6. Elimination

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

GC EGC C EC EGCG GCG ECG

Plasma 91.5 57.4 754.9 235.8 139.0 57.0 1258.4 294.0\* 310.4 59.9 50.8 10.4 159.1 33.9 Aqueous humor – 602.9 116.7\* 127.4 62.8 138.9 58.5 13.2 5.1 33.5 20.4 47.8 8.1 Vitreous humor 110.6 22.1\* 15.9 7.0 96.5 23.3\* 20.5 10.6 15.4 2.7 20.9 9.9 14.0 5.1

Choroid-sclera 11461.8 5168.7\* 1506.3 941.1 477.6 346.9 283.5 66.5 184.4 39.0 220.5 69.7 10.7 4.3 Retina 22729.4 4229.4\* 8020.8 1658.49\* 492.7 235.2 608.0 112.0 259.1 67.2 3.2 1.9 –

Lens 1558.1 318.4\* 1172.3 207.8\* 300.0 151.5 72.3 19.1 149.1 26.5 18.0 6.6 90.3 45.8 Cornea – 359.4 66.8\* 58.5 15.4 30.6 5.7 25.2 15.5 10.7 3.9 91.1 18.7

\* Indicates that the catechin(s) has significant higher (p < 0.05, n = 6) level of the parameter in the corresponding biological fluid or

Table 1. Maximum concentration of catechins in plasma, humors, eye tissues after a single dose of 550 mg/kg of

tissue than the others as analyzed by compared by nonparametric Kruskal-Wallis H method.

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

Sunphenon DCF-1 green tea extract administrated orally to rats.

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 Our latest unpublished data also showed that it inhibited retina inflammation through reduction of microglial cells and suppression of astroglial reactions.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.

ocular development in this critical stage.

Cmax (nM)

Cmax (pmol/g)

Adapted from Chu et.al. [52].

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 administration of [4-3 H]-EGCG [82]. These evidences suggested that the galloyl catechin are excreted through the bile and eliminated through the feces.

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,


Catechins can be widely distributed into various tissues including lung, eye, brain, gastrointestinal tract, kidney, bladder, and even passing through the placenta to the fetal organs. The disposition can be stereo-specific, and affected by food, drug, and catechins themselves indicating the absorption and distribution may involve some sort of transporters mechanisms. Before applying green tea catechins for therapeutic purpose, it is essential to understand their pharmacokinetics behavior and metabolites profiles not only in the plasma but also in various

Pharmacokinetics and Disposition of Green Tea Catechins

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

29

Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong,

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Kai On Chu and Calvin C.P. Pang\*

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2012;4:1679-1691

\*Address all correspondence to: cppang@cuhk.edu.hk

Author details

Hong Kong

References

Adapted from (a) Chu et al. [52] and (b) Chu et al. [53].

\* 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 2. Elimination of catechins in plasma, humors, eye tissues after a single dose of 550 mg/kg of (a) Sunphenon DCF-1 green tea extract, and (b) Theaphenon® E administrated orally to rats.

the elimination rates of catechins in the maternal plasma, in general, were faster than the fetal tissues. The elimination rate of GC and EC were 0.26 and 0.3 h<sup>1</sup> for maternal plasma, whereas 0.08 and 0.1 h<sup>1</sup> for fetal kidney [71].
