Green Tea (Camellia sinensis) 19124972
Pharmacokinetics and Safety of Green Tea Polyphenols after Multiple-Dose Administration of Epigallocatechin Gallate and Polyphenon E in Healthy Individuals CSV JSON

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.

RESULTS:

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.

CONCLUSIONS:

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).

1 . PK and safety after multiple-dose administration of epigallocatechin gallate (EGCG) 800 mg (id=NPDI-QJ8BsA)

In Vivo Pharmacokinetics Study

Results

Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

Multiple dosing

Population

Healthy volunteers

8 subjects with Fitzpatric skin type II or III

The subjects were in performance status 0–1 (determined by Southwest Oncology Group Performance Status Criteria) and have normal liver and renal function. Subjects were excluded if they were pregnant, had cancers of any type within the past 5 years, had severe metabolic disorders or other life-threatening acute or chronic diseases, had weight loss > 10%, or had gastric ulcer within the last 6 months.

Pharmacokinetic (PK) Sampling Information

On the first treatment day, a fasting blood sample was collected before ingestion of the study medication. Blood samples were collected at 0.5, 1, 2, 3.5, 5, 6.5, 8, and 24 h after drug administration on the first and last treatment day. For placebo group, only a fasting blood sample was collected on the last treatment day.

Incomplete sample collection occurred with one patient, therefore only data from 7 subjects were included in the analysis

Drug or Natural Product Administration

Natural Product Administration

Oral

capsule

800 mg epigallocatechin gallate (EGCG)

Fed

with a standard light breakfast

once daily

4 weeks

Natural Product Characteristics

Chemoprevention Agent Development Research Group, National Cancer Institute (Bethesda, MD)

On average, each EGCG capsule contained 200 mg EGCG and pharmaceutical excipients consisting of pregelatinized starch, colloidal silicon dioxide, and magnesium stearate.

not available

On the basis of the content analysis performed every 6 months, green tea polyphenols were found to be stable at room temperature and protected from enviornmental extremes.

Pharmacodynamics (PD) & Adverse Events

Gastrointestinal disorders 35700000
Musculoskeletal and connective tissue disorders 36500000
Nervous system disorders 36700000

All of the reported events have been rated as mild events (grade 1). For most events, the incidence reported in the treatment groups was not significantly more than that in the placebo group. Mild nausea was more frequent after the 800-mg once daily treatment than that in the placebo group (5, 3, and 1 occurrence for 800 mg EGCG once daily, 800 mg EGCG as Polyphenon E once daily, and placebo, respectively). Complete blood count and a panel of blood chemistry profiles were obtained before and after 4 weeks of daily administration of the study agent. No significant changes were observed in these clinical laboratory measurements (data not shown).