在健康個體給予多劑量EGCG和Polyphenon E之後綠茶多酚之藥物動力學與安全性

Pharmacokinetics and Safety of Green Tea Polyphenols after Multiple-Dose Administration of Epigallocatechin Gallate and Polyphenon E in Healthy Individuals

劉紹毅 ； H-H. Sherry Chow ； Yan Cai ； Iman A. Hakim ； James A. Crowell ； Farah Shahi ； Chris A. Brooks ； Robert T. Dorr ； Yukihiko Hara ； David S. Alberts

《中華民國血液淨化醫學會雜誌》 14卷3-4期 (2009/12) Pp. 49-52

https://doi.org/10.30024/JFBPS.200912.0006

摘要

目的
綠茶和綠茶多酚，在臨床前模式系統(pre-clinical model systems)中，已知其具有防癌作用。在準備未來對於綠茶涉入試驗我們已做了一個臨床研究來判定給予4個星期，每天口服EGCG或polyphenon E（一種已確定成份，去咖啡因綠茶多酚混合物）之後，綠茶多酚之安全性與藥物動力學。在探索之形式下，我們也已確認長期給予綠茶多酚，對於紫外線－誘發之紅斑反應的效果。
實驗設計
有著Fitzpatric skin type Ⅱ或type Ⅲ之健康參與者，在一個2星期之出入門診期間，分別以隨意取樣登錄方式，接受5種療法之一的為期4週之給藥：800mg EGCG 每天1次，400mg EGCG，一天兩次；polyphenon E（內含800mg EGCG）每天1次，polyphenon E （內含400mg EGCG)每天兩次以及安慰劑(placebo)每天一次（每個組有8位參加者）。檢體之收集與檢測是在給藥前即給藥4個星期後，以便判定是其安全度，藥物動力學和生物性作用力。
結果
在給綠茶多酚4個星期治療期間，之不良副作用包括有腹脹、胃不舒服感、噁心、胃灼熱、胃痛、腹痛、頭暈、頭痛和肌肉痛，但所有之副作用均屬輕微。而大部分症狀之發生，在多酚處理組(polypheron-treated groups)中，並不會比安慰劑組(placebo group)多。在重複給予綠茶多酚產品(green tea polyphenol products)之後，並不會有血球數目與血液生化方面之明顯改變被發現。而在以800mg劑量經口服方式一天一次給予綠茶多酚4個星期處理之後，其EGCG在血漿濃度－時間曲線下之面機會增加60%以上。而在以400mg每天二次之重複性給予綠茶多酚處理時，並不會觀察到EGCG之藥物動力學有明顯之改變。重複給予處理綠茶多酚，並不會對於EGC與EC之接合性代謝物的藥物動力學造成影響。在選擇性劑量與按劑量時間排定表(selected dose and dosing schedule)給4個星期之綠茶多酚，療法時，並不能提供對抗紫外線－誘發紅斑作用的保護。
結論
我們的結論是，每天飲用8~16杯綠茶或分開劑量每天兩次給兩次同等之EGCG量共計4星期時，對健康人而言是相當安全的。在長期每天給高劑量之綠茶多酚（800mg EGCG或polyphenon E每天一次），那麼游離型EGCG之全身使用性會增加60%以上。

並列摘要

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).