Chow HH, Hakim IA, Crowell JA, Ranger-moore J, Chew WM, Celaya CA et al.. Effects of dosing condition on the oral bioavailability of green tea catechins after single-dose administration of polyphenon E in healthy individuals. Clin Cancer Res 11, 4627-4633

Arizona Cancer Center, The University of Arizona, Tucson, Arizona 85724, USA.
Clinical Cancer Research (Impact Factor: 8.72). 06/2005; 11(12):4627-33. DOI: 10.1158/1078-0432.CCR-04-2549
Source: PubMed


Green tea has been shown to exhibit cancer-preventive activities in preclinical studies. Its consumption has been associated with decreased risk of certain types of cancers in humans. The oral bioavailability of the major green tea constituents, green tea catechins, is low, resulting in systemic catechin levels in humans many fold less than the effective concentrations determined in in vitro systems. We conducted this clinical study to test the hypothesis that the oral bioavailability of green tea catechins can be enhanced when consumed in the absence of food. Experimental Designs: Thirty healthy volunteers were randomly assigned to one of the following doses of Polyphenon E (a decaffeinated and defined green tea catechin mixture): 400, 800, or 1,200 mg, based on the epigallocatechin gallate content (10 subjects per dose group). After an overnight fast, study participants took a single dose of Polyphenon E with or without a light breakfast, which consisted of one or two 4-oz muffins and a glass of water. Following a 1-week wash-out period, subjects were crossed over to take the same dose of Polyphenon E under the opposite fasting/fed condition. Tea catechin concentrations in plasma and urine samples collected after dosing were determined by high-pressure liquid chromatography analysis.
Consistent with previous reports, epigallocatechin gallate and epicatechin gallate were present in plasma mostly as the free form, whereas epicatechin and epigallocatechin were mostly present as the glucuronide and sulfate conjugates. There was >3.5-fold increase in the average maximum plasma concentration of free epigallocatechin gallate when Polyphenon E was taken in the fasting condition than when taken with food. The dosing condition led to a similar change in plasma-free epigallocatechin and epicatechin gallate levels. Taking Polyphenon E in the fasting state did not have a significant effect on the plasma levels of total (free and conjugated) epigallocatechin, but resulted in lower plasma levels of total epicatechin. Urinary epigallocatechin gallate and epicatechin gallate levels were very low or undetectable following Polyphenon E administration with either dosing condition. Taking Polyphenon E under the fasting state resulted in a significant decrease in the urinary recovery of total epigallocatechin and epicatechin. Polyphenon E administered as a single dose over the dose range studied was generally well-tolerated by the study participants. Mild and transient nausea was noted in some of the study participants and was seen most often at the highest study agent dose (1,200 mg epigallocatechin gallate) and in the fasting condition.
We conclude that greater oral bioavailability of free catechins can be achieved by taking the Polyphenon E capsules on an empty stomach after an overnight fast. Polyphenon E up to a dose that contains 800 mg epigallocatechin gallate is well-tolerated when taken under the fasting condition. This dosing condition is also expected to optimize the biological effects of tea catechins.

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    • "We selected the dose of 400 mg twice a day because healthy volunteers in previous studies tolerated this dose for a month well [15]. Single daily doses of 800 mg are also well tolerated [15] while single doses of 1200 mg cause nausea in 70% of participants when given without food and in 20% when given with food [16]. Although Polyphenon E was safe in beagle dogs and rats when given with food, beagle dogs when given Polyphenon E without food had high mortality rates [17]. "
