攝食綠茶和EGCG之後人體內綠茶兒茶素之藥物動力學不同代謝物之形成與個別之差異性

Pharmacokinetics of Tea Catechins after Ingestion of Green Tea and (-)-Epigallocatechin-3-gallate by Humams: Formation of Different Metabolites and Individual Variability

劉紹毅 ； Mao-Jung Lee ； Pius Maliakal ； Lai-Shun Chen ； Xiao-Feng Meng ； Flordeliza Y. Bondoc ； Saileta Prabhu ； George Lambert ； Sandra Mohr ； Chung S. Yang

《中華民國血液淨化醫學會雜誌》 14卷3-4期 (2009/12) Pp. 57-60

https://doi.org/10.30024/JFBPS.200912.0008

摘要

在最近幾年中，綠茶和茶多酚業已廣泛性地被當作化學防護性藥物來研究。在人體內茶酚分之生物利用性(bioavailability)和代謝命運，仍未明確的被了解。在本報告中，將單一口服劑量之綠茶或去咖啡因綠茶（20mg茶葉／kg）或EGCG(2 mg/kg)給8位參加實驗者之後，我們分析了EGCG、EGC、EC之藥物動力學參數。藉用HPLC加上電化學的偵測儀(electrochemical detector) 來定量血漿與尿中之總EGCG、EGC與EC（游離型加上接合體型）。配置在一個區隔式模式(compartment mode1)中，劃出兒茶素(catechins)之血漿濃度－時間相關曲線。以綠茶來作3個重複實驗時，EGCG、EGC、EC血漿最大濃度，分別為77.9±22.2，223.4±35.2與124.03±7.86 ng/ml，和其相關連之，區線下之面積(area under curve, AUC)值分別為508.2±227、945.4±438.4和529.5±244.4(上標 ng-h)/(下標 ml)。而達到濃度之最高點，所需之時間為1.3~1.6小時範圍內。而其在體內被清除之半衰期分別為3.4±0.3和2.0±0.4小時。在如此重覆實驗之間的藥物動力學的參數中，我們可以發現其有重要之個人差異和變異性。當在給予去咖啡因綠茶或純化型的EGCG時，其藥物動力學參數沒有看到明顯差異。在血漿中，EGCG大部分以游離型存在，然而EGC與EC則大部分以接合型存在。超過90%之尿中總EGC和EC之量，大部份皆屬接合物型態，其被排泄時間介於0與8小時之間。隨之在尿中及血漿中檢測到4'-0-methyl EGC之量比EGC高。血漿中4'-0-methyl EGC之濃度，在1.7±0.5小時達到最高點，而其在血漿中之半衰期為4.4±1.1小時。2個環狀－裂解代謝物(ring-fission metabolites)~(-)-5-(3', 4', 5'-trihydroxyphenyl )-γ-valerolactone (M4)和(-)-5-(3', 4'-dihydroxyphenyl)-valerolactone(M6)，於3小時後在尿與血漿中會出現明顯的量，而達到最高點為8~15小時。如此的結果，在茶之介入性療法研究(interventron study)中，可能可以用來設計劑量和給藥之次數，以及可以用來發展出飲用茶之生物標記。

並列摘要

Green tea and tea polyphenols have been studied extensively as cancer chemopreventive agents in recent years. The bioavailability and metabolic fate of tea polyphenols in humans, however, are not clearly understood. In this report, the pharmacokinetic parameters of (-)-epigallocatechin-3-gallate (EGCG), (-)-epigallocatechin (EGC), and (-)-epicatechin (EC) were analyzed after administration of a single oral dose of green tea or decaffeinated green tea (20 mg tea solids/kg) or EGCG (2 mg/kg) to eight subjects. The plasma and urine levels of total EGCG, EGC, and EC (free plus conjugated forms) were quantified by HPLC coupled to an electrochemical detector. The plasma concentration time curves of the catechins were fitted in a onecompartment model. The maximum plasma concentrations of EGCG, EGC, and EC in the three repeated experiments with green tea were 77.9±22.2, 223.4±35.2, and 124.03±7.86 ng/ml, respectively, and the corresponding AUC values were 508.2±227, 945.4±438.4, and 529.5±244.4 ng•h•ml^(-1), respectively. The time needed to reach the peak concentrations was in the range of 1.3-1.6 h. The elimination half-lives were 3.4±0.3, 1.7±0.4, and 2.0±0.4 h, respectively. Considerable interindividual differences and variations between repeated experiments in the pharmacokinetic parameters were noted. Significant differences in these pharmacokinetic parameters were not observed when EGCG was given in decaffeinated green tea or in pure form. In the plasma, EGCG was mostly present in the free form, whereas EGC and EC were mostly in the conjugated form. Over 90% of the total urinary EGC and EC, almost all in the conjugated forms, were excreted between 0 and 8 h. Substantial amounts of 4'-O methyl EGC, at levels higher than EGC, were detected in the urine and plasma. The plasma level of 4'-O-methyl EGC peaked at 1.7±0.5 h with a half life of 4.4±1.1 h. Two ring-fission metabolites, (-)-5-(3', 4', 5'-trihydroxyphenyl)-γ-valerolactone (M4) and (-)-5-(3', 4'-dihydroxyphenyl)-valerolactone (M6), appeared in significant amounts after 3 h and peaked at 8-15 h in the urine as well as in the plasma. These results may be useful for designing the dose and dose frequency in intervention studies with tea and for development of biomarkers of tea consumption.