Absorption, Distribution, and Elimination of Tea Polyphenols in Rats

Tea polyphenols—including (2)-epigallocatechin-3-gallate (EGCG), (2)-epigallocatechin (EGC), and (2)-epicatechin (EC)—are believed to be responsible for the beneficial effects of tea. This study was conducted to investigate the absorption, distribution, and elimination of EGCG, EGC, and EC in rats after administration of decaffeinated green tea (DGT). For comparison, pure EGCG was also studied. The plasma and tissue levels of EGCG, EGC, and EC were quantified by HPLC, and the results were analyzed by the PCNONLIN program. Following intravenous injection of DGT (25 mg/kg), the plasma concentration-time curves of EGCG, EGC, and EC were fitted in a two-compartment model. The b-elimination half-lives (t1/2b) were 212, 45, and 41 min for EGCG, EGC, and EC, respectively; the clearances were 2.0, 7.0, and 13.9 ml z min/kg, and the apparent distribution volumes (Vd) were 1.5, 2.1, and 3.6 dl/kg. When pure EGCG (10 mg/kg) was given, however, a shorter t1/2b (135 min), a larger clearance (72.5 ml z min/kg), and a larger Vd (22.5 dl/kg) for EGCG were observed, suggesting that other components in DGT could affect the plasma concentration and elimination of EGCG. After intragastric administration of DGT (200 mg/kg), ;13.7% of EGC and 31.2% of EC were shown in the plasma, but only 0.1% of EGCG was bioavailable as judged by the ratio of AUCi.g./AUCi.v.. After intravenous administration of DGT (25 mg/kg), the level of EGCG was found to be the highest in the intestine samples, and the intestinal EGCG level declined with a t1/2 of 173 min. The highest levels of EGC and EC were observed in the kidney, and the levels declined rapidly with t1/2 of 29 and 28 min, respectively. The AUC of EGCG in the intestine was 4-fold higher than that in the kidney, but the AUCs of EGC and EC in the intestine were similar to those in the kidney. The liver and lung levels of EGCG, EGC, and EC were generally lower than those in the intestine and the kidney. The distribution results suggest that EGCG is mainly excreted through bile, and that EGC and EC are excreted through both the bile and urine. Tea is a widely consumed beverage in many countries. An estimated 2.5 million metric tons of dried teas are manufactured annually. Of that amount, ;20% is green tea, which is mainly consumed in China and Japan, and ;78% is black tea, which is consumed in many Western countries. Many laboratory studies have demonstrated the inhibition of tumorigenesis by tea and tea polyphenols in different animal models, including mouse skin, mouse lung, rat and mouse esophagi, mouse forestomach, mouse duodenum, rat small intestine, rat colon, and rat and mouse livers (1). In contrast to the consistently observed inhibition of tumorigenesis by tea in many animal models, studies concerning the effects of tea on the incidence of human cancers have been inconclusive. Some epidemiological studies on the effect of tea ingestion on cancer risk have suggested an inhibitory effect (2–5), others an enhancing effect, and still others a lack of an effect (6–8). However, none of these human studies are conclusive, and more epidemiological research is needed. A major problem in investigating the association of tea consumption with cancer incidence is the lack of quantitative data. It is not known whether the inconclusive results in the human studies were due to a presumed lower amount of tea consumption by humans than by experimental animals, or were due to species differences in the bioavailabilities and actions of the active components involved. Even in studies with animals, mechanistic understanding of the inhibitory effect of tea on tumorigenesis is hampered by insufficient information regarding the absorption, distribution, metabolism, and elimination of the effective components of tea. It is believed that most of the cancer-inhibitory activity of tea is due to the tea polyphenols present in tea. The major polyphenols in green tea, commonly known as tea catechins, are EGCG, EGC, ECG, and EC (1, 9, 10) (fig. 1). However, the pharmacokinetic properties of these tea polyphenols are largely unknown. The objective of the present study is to gain an understanding about the pharmacokinetic properties and bioavailabilities of EGCG, EGC, and EC in rats. These tea polyphenols were given to rats either in the form of DGT or as pure EGCG. EGCG was selected as a prototype tea polyphenol for study because it is the most abundant in green tea with demonstrated biological activities, and it is available in high purity. Both administration routes (i.v. and i.g.) were used. The compounds were analyzed with an HPLC method newly developed in our laboratory (11). Materials and Methods Chemicals and Reagents. DGT and purified EGCG, EGC, and EC were obtained from Thomas J. Lipton, Inc. (Englewood Cliffs, NJ). The DGT solids were dehydrate preparations of water extracts of DGT leaves and contained 73, 68, and 27 mg/g of EGCG, EGC, and EC, respectively (11). All other chemicals and solvents were the highest grades of commercially available materials. This study was supported by the National Institutes of Health Grant CA56673 and by the National Institute of Environmental Health Sciences Center Grant