Pharmacokinetics of epigallocatechin-3-gallate in mice and enhancement of bioavailability by other dietary factors

Abstract

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Epigallocatechin-3-gallate (EGCG), the most abundant catechin in green tea (Camellia sinensis), has shown cancer preventive activity in animal models. The bioavailability of EGCG in the most commonly used animal species, mice, is poorly understood. We have determined the pharmacokinetic parameters of EGCG in the mouse and compared these parameters with those of other studies in humans and rats. Following administration of EGCG, at 10 mg/kg, i.v. or 75 mg/kg, i.g., the peak plasma levels of EGCG in male CF-1 mice were 2.7 μM and 0.28 μM, respectively. The absolute bioavailability of EGCG in mice following administration of EGCG (75 mg/kg, i.g.) was 26.5%. This is higher than that previously reported in the rat. EGCG was present in the unconjugated form in the lung, prostate, and other tissues at levels of 0.31 –3.56 nmol/g following intravenous administration. Whereas intragastric administration resulted in lower levels in most tissues, compared to intravenous administration (e.g. 0.006 vs. 2.66 nmol/g in the lung), the levels in the small intestine and colon were high, at 45.2 and 7.86 nmol/g respectively. When the AUC was normalized to the dose, and the present data compared with that of previous studies of humans and rats, it was apparent that humans and mice were more similar in terms of EGCG bioavailability than either was to the rat. However, whereas EGCG was found to be 50 –80% glucuronidated in the plasma of mice, it has been shown to be largely in the free form in humans. Co-treatment of mice with EGCG and a second dietary component, either piperine or curcumin, increased plasma levels of EGCG by 3.0- and 2.5-fold, respectively compared to animals given only EGCG. Piperine appeared to inhibit gastrointestinal transit of EGCG resulting in an increased absorptive period for EGCG. This was manifest in the increased residency of EGCG in the small intestine and delayed appearance in the colon. Accumulation studies with HT-29 cells showed that co-treatment with EGCG (10 μM) and curcumin (20 μM) resulted in a 2-fold increase in intracellular concentrations of EGCG and its methylated and glucuronidated metabolites compared to cells treated only with EGCG. Co-treatment of cells with EGGC and piperine at similar concentrations did not increase the overall intracellular concentrations of EGCG and its metabolites. Rather, piperine co-treatment resulted in a decrease in EGCG-4“-glucuronide and a concomitant increase in 4”-O-methly EGCG. The present studies demonstrate that there are important species differences between humans, rats, and mice in terms of EGCG bioavailability, and indicate that the mouse may represent the better model to study EGCG bioavailability. Further, these studies indicate that active transport and intestinal transit time are important factors in determining EGCG plasma levels. Modulation of these factors by other dietary components may be helpful in improving EGCG bioavailability.