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      Physiologically based pharmacokinetic modeling of tea catechin mixture in rats and humans

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          Abstract

          Although green tea ( Camellia sinensis) ( GT) contains a large number of polyphenolic compounds with anti‐oxidative and anti‐proliferative activities, little is known of the pharmacokinetics and tissue dose of tea catechins ( TCs) as a chemical mixture in humans. The objectives of this study were to develop and validate a physiologically based pharmacokinetic ( PBPK) model of tea catechin mixture ( TCM) in rats and humans, and to predict an integrated or total concentration of TCM in the plasma of humans after consuming GT or Polyphenon E ( PE). To this end, a PBPK model of epigallocatechin gallate ( EGCg) consisting of 13 first‐order, blood flow‐limited tissue compartments was first developed in rats. The rat model was scaled up to humans by replacing its physiological parameters, pharmacokinetic parameters and tissue/blood partition coefficients ( PCs) with human‐specific values. Both rat and human EGCg models were then extrapolated to other TCs by substituting its physicochemical parameters, pharmacokinetic parameters, and PCs with catechin‐specific values. Finally, a PBPK model of TCM was constructed by linking three rat (or human) tea catechin models together without including a description for pharmacokinetic interaction between the TCs. The mixture PBPK model accurately predicted the pharmacokinetic behaviors of three individual TCs in the plasma of rats and humans after GT or PE consumption. Model‐predicted total TCM concentration in the plasma was linearly related to the dose consumed by humans. The mixture PBPK model is able to translate an external dose of TCM into internal target tissue doses for future safety assessment and dose‐response analysis studies in humans. The modeling framework as described in this paper is also applicable to the bioactive chemical in other plant‐based health products.

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          Physiological parameters in laboratory animals and humans.

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            Inhibition of carcinogenesis by tea.

            Tea has received a great deal of attention because tea polyphenols are strong antioxidants, and tea preparations have inhibitory activity against tumorigenesis. The bioavailability and biotransformation of tea polyphenols, however, are key factors limiting these activities in vivo. The inhibition of tumorigenesis by green or black tea preparations has been demonstrated in animal models on different organ sites such as skin, lung, oral cavity, esophagus, forestomach, stomach, small intestine, colon, pancreas, and mammary gland. Epidemiological studies, however, have not yielded clear conclusions concerning the protective effects of tea consumption against cancer formation in humans. The discrepancy between the results from humans and animal models could be due to 1) the much higher doses of tea used in animals in comparison to human consumption, 2) the differences in causative factors between the cancers in humans and animals, and 3) confounding factors limiting the power of epidemiological studies to detect an effect. It is possible that tea may be only effective against specific types of cancer caused by certain etiological factors. Many mechanisms have been proposed for the inhibition of carcinogenesis by tea, including the modulation of signal transduction pathways that leads to the inhibition of cell proliferation and transformation, induction of apoptosis of preneoplastic and neoplastic cells, as well as inhibition of tumor invasion and angiogenesis. These mechanisms need to be evaluated and verified in animal models or humans in order to gain more understanding on the effect of tea consumption on human cancer.
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              Pharmacokinetics and safety of green tea polyphenols after multiple-dose administration of epigallocatechin gallate and polyphenon E in healthy individuals.

              Green tea and green tea polyphenols have been shown to possess cancer preventive activities in preclinical model systems. In preparation for future green tea intervention trials, we have conducted a clinical study to determine the safety and pharmacokinetics of green tea polyphenols after 4 weeks of daily p.o. administration of epigallocatechin gallate (EGCG) or Polyphenon E (a defined, decaffeinated green tea polyphenol mixture). In an exploratory fashion, we have also determined the effect of chronic green tea polyphenol administration on UV-induced erythema response. Healthy participants with Fitzpatric skin type II or III underwent a 2-week run-in period and were randomly assigned to receive one of the five treatments for 4 weeks: 800 mg EGCG once/day, 400 mg EGCG twice/day, 800 mg EGCG as Polyphenon E once/day, 400 mg EGCG as Polyphenon E twice/day, or a placebo once/day (8 subjects/group). Samples were collected and measurements performed before and after the 4-week treatment period for determination of safety, pharmacokinetics, and biological activity of green tea polyphenol treatment. Adverse events reported during the 4-week treatment period include excess gas, upset stomach, nausea, heartburn, stomach ache, abdominal pain, dizziness, headache, and muscle pain. All of the reported events were rated as mild events. For most events, the incidence reported in the polyphenol-treated groups was not more than that reported in the placebo group. No significant changes were observed in blood counts and blood chemistry profiles after repeated administration of green tea polyphenol products. There was a >60% increase in the area under the plasma EGCG concentration-time curve after 4 weeks of green tea polyphenol treatment at a dosing schedule of 800 mg once daily. No significant changes were observed in the pharmacokinetics of EGCG after repeated green tea polyphenol treatment at a regimen of 400 mg twice daily. The pharmacokinetics of the conjugated metabolites of epigallocatechin and epicatechin were not affected by repeated green tea polyphenol treatment. Four weeks of green tea polyphenol treatment at the selected dose and dosing schedule did not provide protection against UV-induced erythema. We conclude that it is safe for healthy individuals to take green tea polyphenol products in amounts equivalent to the EGCG content in 8-16 cups of green tea once a day or in divided doses twice a day for 4 weeks. There is a >60% increase in the systemic availability of free EGCG after chronic green tea polyphenol administration at a high daily bolus dose (800 mg EGCG or Polyphenon E once daily).
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                Author and article information

                Contributors
                flaw@sfu.ca
                Journal
                Pharmacol Res Perspect
                Pharmacol Res Perspect
                10.1002/(ISSN)2052-1707
                PRP2
                Pharmacology Research & Perspectives
                John Wiley and Sons Inc. (Hoboken )
                2052-1707
                17 April 2017
                June 2017
                : 5
                : 3 ( doiID: 10.1002/prp2.2017.5.issue-3 )
                : e00305
                Affiliations
                [ 1 ] Department of Biological SciencesSimon Fraser University 8888 University Drive Burnaby British ColumbiaCanada
                [ 2 ] School of Pharmaceutical SciencesSun Yat‐sen University Guangzhou GuangdongChina
                [ 3 ] Departments of Respiratory MedicinePathology and Cancer Imaging British Columbia Cancer Agency, and the University of British Columbia Vancouver British ColumbiaCanada
                Author notes
                [*] [* ] Correspondence

                Francis C. P. Law , Department of Biological Sciences, Simon Fraser University , 8888 University Drive, Burnaby, B.C. Canada V5A 1S6. Tel: 778 782 4285; Fax: 778 782 3496; E‐mail: flaw@ 123456sfu.ca

                Author information
                http://orcid.org/0000-0001-5172-076X
                Article
                PRP2305
                10.1002/prp2.305
                5464336
                28603626
                086e5f5b-f5f8-4dd7-9c2f-55de6ac167fe
                © 2017 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 12 February 2017
                : 13 February 2017
                Page count
                Figures: 11, Tables: 7, Pages: 18, Words: 12224
                Funding
                Funded by: United States Public Health Service
                Award ID: PO1 CA096964‐01A1
                Funded by: South China Normal University, Guangzhou, China
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                prp2305
                June 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.1.0 mode:remove_FC converted:02.06.2017

                pbpk model,tea catechins,systemic dosimetry
                pbpk model, tea catechins, systemic dosimetry

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