以家兔探討茶多酚對Levodopa之藥物動力學的影響

Influence of Tea Polyphenol on the Pharmacokinetics of Levodopa in Rabbits

黃妤婕(Yu-Jie Huang)

指導教授 ： 王莉萱

臺北醫學大學/藥學院/藥學研究所/碩士(2012年)

摘要

Catechol-O-methyl transferase (COMT)為代謝levodopa的主要酵素之一。長期使用levodopa替代療法的帕金森氏症病人，經過若干年的治療後，常會出現藥效減弱、波動的現象，此時將會建議合併使用COMT抑制劑以減少levodopa在周邊組織的代謝。COMT抑制劑之藥物結構屬於di-substituted catechol，而綠茶中的茶多酚結構亦是屬於substituted catechol，根據體外實驗結果，發現茶多酚具有抑制COMT的活性。因此，我們的研究目的是要探討市售綠茶萃取膠囊與levodopa並用時，是否會產生交互作用。
本實驗以紐西蘭大白兔為實驗動物，同時以經口胃管管灌方式，投與levodopa/carbidopa及綠茶萃取素粉末，研究同時給予兩者時，綠茶萃取素中的茶多酚是否會影響levodopa之藥物動力學。
研究設計是以交叉投與(crossover)方式，分別給予口服單一劑量levodopa/carbidopa 每公斤5/1.25毫克，或是合併levodopa/carbidopa每公斤5/1.25毫克與綠茶萃取素粉末每公斤150毫克，之後，於原實驗動物族群中隨機挑選八隻實驗動物，進行多劑量實驗。給予多劑量組口服綠茶萃取素粉末每公斤150毫克，連續投與至第14天，於第15日合併投與levodopa/carbidopa每公斤5/1.25毫克與綠茶萃取素粉末每公斤150毫克，並且分析levodpa與其經COMT代謝後之代謝物3-O-methyldopa(3-OMD)之血中濃度，並計算其藥物動力學參數，以代謝轉換比率(AUC of 3-OMD/AUC of leovodpa)的差異為觀察結果主要指標，levodopa與3-OMD的相關各項藥動參數變化為次要指標。
當單獨投與單一劑量levodopa/carbidopa 5/1.25 mg/kg時，代謝轉換比率(AUC0-t of 3-OMD/AUC0-t of leovodpa)為2.09，而合併投與levodopa/carbidopa 5/1.25 mg/kg與綠茶萃取素150 mg/kg後，代謝轉換比率為1.69，兩者代謝轉換比率減少19.1% (P<0.05)。比較投與綠茶萃取素粉末前後之levodopa藥動參數變化，以geometric mean計算，平均AUC0-t增加26.9% (1161.94 vs. 1474.06 ng*hr/mL)，最高血中濃度增加50.5% (723.76 vs. 1089.32ng/mL)，達最高血中濃度時間縮短10.1% (0.61 vs. 0.55hr)，而清除率減少20.4% (13.31 vs. 10.59 L/hr, P<0.05)。比較3-OMD之藥動參數變化，則皆未具有統計上的差異。由實驗結果可知，綠茶萃取素可有意義減少levodopa與3-OMD之代謝轉換比率。
於連續口服綠茶萃取素粉末組，代謝轉換比率為2.75，與單劑量組相比，代謝轉換比率增加29.3% (2.13 vs. 2.75)。比較投與多劑量與單劑量綠茶萃取素之levodopa藥動參數變化，發現平均AUC0-t減少16.0% (2186.57 vs. 1837.51 ng*hr/mL)，最高血中濃度減少9.4% (1613.61 vs. 1462.64 ng/mL)，達最高血中濃度時間縮短17.2% (0.57 vs. 0.47hr)，清除率增加19.0% (8.05 vs. 9.57 L/hr)，然而此差異皆無統計學上意義。比較3-OMD之藥動參數變化，則無論在哪一組，亦皆未具有統計上的差異。
綜合以上實驗結果發現，在單劑量投與levodopa與綠茶萃取素時，可顯著地減少levodopa對3-OMD的代謝轉換率及降低levodopa的清除率，然而在多劑量投與之後，與單劑量相比，對於levodopa或3-OMD之藥物動力學皆未有影響。

關鍵字

Levodopa ； COMT抑制劑 ； 綠茶 ； 茶多酚 ； 藥物-食物交互作用 ； 動物實驗 ； 兔

並列摘要

Catechol-O-methyl transferase (COMT) is one of the enzymes that metabolized levodopa. In Parkinson’s disease, after levodopa replacement therapy for few years, patients may encounter with the problem of motor fluctuation. COMT inhibitor will be considered to co-administration with levodopa to decrease the metabolism of levodopa in peripheral tissue. Most of COMT inhibitors structurally belong to di-substituted catechol, the structure of polyphenols in green tea also belong to substituted catechol. In the in-vitro study, polyphenols in green tea reveal the characteristic of inhibiting COMT acitivity.
The purpose of this study was to evaluate the possible effect of polyphenols in green tea on levodopa by investigating the pharmacokinetics of levodopa. Levodopa and green tea essence were simultaneously intragastric (ig) administration to experiment animals via oral-gestural tube.
For this crossover study, the rabbits received ig levodopa/carbidopa (5/1.5mg/kg) as control group, or co-administrated with green tea essence (150mg/kg) as single group. Then, we separated eight rabbits into multiple dose group, the rabbits received green tea essence 150mg/kg until day 14. In day 15, these rabbits received levodopa/carbidopa (5/1.5mg/kg) co-administrated with green tea essence 150mg/kg. After analysis, we calculated the pharmacokinetic parameter of levodopa and 3-OMD to evaluate the difference between these groups. The primary endpoint was the metabolic ratio (AUC0-t of 3-OMD/AUC0-t of leovodpa), and the secondary endpoint was related pharmacokinetic parameters.
In control and single dose group, the metabolic ratio was 2.09 and 1.69, respectively. After co-administration with green tea essence, the metabolic ratio decreased 19.1% (P<0.05). Comparing the related pharmacokinetic parameter of levodopa, after co- administration with green tea essence in single dose, average AUC0-t increased 26.9% (1161.94 vs. 1474.06 ng*hr/mL), Cmax increased 50.5% (23.76 vs. 1089.32ng/mL), and Tmax decreased 10.1% (0.61 vs. 0.55hr). There was no statistical defference in these parameters. However, the clearance decreased 20.4% (13.31 vs. 10.59 L/hr, P<0.05).
In single and multiple dose group, the metabolic ratio was 2.13 and 2.75, respectively. The metabolic ratio increased 29.3% (2.13 vs. 2.75), but there was no statistical difference in metabolic ratio. Comparing the related pharmacokinetic parameters of levodopa, average AUC decreased 16.0% (2186.57 vs. 1837.51 ng*hr/mL), Cmax decreased 9.4% (1613.61 vs. 1462.64 ng/mL), Tmax decreased 17.2% (0.57 vs. 0.47hr), and clearance increased 19% (8.05 vs. 9.57 L/hr). There was no statistical defference in these parameters. Otherwise, there was no statictical defference in the pharmacokinetic of 3-OMD, despite in control goup, single dose group or multiple dose group.
According to the result of this study, co-administration of green tea essence and levodopa decreased the metabolic ratio of levodopa to 3-OMD in single dose group. However it did not appear in multiple dose group when comparing with single dose group.

並列關鍵字

Levodopa ； COMT inhibitor ； green tea ； polyphenol ； drug-food interaction ； animal study ； rabbit

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