臺灣博碩士論文加值系統

近代流行病學研究顯示，蔬果中的多酚對心血管疾病、癌症等慢性病有預防之功效。因此市場上多酚類保健食品應運而生且蔚為風行。保健食品攝入體內後，與藥物一樣，其體內處置與藥物運轉蛋白如P-醣蛋白 (P-gp)、多重抗藥性蛋白 (MRPs) 或代謝酵素等息息相關。因此，併服保健食品可能調控此些蛋白而導致其他西藥動力學的改變，甚而影響療效及安全。因此，慢性病患使用保健食品的利與弊值得關注。本研究探討併服香椿 (TS)、白藜蘆醇 (RDS)、牛奶薊 (MT)、聖約翰草 (SJW) 等保健食品對治療指數狹窄之免疫抑制劑cyclosporin (CsA)、methotrexate (MTX) 動力學之影響及相關機轉。
Cyclosporin (CsA) 為 P-glycoprotein (P-gp) 與 cytochrome 3A4 (CYP3A4) 之受質。本研究以大鼠探討併服 MT、RDS、TS 對 CsA 動力學之影響。結果顯示，併用 MT、RDS、TS 皆顯著降低 CsA 之血藥面積及血峰濃度。機轉研究顯示， TS、RDS 藉由活化 P-gp、CYP3A4，而 MT 藉由活化 P-gp，造成 CsA 生可用率之降低。
MT、RDS、SJW 口服後，其多酚成分於體循環中主要以sulfates/glucuronides 存在，它們在生理 pH 環境下皆為陰離子，為 multidrug resistance proteins (MRPs)、organic anion transporter (OATs)之可能受質。 Methotrexate (MTX) 為 MRPs、OATs 之受質。因此本研究以大鼠探討 MT、RDS、SJW 對 MTX 動力學之影響。結果顯示，併服單劑量 RDS、SJW 皆使 MTX 之血藥面積及平均滯留時間顯著增加，其中以 SJW-MTX 之交互作用最為嚴重，實驗組七隻大鼠中有三隻於第 7－13 天死亡。機轉研究顯示， SJW、RDS 之代謝物藉由抑制外排蛋白 MRP2 ，造成 MTX 生可用率之提高。
綜言之，大鼠併服多酚保健食品時，顯著降低 CsA 之血藥濃度，然而卻顯著提高 MTX 之血藥濃度。因此，對於使用 P-pg 、 CYP3A4 或 MRP2 之慢性病患，多酚保健食品可能影響療效及安全，使用不可不慎。

Recent epidemiologic researches have reported that plant polyphenols play a probable role in the prevention of cardiovascular disease and cancer. Therefore, polyphenol－rich botanical products, claimed to support health are easily purchasable in the market worldwide. Like other xenobiotics, the concentrated dietary supplements are absorbed, metabolized and excreted by human body. The biological fates of dietary supplements are also associated with metabolizing enzymes and drug transporters. Hence, when critical medicines are coadministered with dietary supplements, there is probable toxic interaction between them. This study investigated the effects of Toona sinensis leaves (TS), resveratrol dietary supplements (RDS), milk thistle (MT) and St. John’s wort (SJW) on the pharmacokinetics of cyclosporine (CsA) and methotrexate (MTX) in rats and the underlying mechanism.
CsA, an immunosuppressive agent with narrow therapeutic window, is a substrate of P-glycoprotein (P-gp) and CYP 3A4. Our results showed that coadminstration with TS, MT and RDS significantly decreased the AUC0-t and Cmax of CsA. The mechanism studies indicated that TS and RDS reduced CsA absorption via activating P-gp and CYP3A4, whereas MT lowered CsA absorption mainly through activating P-gp.
MTX, an immunosuppressant with narrow therapeutic window, is a substrate of multiple resistance proteins (MRPs) and organic anion transporters (OATs). Our results showed that coadminstration with RDS and SJW significantly increased the AUC0-t and Cmax of MTX. The mechanism study indicated that RDS and SJW decreased MTX elimination via inhibiting MRP2, More importantly, higher mortality of rats was observed.
In conclusion, coadministration of polyphenol－rich dietary supplements significantly altered the pharmacokinetics of CsA and MTX. We suggest that for the sake of drug safety, the concurrent use of polyphenol－rich dietary supplements with critical medicines which are substrates of P-gp, CYP3A4 and/or MRP2 should be with caution.

目錄……………………………………………………………………I
附圖目錄 ……………………………………………………………IV
附表目錄 ……………………………………………………………VIII
中文摘要 ……………………………………………………………XII
英文摘要 ……………………………………………………………XIV
研究架構 ……………………………………………………………XVI
縮寫表 ……………………………………………………………XVII
第一章 緒論…………………………………………………………1
第二章 總論…………………………………………………………7
第一節 香椿之簡介…………………………………………………7
第二節 白藜蘆醇(Resveratrol)之簡介…………………………10
第三節 牛奶薊(Milk thistle)之簡介……………………………14
第四節 聖約翰草(St John’s wort)之簡介……………………19
第五節 藥物運輸蛋白之簡介………………………………………25
1. 多重藥物抗藥性蛋白之特性………………………………25
2. 有機陰離子運送蛋白之特性………………………………30
3. P-醣蛋白之特性……………………………………………33
第六節 環孢靈(Cyclosporin)之特性……………………………35
第七節 胺甲葉酸(Methotrexate)之特性…………………………38
第三章 實驗材料與方法……………………………………………43
第一節 實驗材料……………………………………………………43
第二節 溶液配製……………………………………………………49
第三節 香椿(TS)分析、長期生化值及對CsA動力學之影響……53
1. 香椿水煎劑指標成分之定量分析…………………………53
2. 大鼠口服香椿水煎劑之代謝動力學………………………54
3. 大鼠口服香椿水煎劑後之生化值檢測……………………59
4. 大鼠併服香椿水煎劑對 CsA 動力學之影響……………60
5. 香椿與CsA 交互作用之機制探討…………………………61
第四節 白藜蘆醇分析及對CsA、MTX動力學之影響…………………67
1. Resveratrol分析方法之建立與確效……………………67
2. 大鼠併服RDS對 CsA 動力學之影響………………………68
3. 大鼠併服RDS對胺甲葉酸 (MTX) 動力學之影響…………69
4. RDS與CsA 交互作用機制探討……………………………70
5. RDS與MTX 交互作用機制探討……………………………72
第五節 Milk thistle對CsA及MTX動力學之影響……………………75
1. 大鼠併服Milk thistle(MT)對 CsA 動力學之影響……75
2. 大鼠併服MT對胺甲葉酸 (MTX) 動力學之影響…………75
3. Millk thistle與CsA 交互作用機制探討………………76
第六節St John’s wort對胺甲葉酸 (MTX) 動力學之影響…………79
1. 大鼠併服St John’s wort (SJW)對胺甲葉酸 (MTX) 動力學之影響…………………………………………………………………………79
2. SJW與MTX 交互作用機制探討………………………………………79
第四章 結果與討論…………………………………………………81
第一節　香椿之代謝動力學及對大鼠生化值之影響…………………81
第二節　白藜蘆醇保健食品 (RDS) 對 CsA、MTX 動力學之影響…87
第三節　牛奶薊保健食品 (MT) 對CsA、MTX動力學之影響…………94
第四節 聖約翰草 (SJW) 對MTX動力學之影響………………………97
第五章 結論………………………………………………………100
參考文獻………………………………………………………………102

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