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研究生:陳怡琳
研究生(外文):I-Lin Chen
論文名稱:槲黃素與芸香素在大鼠血漿與淋巴液中之藥物動力學
論文名稱(外文):Pharmacokinetics of quercetin and rutin in rat plasma and lymph
指導教授:蔡東湖蔡東湖引用關係
指導教授(外文):Tung-Hu Tsai
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:傳統醫藥學研究所
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:2009
畢業學年度:97
語文別:中文
論文頁數:72
中文關鍵詞:槲黃素芸香素藥物動力學淋巴淋巴吸收動物模式
外文關鍵詞:quercetinrutinpharmacokineticslymphlymphatic absorptionanimal model
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偏脂溶性的物質、或是具有巨大分子的物質容易被吸收進入淋巴系統,並因此避免受到肝臟首渡效應的代謝,直接注入全身血液循環中。本實驗目標在於建立一個可以適用於探討口服投與藥物在血液及淋巴系統中藥物動力學之淋巴管插管動物模式。本實驗使用槲黃素作為待測藥物,建立麻醉下十二指腸與腸間淋巴管插管的大鼠模式,用以探討淋巴性吸收在腸內藥物吸收中所佔的角色。槲黃素溶解於PEG400比乙醇為4比1體積比之混合溶液中,以30 mg/kg之劑量投與至動物模式之十二指腸內。淋巴液與血液樣品為每30分鐘採集一次,以乙腈蛋白質沈澱法處理後,注入高效液相層析結合紫外光偵測系統中分析。分離槲黃素使用矽基質逆相碳18的分析管柱,並以磷酸二氫鈉(10 mM,pH值為2.75)比乙腈為55比45體積比之混合溶液作為固定梯度的移動相。
藥物動力學參數的計算利用電腦程式WinNonlin標準版1.1。於淋巴液中所測量到槲黃素的最高濃度(Cmax)為1.97 ± 0.96 μg/mL,約為於血液中所測量到濃度0.41 ± 0.08 μg/mL的4至5倍,而槲黃素於淋巴液中達到最高濃度所需時間(Tmax)較血液中之最高濃度點要多出30分鐘。
在第二部份的實驗中,利用前半實驗所建立的麻醉下腸間淋巴管插管大鼠模式,探討十二指腸內投與芸香素之微血管吸收及淋巴吸收。芸香素為一廣泛利用的營養補給品,以及治療人類淋巴性水腫、犬貓乳糜胸之傳統藥物。芸香素溶解於PEG400比乙醇為4比1體積比之混合溶液中,以300 mg/kg之劑量投與至動物模式之十二指腸內。淋巴液與血液樣品為每30分鐘採集一次,以乙腈蛋白質沈澱法和離心真空乾燥處理後,以乙腈與醋酸銨(10 mM,pH值為3.75)的混合溶液(20:80,v/v)回溶並注入高效液相層析結合紫外光偵測系統中分析。分離芸香素使用苯基分析管柱,並以醋酸銨(10 mM,pH值為3.75)與乙腈設定濃度梯度隨時間而改變的移動相。
藥物動力學參數的計算利用電腦程式WinNonlin標準版1.1。於淋巴液中所測量到芸香素的最高濃度為0.86 ± 0.13 μg/mL,稍小於血液中測到芸香素的最高濃度1.35 ± 0.37 μg/mL。但是芸香素在淋巴液中計算出的曲線下面積(AUC)為359.3 ± 41.0 min.μg/mL,約為血液中所計算出的曲線下面積150.0 ± 22.2 min.μg/mL的2倍。造成這個現象的原因是由於在淋巴系統中,芸香素的濃度降低幅度較在血循系統中來得緩慢。芸香素於血液與淋巴液中達到最高濃度所需時間為相同的。
本實驗證明原型的芸香素藥物分子可直接被吸收進入小腸絨毛中的微血管與乳糜管中,而不一定需要經過腸內微生菌叢的水解作用後才可被生體吸收。與槲黃素相較,芸香素更傾向由小腸絨毛內微血管所吸收與運輸,這個結果與芸香素有較高的親水性是相符合的。
Hydrophobic substances and macro-molecules absorbed via the lymphatic system can avoid hepatic first-pass effect and directly enter the blood circulation system. In this study, it was aimed to set up a lymphatic-cannulated animal model suitable for conducting the pharmacokinetic study of orally administered drugs in lymphatic and blood circulating system. Using quercetin as a testing drug, an anesthetized, mesenteric lymphatic/duodenum-cannulated rat model was established to investigate the role of lymphatic absorption with intra-duodenally administered drugs. Quercetin dissolved in PEG400:ethanol [4:1 (v/v)] solution was administered at a dosage of 30 mg/kg intra-duodenally. Lymph fluid and plasma samples were collected every 30 min. These samples were prepared by protein precipitation, and then analyzed by high performance liquid chromatography with an ultra-violet detector. Quercetin was separated by a C18 reversed-phase column. The mobile phase consisted of acetonitrile and 10 mM NaH2PO4 (38:62, v/v, pH 2.75).
Pharmacokinetic study was carried out using the software WinNonlin Standard Edition Version. The maximun concentration (Cmax) of quercetin recovered in lymph, 1.97 ± 0.96 μg/mL, was about five-fold higher than that in plasma, 0.41 ± 0.08 μg/mL. The time to reach the highest concentration (Tmax) of quercetin in lymph fluid after quercetin intra-duodenal administration was 30 minutes longer than that in plasma.
