臺灣博碩士論文加值系統

水飛薊（silymarin）為一種暢銷且廣受歡迎的草藥萃取物，從古至今廣泛被用於肝臟保護方面。本研究的目的在於探討水飛薊以及其所含的主要活性成分水飛薊賓（silibinin），對於抗憂鬱劑查諾頓（trazodone）的藥物動力學影響。動物實驗採用平行設計，將雄性的SD大鼠隨機分配至六組中，分別為控制組、單一高劑量（1.0 g/kg，於查諾頓給藥前4小時口服）水飛薊組、低、高劑量水飛薊賓預處理組（劑量：0.175和 0.35 g/kg/day）、低及高劑量水飛薊預處理組（劑量：0.5和 1.0 g/kg/day），其中預處理組設計成連續七天管餵水飛薊賓或水飛薊。待各組接受完各種不同處置後，以靜脈注射方式給予大鼠5 mg/kg的查諾頓，以探討上述不同處置對於查諾頓的藥物動力學影響。本研究採用微透析技術採樣，以求同時收取來自於大鼠身上血液及膽汁中的非蛋白結合態查諾頓，繼之再以高效液相層析儀搭配螢光偵測器分析其中濃度。實驗結果顯示，當給予七天高劑量水飛薊（1.0 g/kg/day）預處理時，和控制組比較，血液中查諾頓的曲線下面積（AUC）明顯減少了43%，分佈半衰期（t1/2,α)以及排除半衰期（t1/2,ß）各減少了52及31%,平均滯留時間（MRT）也減少了44%。反觀，清除率則是顯著地增加61%，其餘各組則無統計上的差異存在。另外一方面，在查諾頓的膽汁排泄上，單一高劑量（1.0 g/kg，於查諾頓給藥前4小時管餵）水飛薊組較控制組減少了49%的曲線下面積，而其餘各組對於查諾頓的膽汁排泄之影響，不具有統計上的差異。本研究結果指出當給予連續七天大鼠水飛薊時，可能會誘導細胞色素P450（cytochrome P450）產生，進而促進了查諾頓的代謝作用。至於單一高劑量的水飛劑併用查諾頓則可能抑制了運輸機制（transporter），導致查諾頓的膽汁排泄遭受阻擾。有鑑於此，當查諾頓與水飛薊長期併用時，可能會產生潛在性的藥物交互作用（potential herb-drug interaction）。

Silymarin, one of the most popular herbal medicines, has been widely used for its hepatoprotective effects. The aim of this study is to investigate the effects of silymarin and its major ingredient silibinin on the pharmacokinetics of the antidepressant trazodone. Male Sprague-Dawley rats were randomly divided into six groups in a parallel design as follows: one group treated single-dose silymarin (1.0 g/kg) 4 h prior to the administration of trazodone, the control group treated with vehicle, two groups pretreated with 0.175 and 0.35 g/kg/day silibinin and another two groups treated with 0.5 and 1.0 g/kg/day silymarin for 7 consecutive days. A microdialysis coupled with high performance liquid chromatography system (HPLC) was used to simultaneously monitor blood and bile concentrations of trazodone in rats. The results indicate that pretreatment with 1.0 g/kg/day silymarin significantly decreases trazodone’s area under the concentration curve (AUC) by 43%, distribution half-life (t1/2,α) by 52%, elimination half-life (t1/2,ß) by 31%, and mean residence time (MRT) by 44%. In contrast, the clearance (Cl) is markedly increased by 61%. In addition, single-dose silymarin (1.0 g/kg) significantly decreased the AUC of trazodone in bile by 49% when compared with the control group. The results revealed that 7-day silymarin treatments might result in enhanced cytochrome P450 expression, which facilitated the metabolism of trazodone. Single-dose silymarin treatments might lead to the inhibition of transporter, which suppressed the bile excretion of trazodone. In conclusion, the present study points out a potential herb-drug interaction between long-term silymarin ingestion and trazodone.

Abstract 1
中文摘要 2
第一章　緒論 3
第一節　水飛薊（silymarin）及水飛薊賓（silibinin）之簡介與相關研究 3
1-1-1　研究背景 3
1-1-2　相關藥理作用及臨床使用 3
1-1-3　相關藥物動力學研究 4
第二節　查諾頓（trazodone）之簡介與相關研究 5
1-2-1　研究背景 5
1-2-2　相關藥理作用及臨床使用 6
1-2-3　相關藥物動力學研究 6
第三節　藥物動力學之簡介 7
1-3-1　概論 7
1-3-2　定義 7
1-3-3　藥物動力學參數—藥物濃度曲線下面積 10
1-3-4　藥物動力學參數—清除率 10
1-3-5　藥物動力學參數—分佈體積 10
1-3-6　藥物動力學參數—半衰期 11
1-3-7　藥物動力學參數—平均滯留時間 11
1-3-8　藥物動力學參數—膽汁排泄 12
第四節　微透析（microdialysis）之簡介 12
1-4-1　概論 12
1-4-2　微透析原理 13
1-4-3　微透析採樣裝置 13
1-4-4　微透析技術應用於藥物動力學上的優缺點 14
1-4-5　微透析技術的應用 16
第五節　草藥－藥物交互作用 16
第二章　研究動機與目的 18
第三章　實驗材料及方法 19
第一節　實驗材料 19
3-1-1　化學試藥 19
3-1-2　實驗儀器及裝置 19
3-1-3　實驗動物 21
3-1-4　應用軟體 21
第二節　水飛薊中水飛薊賓含量之測定 22
3-2-1　實驗藥品之配製 22
3-2-2　高效液相層析分析條件 22
第三節　以微透析技術探討水飛薊及水飛薊賓對大白鼠體內非蛋白結合之查諾頓於藥物動力學上影響 23
3-3-1　實驗設計與動物分組 23
3-3-2　實驗藥品之配製 24
3-3-3　微透析系統及取樣 24
3-3-4　微透析的實驗動物模式 25
3-3-5　高效液相層析分析條件 26
3-3-6　層析系統－檢量線之配製 26
3-3-7　層析系統–分析方法之確效 27
3-3-8　微透析探針之體內回收率（in vivo recoveries）測定 27
3-3-9　藥物動力學參數之計算 28
第四節　數據處理及統計方法 29
第四章　實驗結果 30
第一節　水飛薊中水飛薊賓含量之測定 30
4-1-1　水飛薊中水飛薊賓含量之測定 30
第二節　微透析取樣與大白鼠血液及膽汁中非蛋白結合查諾頓之分析 31
4-2-1　血液與膽汁透析液之查諾頓層析圖 31
4-2-2　層析系統之分析確效 31
4-2-3　血液與膽汁微透析探針之體內回收率 32
第三節　水飛薊及水飛薊賓對於大白鼠血液及膽汁中非蛋白結合查諾頓之影響 33
4-3-1　對於血液中非蛋白結合查諾頓之影響 33
4-3-2　對於膽汁中非蛋白結合查諾頓之影響 35
第五章　實驗討論 38
第一節　採樣與分析方法 38
第二節　水飛薊賓及水飛薊對於大白鼠體內非蛋白結合查諾頓之藥物動力學影響 39
5-2-1　對於血液中非蛋白結合查諾頓之影響 39
5-2-2　對於膽汁中非蛋白結合查諾頓之影響 43
第六章　結論 47
參考文獻 48

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