4. Metabolism

lumen. Consistently, there was 6–11 times increase in intestinal uptake of total catechins comparing to green tea control following administered green tea with xylitol/citric acid and

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

Besides the effect of food and drug interaction, we found catechins absorption steric and structural dependent [52]. In one study, we fed 550 mg/kg GTE to SD rats. After normalization with the input oral doses, the relative AUC0-20 h of epi-isomers in the plasma was higher than its enantiomers, with the level of EGC > GC, EC > C, and EGCG>GCG. Also, the plasma levels of ungallated catechins (EGC, GC, and EC) were higher than gallated catechins (EGCG, GCG,

Figure 3. Diagrams showing the normalized relative AUC levels of total catechins (conjugated and free form) in ocular fluid and tissues. (a) Relative AUC levels of different catechins in the plasma after normalization by the corresponding input catechin dose in the GTE. Ungallate levels showed higher than gallate derivatives while epimers were higher than non-epimers. (b) Relative AUC levels of catechins in vitreous and aqueous humor. Vitreous humor showed selective to non-epimer but no selectivity on gallated and ungallated catechins. No particular trends of catechins selectivity appeared in aqueous humor. (c) Relative AUC levels of catechins in retina, lens, cornea and choroids-sclera. Adapted from Chu et al.

xylitol/vitamin C [51].

[52].

### 4.1. Effects of conjugations

Catechins are mainly metabolized by phase 2 conjugation processes through methylation, sulfation, and glucuronidation in the intestine and liver after oral administration. Glucuronidation and sulfation mainly occur in the intestine, whereas glucuronidation, sulfation, and methylation occur in the liver. Some conjugates are further methylated. Glucuronidation and sulfation can increase the polarity of catechins to enhance solubility and facilitate their eliminations through urine. EGCG, EGC and EC glucuronide and sulfate were commonly found in plasma [20, 27]. Omethyl-EGC-O-glucuronides and O-methyl-EC-O-sulfates were found in human urine [54] and methylated EGC conjugates were detected in human plasma after oral GTE administration [55], but the metabolites were not found in plasma in the other study [56].

4.3. Effects of metabolism on pharmacokinetics

pharmacokinetics data in reported studies.

non-methylated conjugations, and 3<sup>0</sup>

5. Distribution

Catechins are suffered from extensive and different types of metabolisms. Also, some conjugates formation, like sulfates, are resistant to enzymatic hydrolysis during the sample preparation of chemical analysis [65]. These are reasons contributing to the large variation of

Catechins contain many epimers with different steric structures, the enantiomers are absorbed and metabolized differently. For example, absorption of (�)-C was lower than (+)-C [66]. A study on metabolism of flavan-3-ols in human males ingested with equal quantities of (�)-EC, (�)-C, (+)-EC, and (+)-C reported different bioavailability. The plasma and urine showed different levels of stereoisomers with (�)-EC > (+)-EC > (+)-C > (�)-C. Also, different levels of

stereoisomers can affect the metabolism of each other in the phase II metabolism [67]. Unlike ungallated catechin, the conjugation of gallate derivatives, such as ECG and EGCG, were not found in plasma and urine [68]. The galloyl moiety might inhibit phase II metabolism. In another study, about 50% of ingested EGCG was found from ileal fluid in ileostomists indicating EGCG was hardly absorbed. Only 1% of phase II conjugate of EGCG was detected in ileal fluid, showing excretion of EGCG directly from the enterocytes rather than being metabolized

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 the liver and entering into the enterohepatic recirculation [69].


Pharmacokinetics and Disposition of Green Tea Catechins

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

25

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 acid and phenylvalerolactones, such as 5-(3<sup>0</sup> , 4<sup>0</sup> , 5<sup>0</sup> -trihydroxyphenyl)-γ-valerolactone (M4) and 5-(3<sup>0</sup> , 4<sup>0</sup> -dihydroxyphenyl)-γ-valerolactone (M6) [57]. They can be further metabolized 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-30 -O-sulfate, pyrogallol-2-O-sulfate, Pyrogallol-2-O-glucuronide, and vanilloylglycine for excretion in urine [58]. EGC and EC were metabolized into M4 and M6 and excreted likewise. EGCG was metabolized to EGC and 5-(3<sup>0</sup> ,50 -dihydroxyphenyl)-γ-valerolactone in the rat. The amount 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 to ileostomist also indicated extensive catabolism of catechins in the colon [60].

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.

### 4.2. Microbial metabolism

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.

### 4.3. Effects of metabolism on pharmacokinetics

Catechins are suffered from extensive and different types of metabolisms. Also, some conjugates formation, like sulfates, are resistant to enzymatic hydrolysis during the sample preparation of chemical analysis [65]. These are reasons contributing to the large variation of pharmacokinetics data in reported studies.

Catechins contain many epimers with different steric structures, the enantiomers are absorbed and metabolized differently. For example, absorption of (�)-C was lower than (+)-C [66]. A study on metabolism of flavan-3-ols in human males ingested with equal quantities of (�)-EC, (�)-C, (+)-EC, and (+)-C reported different bioavailability. The plasma and urine showed different levels of stereoisomers with (�)-EC > (+)-EC > (+)-C > (�)-C. Also, different levels of non-methylated conjugations, and 3<sup>0</sup> - and 400-O-methylation of epimers were found, indicating stereoisomers can affect the metabolism of each other in the phase II metabolism [67]. Unlike ungallated catechin, the conjugation of gallate derivatives, such as ECG and EGCG, were not found in plasma and urine [68]. The galloyl moiety might inhibit phase II metabolism. In another study, about 50% of ingested EGCG was found from ileal fluid in ileostomists indicating EGCG was hardly absorbed. Only 1% of phase II conjugate of EGCG was detected in ileal fluid, showing excretion of EGCG directly from the enterocytes rather than being metabolized in the liver and entering into the enterohepatic recirculation [69].