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    ABSTRACT: Objectives: Phase I (PhI): assess the safety of Polyphenon E in people with multiple sclerosis (MS) and determine the futility of Polyphenon E as a neuroprotective agent. Correlate plasma levels of EGCG with neuroprotective effects. Phase II (PhII): Further assess safety and confirm the neuroprotective effects of Polyphenon E. Design: PhI: single group futility study. PhII: parallel group randomized double-blind placebo-controlled study. Participants: Recruitment area (both studies): LSU MS Center, New Orleans, LA and general public from surrounding areas. Inclusion criteria (both studies): 1) MS per 2005 McDonald criteria; 2) relapsing remitting or secondary progressive MS; 3) stable for six months prior to enrollment on either no therapy or glatiramer acetate (GA) for the PhI study and on either on GA or Interferon β for the PhII study. Exclusion criteria (both studies): 1) complete bone marrow ablation or alentuzumab use at any time; 2) mitoxantrone, cyclophosphamide, natalizumab or fingolimod use in the prior nine months; 3) liver problems or significant medical problems. Interventions: PhI: Polyphenon E, a green tea extract containing 50% of the antioxidant Epigallocatechin-gallate (EGCG), two capsules twice daily (200mg of EGCG per capsule; total daily dose 800mg) for six months. PhII: Polyphenon E or matching placebo capsules, same dose for one year. Only the research pharmacist knew treatment assignment and she randomized participants (one-to-one, stratified by GA or Interferon β, blocks of 4 or 6). Outcome evaluators did not discuss side effects with participants. Outcome measures: PhI: 1) adverse events (AE); 2) futility: decrease in N-acetyl aspartate (NAA) from baseline to six months of 10% or more; 3) association between EGCG plasma levels and change in NAA. PhII: 1) AEs; 2) difference in the rate of change of NAA-levels over twelve months.We measured NAA using a point resolved magnetic resonance spectroscopic imaging sequence (TE30/TR2000) on a 10cm×10cm×1cm volume of interest (VOI) located just superior to the lateral ventricles. The field of view was 16×16 resulting in 1cm(3) voxels. We quantified NAA and creatine/phosphocreatine (Cr) levels using LCModel for post-processing. Results: PhI: Ten participants enrolled and completed all assessments with no serious AEs. One discontinued therapy due to grade (G) I abnormal liver function tests (LFTs). We included all participants in the analysis. NAA adjusted for creatine increased by 10% [95% CI(3.4%,16.2%), p<0.01] rejecting the futility endpoint. PhII: Thirteen participants enrolled and twelve started treatment. The DSMB stopped the study because 5/7 participants on Polyphenon E had abnormal LFTs (G I, and 1G III). Median time to onset of abnormal LFTs was 20weeks [Inter-Quartile Range (IQR) (10,23)]. Only two participants completed the six-month visit, so we could not analyze the NAA levels. PhI participants took capsules from lot 189I1107 while 6/7 PhII participants took capsules from a new lot (L0206306). Both lots had similar levels of EGCG but differed in the levels of minor catechins. There were no significant differences between the lots on participants' median free EGCG plasma levels at either 3h or 8h as well as conjugated EGCG levels at 3h (all p>0.4, Wilcoxon exact test). Free EGCG levels at 8h correlated with changes in NAA adjusted by water content. A 1ng/ml higher EGCG plasma concentration correlated with a 0.9% increase in NAA[95% CI(0.5%,1.4%), visit*level interaction F=14.4, p<0.001]. However, EGCG plasma concentrations did not correlate with NAA adjusted by creatine (1ng/ml higher EGCG was associated with 0.02%,[95% CI(-0.27%,0.3%) change in NAA, p>0.5]). There was a trend towards an increase in creatine levels (referenced to water content) from baseline to exit (1 5% increase, [95% CI(-6%,17%), p=0.4]). The free EGCG levels at 8hours correlated significantly with change in creatine levels (1ng/ml higher EGCG level at 8h was associated with a 1.1% increase in creatine [95% CI(0.6%,1.6%)]). Thus it is possible that the discrepancy between the correlation of the EGCG 8h levels with NAA changes referenced to water and the 8h EGCG levels with NAA changes referenced to creatine was due to a change in creatine among the subjects with higher EGCG levels. Conjugated 3h and 8h levels and free 3h levels did not correlate with NAA changes (all p >0.5). Conclusions/classification of evidence: Class III evidence: Polyphenon E at a dose of 400mg of EGCG twice a day is not futile at increasing brain NAA levels. Class I evidence: some lots of Polyphenon E have a high risk of hepatotoxicity. Funding: National Center for Complementary and Alternative Medicine K23AT004433, National Multiple Sclerosis Society RG4816-A-1 and National Institute of General Medical Sciences 1 U54 GM104940. Mitsui Norin provided Polyphenon E and placebo and their representative reviewed the manuscript prior to publication. Mitsui Norin was not involved in other aspects of the study. The decision to submit the manuscript remained with the investigators. Registration: NCT00836719 and NCT01451723NCT00836719NCT01451723.