In the second part of the study, the established anesthetized, mesenteric lymphatic/duodenum-cannulated rat model was used to explore the capillary absorption and lymphatic absorption of intra-duodenally administered rutin. Rutin is a nutritional supplement and a drug treating lymphedema and chylothorax in ethnomedicine and veterinary medicine. Rutin dissolved in PEG400:ethanol [4:1 (v/v)] solution was administered at a dosage of 300 mg/kg intra-duodenally. Lymph fluid and plasma samples were collected every 30 min. These samples were prepared by protein precipitation and dried to dryness, and then re-dissolved with acetonitrile and 10 mM ammonium acetate (20:80, v/v, pH 3.75) and analyzed by high performance liquid chromatography with an ultra-violet detector. Rutin was separated by a phenyl column. The gradient mobile phase consisted of acetonitrile and 10 mM ammonium acetate (pH 3.75).
Pharmacokinetic study was carried out using the software WinNonlin Standard Edition Version. The maximun concentration of rutin recovered in lymph, 0.86 ± 0.13 μg/mL, was slightly lower than that in plasma, 1.35 ± 0.37 μg/mL. But the area under curve (AUC) value of rutin recovered in lymph, 359.3 ± 41.0 min.μg/mL, was about two-fold higher than that in plasma, 150.0 ± 22.2 min.μg/mL. This phenomenon was due to the milder concentration decline of rutin in lymphatic system. The time to reach the highest concentration of rutin in lymph fluid after rutin intra-duodenal administration was equal to that in plasma.
This study proved that rutin could be directly absorbed into intestinal capillaries and lacteal ducts without hydrolysis by intestinal microflora. Compared to quercetin, rutin was more likely to be absorbed into intestinal capillaries than into lacteal ducts. This result corresponded with the higher hydrophilicity of rutin than quercetin.
附表目錄 III
附圖目錄 IV
Abstract V
中文摘要 VII
第一章 序論 1
1-1 淋巴系統 1
1-1-1 淋巴系統與淋巴吸收簡介 1
1-1-2 淋巴吸收的重要性與應用性 2
1-1-3 應用於探討淋巴吸收之動物模式簡介 4
1-2 槲黃素(quercetin)簡介 5
1-3 芸香素(rutin)簡介 6
1-4 藥物動力學(pharmacokinetics)簡介 8
1-4-1 藥物動力學 8
1-4-2 藥物動力學模式 8
1-4-3 藥物動力學參數-藥物濃度曲線下面積 10
1-4-4 藥物動力學參數-清除率 10
1-4-5 藥物動力學參數-分布體積 11
1-4-6 藥物動力學參數-平均滯留時間 11
1-4-7 藥物動力學參數-半衰期 12
1-5 研究動機與目的 12
第二章 實驗材料與方法 14
2-1 實驗材料 14
2-1-1 實驗試劑 14
2-1-2 儀器設備 14
2-1-3 實驗動物 15
2-2 手術過程 15
2-3 利用麻醉下腸間淋巴管插管大鼠模式探討血液與淋巴液中槲黃素藥物動力學 16
2-3-1 藥物投與及檢體採集 16
2-3-2 液相層析系統 16
2-3-3 藥品配製方法 17
2-3-4 檢量線之配製 17
2-3-5 樣品前處理 18
2-3-6 方法確效 18
2-3-7 回收率 19
2-4 利用麻醉下腸間淋巴管插管大鼠模式探討血液與淋巴液中芸香素藥物動力學 19
2-4-1 藥物投與及檢體採集 19
2-4-2 液相層析系統 19
2-4-3 藥品配製方法 20
2-4-4 檢量線之配製 20
2-4-5 樣品前處理 20
2-4-6 方法確效 21
2-4-7 回收率 21
2-5 藥物動力學計算與統計方法 22
第三章 實驗結果 23
3-1 利用麻醉下腸間淋巴管插管大鼠模式探討血液與淋巴液中槲黃素藥物動力學之分析結果 23
3-1-1 血液與淋巴液中的藥物層析分析 23
3-1-2 利用高效液相層析系統的穩定性與分析校正曲線之確認 23
3-1-3 血液與淋巴液檢體分析前處理的回收率 24
3-1-4 槲黃素在血液與淋巴液中的經時變化 25
3-1-5 槲黃素在血液與淋巴液中之藥物動力學參數結果 25
3-2 利用麻醉下腸間淋巴管插管大鼠模式探討血液與淋巴液中芸香素藥物動力學之分析結果 26
3-2-1 血液與淋巴液中的藥物層析分析 26
3-2-2 利用高效液相層析系統的穩定性與分析校正曲線之確認 27
3-2-3 血液與淋巴液檢體分析前處理的回收率 27
3-2-4 芸香素在血液與淋巴液中的經時變化 28
3-2-5 芸香素在血液與淋巴液中之藥物動力學參數結果 29
第四章 實驗討論 30
4-1 實驗動物模式之選擇 30
4-2 槲黃素與芸香素之分析方法 32
4-3 槲黃素於血液與淋巴系統中之藥物動力學研究 33
4-4 芸香素於血液與淋巴系統中之藥物動力學研究 35
第五章 結論 38
參考文獻 40
附錄 48
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