of the parameter in the corresponding biological fluid or tissue than the others as analyzed by compared by nonparametric Kruskal-Wallis H method.

Table 1. Maximum concentration of catechins in plasma, humors, eye tissues after a single dose of 550 mg/kg of Sunphenon DCF-1 green tea extract administrated orally to rats.

pro-oxidative status and reducing the anti-apoptotic effect. Catechins disposition into ocular compartments also exhibited steric selectivity. Vitreous humor was selective to non-epimer catechins but without any structural preference to ungallated catechins as shown in the plasma. Ocular tissues, on the contrary, did not show any specific disposition except GC was dominated in retina, choroid-sclera, and the lens. Of note, it is our study on rat fetus. We also found catechins can penetrate into various fetal tissues, including brain, eye, lung, heart, liver, and kidney, following feeding to pregnant SD rat [71]. However, the Cmax levels of catechins were below micromolar level. The effective biological activity on the fetus is still questionable. Nevertheless, the Cmax of EGCG in the fetal eye could reach to 0.83 μM that may affect the ocular development in this critical stage.

We have found GTE, Theaphenon® E, containing 70% EGCG, exerted biological effects on various ocular diseases models. High oral dose of GTE, 550 mg/kg, suppressed various inflammation responses in the iris and ciliary body, and aqueous humor following LPS-induced ocular inflammation [69]. Our latest unpublished data also showed that it inhibited retina inflammation through reduction of microglial cells and suppression of astroglial reactions. In another sodium iodate-induced retina degeneration model, oral administration of 550 mg/kg Theaphenon® E or catechins mixtures containing 438 mg/kg EGCG could protect retina from disruptive folding caused by sodium iodate [72]. Such effects were possibly exerted through their anti-oxidative effects as demonstrated by the reduction of 8-iso-PGF2α, superoxide dismutase, and glutathione peroxidase levels in the retina. The anti-oxidative properties also contributed to cataract inhibition, through cataracto-static ability as convincingly revealed by Thiagarajan et al. [73]. The antioxidation protection was also supported by our previous study [53]. Theaphenon® E increased the GSH/GSSG ratio and reduced 8-iso-PGF2α level in the lens, although the catechins levels inside the lens was relative low comparing to other ocular tissues. In a human study, green tea and black tea were given to patients 5 days prior to undergoing prostatectomy surgery. Four main catechins were found in the prostate tissue ranging from 21 to 107 pmol/g [74]. Similar amount of EGCG and 400-O-methyl EGCG were found in the prostate tissue in a following study [75]. Since only trace amounts of 400-O-methyl EGCG were present in human plasma after green tea consumption, it suggested that catechol O-methyltransferase was present in prostate to methylate EGCG [76].