    Journal of the neurological sciences 08/2015; DOI:10.1016/j.jns.2015.08.006 · 2.47 Impact Factor
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    • "Above pH 7 and 37 • C, the stability of free-form catechins is reduced due to degradation and epimerisation , and therefore, most free-form analysis utilises a low pH and low temperature environment with the addition of an antioxidant , such as ascorbic acid, to improve the stability [19] [20] [21]. As most of the conjugated catechins are commercially unavailable, enzyme deconjugation of green tea catechin metabolites present within biological samples [22] [23] [24] [25] allows for the assessment of the metabolites relative to the free-form standards. However, the employment of this method has been questioned due to inefficient and incomplete hydrolysis [26], and as a result the more stable conjugated catechin forms have been assessed by monitoring the fragmentation patterns of the compounds using liquid chromatography mass spectrometry (LC–MS 2 ) analysis [27] [28] [29] [30] [31]. "
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    ABSTRACT: The simultaneous analysis of free-form and conjugated flavonoids in the same sample is difficult but necessary to properly estimate their bioavailability. A method was developed to optimise the extraction of both free and conjugated forms of catechins and metabolites in a biological sample following the consumption of green tea. A double-blind randomised controlled trial was performed in which 26 volunteers consumed daily green tea and vitamin C supplements and 24 consumed a placebo for 3 months. Urine was collected for 24h at 4 separate time points (pre- and post-consumption) to confirm compliance to the supplementation and to distinguish between placebo and supplementation consumption. The urine was assessed for both free and conjugated metabolites of green tea using LC-MS(2) analysis, after a combination extraction method, which involved an ethyl acetate extraction followed by an acetonitrile protein precipitation. The combination method resulted in a good recovery of EC-O-sulphate (91±7%), EGC-O-glucuronide (94±6%), EC (95±6%), EGC (111±5%) and ethyl gallate (74±3%). A potential total of 55 catechin metabolites were investigated, and of these, 26 conjugated (with methyl, glucuronide or sulphate groups) and 3 free-form (unconjugated) compounds were identified in urine following green tea consumption. The majority of EC and EGC conjugates significantly increased post-consumption of green tea in comparison to baseline (pre-supplementation) samples. The conjugated metabolites associated with the highest peak areas were O-methyl-EC-O-sulphate and the valerolactones M6/M6'-O-sulphate. In line with previous studies, EC and EGC were only identified as conjugated derivatives, and EGCG and ECG were not found as mono-conjugated or free-forms. In summary, the method reported here provides a good recovery of catechin compounds and is appropriate for use in the assessment of flavonoid bioavailability, particularly for biological tissues that may contain endogenous deconjugating enzymes.
    Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 12/2014; 972C:29-37. DOI:10.1016/j.jchromb.2014.09.035 · 2.73 Impact Factor
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    • "Studies have shown that EGCG mediates its anti-cancer effect by regulating cancer cell angiogenesis and metastasis [1, 2, 8]. Another important characteristic of EGCG is its relatively low systemic toxicity [9, 10]. Thus, EGCG has been proposed to merit possible use as an adjuvant or immunostimulant in cancer therapy [11]. "
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    ABSTRACT: Background Cancer immunotherapy requires proper manipulation of the immune system, lymphocytes in particular, in order to identify and destroy the cancer cells as non-self. In this study we investigated the effect of the flavonoid present in green tea, namely epigallocatechin-3-gallate (EGCG), on the proliferation of, and IFN-γ production by, peripheral blood mononuclear cells (PBMC) from breast cancer patients stimulated with a mitogen, anti-CD3 and the common breast cancer peptides Her-2/neu, and p53. Methods Blood samples were collected from 25 patients with breast cancer at the Kuwait Cancer Control Centre (KCCC). The patients were newly diagnosed, and had not undergone any treatment or surgery at the time of sample collection. The control group consisted of 25 healthy women age-matched (±5 years) to the patients. PBMC were isolated from the patients and controls, and were cultured separately with the mitogen PHA, anti-CD3 antibodies, and Her-2/neu and p53 in the presence or absence of standardized doses of EGCG. The degree of proliferation and interferon-γ [IFN-γ) release were then analyzed. Results EGCG significantly suppressed the proliferation of PBMC in response to stimulation separately with (i) the mitogen, (ii) anti-CD3, and (iii) the cancer antigen peptides. IFN-γ production was also significantly suppressed by EGCG in vitro. Conclusions EGCG appears to have an immunosuppressive effect on the proliferation of PBMC, indicating that EGCG is worth exploring for immunomodulatory effects in autoimmune diseases and tissue transplantation.
    BMC Complementary and Alternative Medicine 08/2014; 14(1):322. DOI:10.1186/1472-6882-14-322 · 2.02 Impact Factor
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