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研究生:高于涵
研究生(外文):Yu-Han Kao
論文名稱:探討flavonoids調節P-glycoprotein引起的多重抗藥性之研究
論文名稱(外文):Modulation of Flavonoids on P-glycoprotein-mediated Multidrug Resistance
指導教授:何秀娥
學位類別:碩士
校院名稱:臺北醫學大學
系所名稱:藥學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2008
畢業學年度:96
語文別:中文
論文頁數:71
中文關鍵詞:P-glycoprotein多重抗藥性人類結腸癌症細胞株fexofenadine
外文關鍵詞:P-glycoproteinMDRflavonoidsHCT15 cellsfexofenadine
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Flavonoids是植物的二次代謝多酚化合產物,富含在現代人的日常飲食中,包括蔬果和中草藥,一般認為flavonoids的抗氧化、抗病毒、和抗癌能力可促進人類健康。此外,研究指出Flavonoids會與腸道的運輸蛋白產生交互作用,尤其是P-glycoprotein (P-gp)。P-gp是一種廣泛存在於人體中具有170-kDa的運輸蛋白,而P-gp的過度表現和腫瘤細胞的抗藥性 (MDR) 有密切的關係。利用中草藥成分抑制P-gp作用,改變腫瘤細胞的多重抗藥性為一新穎的研究。本研究之體外試驗,利用人類腸道腺癌細胞 (HCT-15 cells),以fexofenadine作為P-gp受質藥物,分析flavones、flavonols、flavanols和isoflavones四種類的flavonoids成分,探討此四類flavonoids成分對於P-gp活性抑制之能力,並藉由此實驗討論flavonoids結構與抑制P-gp活性能力的關係。體外試驗發現galangin、apigenin和baicalein具有高度抑制P-gp活性的能力,並歸納出flavonoids結構上的OH基數量、立體結構以及疏水性為影響flavonoids抑制P-gp活性能力的因子。本研究之體內試驗,實驗動物兔子併服baicalein和fexofenadine,baicalein會經由抑制P-gp而明顯地增加fexofenadine的生體可用率。因此,flavonoids確實會與P-gp受質藥物產生交互作用,而baicalein可能為一有潛力的可改變多重抗藥性之調控劑。
Flavonoids are a subclass of dietary polyphenolic compounds present in fruits, vegetables, and herbal plants and are proposed to promote human health by their antioxidant, antiviral, or anticarcinogenic properties. They are suggested to interact with intestinal transport systems including P-glycoprotein (P-gp). Overexpression of the 170-kDa P-gp has been associated with the multidrug resistance (MDR) of cancer cells. The inhibition of P-gp by herbal constituents may provide a novel approach for reversing multidrug resistance in tumor cells. Using human colorectal adenocarcinoma (HCT15) cells as an in vitro model and fexofenadine as a P-gp substrate, four flavonoid families (flavones, flavonols, flavanols, and isoflavones) were evaluated for their inhibitory effects on P-gp to create a structure-activity relationship (SAR). The in vitro data show that galangin, apigenin, and baicalein possess high inhibitory effect on P-gp activity. We may conclude from our results that the number of hydroxyl groups, dimensional structure, and the hydrophobicity of flavonoids play significant influences on their inhibitory effects. The bioavailability of fexofenadine in the rabbits co-administration with baicalein, which inhibits the efflux pump P-gp, is increased significantly compared with the control. The findings of this study indicate potential flavonoids-drug interactions with P-gp substrates. Furthermore, baicalein could be a useful strategy for the development of potential modulators and a promising reversal agent for overcoming MDR.
目錄 I
附表目錄 III
附圖目錄 IV
中文摘要 VI
Abstract VII
縮寫表 VIII
第一章 緒論 1
第一節 研究背景介紹 2
一、 多重抗藥性(MDR) 2
二、 P-glycoprotein(P-gp) 5
(一) P-glycoprotein的特性 5
(二) P-glycoprotein的結構功能及其分佈 6
(三) P-glycoprotein與藥物動力學的影響 9
(四) P-glycoprotein的受質及作用機轉 11
(五) P-glycoprotein的抑制劑及其調控機轉 13
三、 Flavonoids 16
第二節 研究動機與目的 20
第二章 實驗材料與方法 22
第一節 實驗材料 22
第二節 儀器設備 24
第三節 實驗方法 25
一、 Fexofenadine分析方法之開發與確立 25
(一) Fexofenadine標準品溶液之配製 25
(二) LC/MS/MS分析方法 25
(三) 分析方法確效 26
二、 建構P-glycoprotein體外細胞模式 27
(一) 細胞株 27
(二) P-gp受質藥物與濃度 29
(三) 培養時間 29
三、 評估flavonoids調控P-gp活性之試驗 31
(一) 試藥flavonoids標準品溶液之配製 31
(二) Flavonoids對fexofenadine在HCT-15 cells的藥物累積量之影響評估 31
四、 動物試驗 34
(一) 實驗動物 34
(二) 試驗方法 34
(三) 血漿檢品處理 35
(四) 藥物動力學數據分析 35
第三章 結果與討論 36
第一節 Fexofenadine的分析方法之建立與確效 36
一、 LC/MS/MS分析方法之開發與建立 36
二、 Fexofenadine在細胞中之分析方法確效 37
三、 Fexofenadine在血漿中之分析方法確效 41
第二節 建構P-glycoprotein體外細胞模式 44
一、 細胞株 44
二、 P-gp抑制劑 44
三、 P-gp受質藥物與濃度 45
四、 培養時間 48
第三節 評估flavonoids調控P-gp活性之試驗 50
第四節 動物口服fexofenadine試驗 62
第四章 結論 65
參考文獻 67
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