臺灣博碩士論文加值系統

黃芩甘元是中藥黃芩中類黃酮類物質之一，是由黃芩 (Scutellaria baicalensis Georgi) 植物根部所分離出的成分。中國已有多年的歷史用黃芩治療過敏、發炎的疾病。本實驗是探討黃芩甘元在大白鼠血液、腦部和膽汁中的動向及與環孢靈素A的交互作用。三支微透析探針同時分別置入雄性的SD大白鼠，經頸靜脈進入右心房、腦部的海馬迴和膽管。在股靜脈給黃芩甘元之後，以等張性的人造體液灌流採樣。
實驗設計兩組：控制組為六隻大白鼠單獨投與黃芩甘元 (10, 30和60 mg/kg的劑量)；給藥組為六隻大白鼠以右股靜脈投與環孢靈素A (20 mg/kg) 10分鐘之後再注射黃芩甘元。以非腔室模式計算藥物動力學參數。
黃芩甘元在大白鼠腦部的藥物動力學呈現劑量相關的現象，注射黃芩甘元20分鐘之後會在腦部達到最高濃度。黃芩甘元血與腦的分配係數分別為0.023 ±0.001 (30 mg/kg) 和 0.023 ±0.003 (60 mg/kg)。其計算方式為黃芩甘元在腦部的AUC除以相同劑量在血液AUC (k=AUCbrain/AUCblood)。而黃芩甘元血與膽汁的分配係數分別為0.21 ±0.01 (10 mg/kg)、0.18 ±0.04 (30 mg/kg) 和0.18 ±0.09 (60 mg/kg)。
實驗結果顯示黃芩甘元在血液的藥物動力學不受環孢靈素A影響，但在腦部和膽汁的AUC卻因環孢靈素A的加入而分別增加和減少。另外，我們以高效液相層析串聯質譜儀 (LC/MS/MS) 確定黃芩甘為黃芩甘元在膽汁的代謝物之一。血液和膽汁中黃芩甘的AUC皆比黃芩甘元高。本研究發現黃芩甘元可以穿過血腦障壁和進行膽汁排泄。此外，黃芩甘元在腦部及膽汁的動向可能會受到P-醣蛋白的調節。

Baicalein is one of the naturally occurring flavonoid, which is isolated from the rhizoma of in Scutellaria baicalensis Georgi. The herb has been used for amelioration of allergic and inflammatory diseases in Chinese for a long time. This study was to investigate the disposition of baicalein in rat blood, brain and bile, and its interaction in the presence of cyclosporin A. Three microdialysis probes were simultaneously inserted into the jugular vein toward right atrium, brain hippocampus and bile duct of a male Sprague-Dawley rat for biological fluids sampling after the administration of baicalein through the femoral vein.
The study design was parallel the following two groups: for the control-group, the six individual rats were received baicalein (10, 30 and 60 mg/kg) alone; for the cyclosporin A treated-group, a 20 mg/kg of cyclosporin A was concomitantly injected via the right femoral vein 10 min prior to baicalein injection in six individual rats. Pharmacokinetic parameters of baicalein were derived using a non-compartmental model.
The pharmacokinetic profile of baicalein in rat brain shows to be a dose relative phenomenon and reach a peak brain concentration at 20 min after baicalein administration. Following baicalein administration at doses of 30 and 60 mg/kg, the blood-to-brain coefficients of distribution were 0.023 ±0.001 and 0.023 ±0.003, respectively. This was calculated by dividing the area under the concentration-time curve (AUC) of baicalein in brain by the AUC in blood (k=AUCbrain/AUCblood) at its related dose. The blood-to-bile coefficients of distribution were 0.21 ±0.01, 0.18 ±0.04 and 0.18 ±0.09 at doses of 10, 30 and 60 mg/kg, respectively.
Our results indicate that the pharmacokinetics of baicalein in blood was not significantly altered by cyclosporin A, but increasing the AUC of baicalein in brain and decreasing the AUC of baicalein in bile, respectively as cyclosporin A was co-administrated. Furthermore, we use the liquid chromatographic tandem mass spectrometry (LC/MS/MS) to confirm that baicalin was one of the metabolites of baicalein in rat bile. The concentration of metabolite, baicalin, in blood and bile were higher than that of baicalein. These results reveal that baicalein was able to penetrate the blood-brain barrier and undergo hepato-biliary excretion. In addition, the disposition of baicalein in the brain and bile might be regulated by P-glycoprotein mediated transportation.

中文摘要 1
英文摘要 2
第一章緒論 3
第一節前言 3
第二節研究動機 15
第二章材料與方法 16
第一節實驗材料 16
一、儀器設備 16
二、化學試劑及藥品 17
三、藥品配製 17
四、微透析的製備 18
五、實驗動物 18
第二節黃芩甘元的藥物動力學研究方法 19
一、手術方法 19
二、藥物測定條件及方法 19
三、黃芩甘元檢量線的製作 20
四、測定方法的確認 20
五、回收率 21
六、藥物動力學研究 21
七、藥物動力學參數分析 22
八、藥物腸肝循環之研究 22
九、腦組織均質化及全血分析 23
十、腦組織均質化及全血分析的回收率 24
十一、黃芩甘元的蛋白質結合率 25
第三節代謝物-黃芩甘的藥物動力學研究方法 26
一、LC/MS/MS定性分析黃芩甘 26
二、黃芩甘的檢量線的製作 27
三、藥物測定條件及方法 27
四、測定方法的確認 27
五、手術方法 28
六、微透析探針體內回收率 28
七、藥物動力學研究 29
八、藥物動力學參數分析 30
九、藥物腸肝循環之研究 30
第四節統計方法 31
第三章研究結果 32
第一節黃芩甘元的藥物動力學研究 32
一、循環伏特安培圖 32
二、層析圖結果 32
三、測定方法的確認 33
四、微透析探針體內回收率 33
五、藥物濃度-時間的關係 34
六、藥物動力學參數 34
七、環孢靈素A的影響 35
八、藥物腸肝循環之研究 37
九、腦組織均質化及全血分析的回收率 37
十、腦組織均質化及全血分析 37
十一、黃芩甘元的蛋白質結合率結果 37
第二節黃芩甘的藥物動力學研究 38
一、LC/MS/MS定性分析結果 38
二、層析圖結果 38
三、測定方法的確認 38
四、微透析探針體內回收率 39
五、藥物濃度-時間的關係 39
六、藥物動力學參數及受環孢靈素A的影響40
七、藥物腸肝循環之研究 40
第四章討論 41
第一節高效液相層析法 41
第二節實驗動物模式 44
第三節藥物動力學參數的研究 45
第四節環孢靈素A的影響 48
第五節代謝物-黃芩甘 50
第六節腸肝循環 52
第五章結論 53
第六章參考文獻 54
表 65
圖 77
附錄研究發表論文 100

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