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研究生:葉津杏
研究生(外文):Chin-hsing Yeh
論文名稱:中藥藥引對抗排斥藥物吸收之影響
論文名稱(外文):The Effect of Chinese Herbal Enhancer on Cyclosporin A Bioavailability
指導教授:宋國峻宋國峻引用關係
學位類別:碩士
校院名稱:嘉南藥理科技大學
系所名稱:生物科技系暨研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:中文
論文頁數:90
中文關鍵詞:中藥藥引環胞靈
外文關鍵詞:P-glycoproteinCYP3A4FPIAChinese herbal enhancerNEORALmonoterpeneCyclosporin A
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P-glycoprotein (Pgp) 在人體中廣泛分佈於正常細胞表層,尤其腸道細胞中之Pgp造成藥物吸收不佳,而影響藥物治療的效果,所以提升藥物在腸胃道的吸收為口服藥物治療的一個重要課題。Cyclosporin A為一用於移植手術中抗排斥的免疫抑制劑,由於其為CYP3A4及Ppg之受質,故其口服生體可用率差且變異性大。若能併用CYP3A4及Ppg之抑制劑,便能提高cyclosporin A的生體可用率,降低其臨床使用劑量並可維持較穩定之血中濃度。
HUCHE為中藥藥引中純成分,為一單萜類化合物,廣泛地存在常見植物之精油中,經體外實驗發現HUCHE具有抑制Cytochrome 450及Pgp活性之作用。為瞭解HUCHE在活體中對不同cyclosporin A劑型之藥物動力學影響,本研究乃以大白鼠為模型,利用螢光偏極免疫定量法(Fluorescence Polarization Immunoassay, FPIA) 檢測大白鼠血液中的cyclosporin A濃度。在比較單服不同劑型配方之cyclosporin A (10 mg/kg) 之大白鼠血中cyclosporin A濃度的變化,其結果顯示以有機溶媒之劑型其口服吸收較以油相為溶媒之劑型好。而於不同劑型配方之cyclosporin A (10 mg/kg) 合併給予HUCHE之結果顯示,HUCHE可增加NEORAL®及配方1 (F1; alcohol, olive oil) 之口服吸收,其血中濃度曲線下面積AUC0~24分別增加54%及58% ( p<0.05)。各劑型之排除半衰期 (t1/2) 有增加之趨勢。而配方3 (F3; alcohol, Tween 80, propylene glycol) 併服HUCHE之劑型相較NEORAL®之AUC0~24增加2倍。而完全以橄欖油當溶劑之配方2 (F2; olive oil) 劑型併服HUCHE,其血中cyclosporin A最高濃度Cmax與血藥面積AUC0~24則有降低之趨勢。
由以上實驗結果得知,對某些配方而言,中藥藥引純成分HUCHE的確可以改善某些劑型cyclosporin A之口服吸收,因此併用cyclosporin A時預期可改善其臨床上低生體可用率及吸收差異之問題。
Physiologically, P-glycoprotein is widely expressed in the epithelial cells of tissue, especially in the intestine, which is one of critical factors in drug absorption and disposition. Cyclosporin A is an immunosuppressant that used to prevent allograft rejection in transplantation. Since it is a substrate of CYP3A4 and P-glycoprotein, the absorption of cyclosporin A is highly variable and with a poor bioavailibity. As a result, the use of P-glycoprotein and CYP3A4 inhibitors may properly increase the absorption of cyclosporin A and may decrease the dose needed as well as blood concentration fluctuation in cyclosporin A treatment. HUCHE is a compound of Chinese herbal enhancer. It is monoterpene found in the essential oil of several useful plants. It has been reported HUCHE may inhibit Cytochrome 450 and P-glycoprotein activity.
In this study, the rats were treated with different cyclosporin A formulations with and without HUCHE to explore the effect of Chinese herbal enhancer as well as formulation on cyclosporin A absorption. The blood cyclosporin A concentration was determined by fluorescence polarization immunoassay (FPIA). The results showed that organic-base solvent had better absorption than oil-base solvent. Different cyclosporin A (10 mg/kg) formulas coadministered HUCHE showed that HUCHE can increased NEORAL® and formula 1 (F1; alcohol, olive oil) oral absorption, and the area under the concentration-time curve from time zero to 24 hours (AUC0~24 ) increased 54% and 58% (p<0.05), respectively. The AUC0~24 of formula 3 (F3; alcohol, Tween 80, propylene glycol) with HUCHE compared with that of NEORAL® increased 2 folds. However, Cmax and AUC0~24 decreased in the olive oil formulation coadministered with HUCHE.
The study suggests that through the inhibition of CYP3A4 and P-glycoprotein, HUCHE may improve the bioavailability of some cyclosporin A formulas.
中文摘要……………………………………………………… Ⅰ
英文摘要……………………………………………………… Ⅲ
目錄…………………………………………………………… Ⅴ
表目錄………………………………………………………… Ⅶ
圖目錄………………………………………………………… Ⅹ
縮寫表………………………………………………………… XII
第壹章、緒論………………………………………………… 1
第一節、前言………………………………………………… 1
第二節、影響口服藥物生體可用率之因素:
P-glycoprotein及CYP3A………………………… 2
第三節、模式藥物:環孢靈 (Cyclosporin A)…………… 9
第四節、中藥藥引之簡介…………………………………… 11
第貳章、研究目的…………………………………………… 26
第參章、試劑儀器與實驗…………………………………… 27
第一節、藥品試劑與儀器…………………………………… 27
第二節、Cyclosporin A劑型設計………………………… 28
第三節、動物實驗…………………………………………… 29
第肆章、結果………………………………………………… 36
第伍章、討論………………………………………………… 43
第陸章、結論………………………………………………… 45
參考文獻……………………………………………………… 70
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