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研究生:張峻豪
研究生(外文):Chun-Hao Chang
論文名稱:應用微透析技術探討未結合態咖啡因在大白鼠之藥物動力學及其與吳茱萸之交互作用
論文名稱(外文):Pharmacokinetic Study of Unbound Caffeine and Its Interaction with Evodia Rutaecarpa in Rat by Microdialysis
指導教授:何禮剛何禮剛引用關係蔡東湖蔡東湖引用關係
指導教授(外文):Li-Kang HoTung-Hu Tsai
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:藥理學研究所
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:2004
畢業學年度:92
語文別:中文
論文頁數:120
中文關鍵詞:微透析咖啡因藥物動力學吳茱萸
外文關鍵詞:microdialysiscaffeinepharmacokineticsEvodia rutaecarpa
相關次數:
  • 被引用被引用:2
  • 點閱點閱:355
  • 評分評分:
  • 下載下載:35
  • 收藏至我的研究室書目清單書目收藏:3
咖啡因為一種生物鹼並廣泛存在於日常飲食中。然而,卻鮮少人會注意咖啡因在人體內對我們所造成的影響。本實驗主要探討咖啡因的藥物動力學與P-醣蛋白於咖啡因藥物動力學中所扮演的角色,以及其與中藥,吳茱萸萃取物與其中藥複方,之交互作用。實驗以微透析 (microdialysis) 取樣技術結合高效液相層析 (HPLC) 系統,可以同時且連續性地偵測大白鼠血液、腦部與膽汁中游離態咖啡因。實驗大白鼠經麻醉後,由股靜脈給予咖啡因 (3與10 mg/kg),而以三組微透析探針,分別植入在右頸靜脈向右心房,腦部的紋狀體,以及膽管進行取樣,所得的透析液檢品可以直接以液相層析系統分析。並應用此分析方法於咖啡因藥物動力學及其與環孢靈素A (cyclosporin A) 和吳茱萸的交互作用之研究。
股靜脈給予咖啡因 3與10 mg/kg劑量下,咖啡因於血液中濃度時間曲線下面積 (AUC) 分別為710+124與2533+226 min □g/mL,AUC/Dose分別為184+30 and 249+22,於腦中AUC分別為226+27與1060+110 min □g/mL,於膽汁中708+111與3006+386 min □g/mL。由結果可得知,咖啡因3和10 mg /kg的劑量範圍呈現非線性藥物動力學模式,於血液、腦部與膽汁中濃度的下降,推測其可以於中樞及週邊快速的平衡交換;咖啡因可以穿越血腦障壁,並經由膽汁排泄。在併用環孢靈素A後,咖啡因的藥動學並沒有改變,雖然並無有關於影響咖啡因運輸機制的研究,而影響穿越血腦障與膽汁排泄有許多的因素,但是由本實驗結果認為P-醣蛋白可能不調節咖啡因運輸的機制。
吳茱萸萃取物與其中藥複方,經研究指出會誘導cytochrome P450 1A2。為評估咖啡因與中草藥的交互作用,將大白鼠口服給予吳茱萸次鹼 (25 mg/kg/day)、吳茱萸凍晶 (1 g/kg/day) 與吳茱萸湯 (1 g/kg/day),連續給予三天,至第四天以股靜脈給予咖啡因 (5 mg/kg),進行其藥物交互作用之研究。由結果可得知,預處理吳茱萸凍晶、吳茱萸次鹼與吳茱萸湯後,會顯著的減少咖啡因於大白鼠體內之濃度,咖啡因併用中草藥吳茱萸會發生交互作用,增加咖啡因的代謝速率。
總而言之,咖啡因3和10 mg /kg的劑量範圍呈現非線性藥物動力學模式;咖啡因可以穿越血腦障壁,並經由膽汁排泄;P-醣蛋白可能不調節咖啡因運輸的機制。中草藥的使用更應小心、謹慎,避免危害健康的交互作用產生。
Caffeine is an alkaloid and present widely in daily sources. However, few consumers give much attention in the fate of caffeine works in the body. This study focused on its pharmacokinetics as well the possible roles of the P-glycoprotein. In addition, to investigate the interaction of caffeine and herb-drug, Evodia rutaecarpa extract and its preparation were pretreated daily for three consecutively days. A method based on microdialysis technique and liquid chromatography that allows continuous and concurrent in vivo monitoring of extracellular unbound caffeine in the blood, brain and bile of anaesthetized rat following the administration of caffeine (3 or 10 mg/kg, i.v.) through the femoral vein. Sampling was achieved using three microdialysis probes which were implanted into jugular vein toward heart, brain striatum and bile duct. Dialysates of blood, brain and bile were directly injected onto the liquid chromatographic system. This method has applied in the pharmacokinetics of caffeine and its interaction in the presence of cyclosporin A and Evodia rutaecarpa.
Following caffeine administration, the results indicate that the area under the concentration versus time curve (AUC) of caffeine in blood was 710+124 and 2533+226 min □g/mL and the AUC/Dose ratios were 184+30 and 249+22, for the doses of 3 and 10 mg/kg after intravenous administration, respectively. These results suggest that the caffeine was characterized as nonlinear pharmacokinetics. The AUCs of caffeine in brain and bile were 226+27 and 1060+110, and 708+111 min □g/mL and 3006+386 min □g/mL for the dosages of 3 and 10 mg/kg, respectively. The decline of caffeine in the blood, striatum and bile suggested that caffeine was rapid exchange and equilibration between the peripheral compartment and the central nervous system. Caffeine was able to penetrate the blood-brain barrier as well as undergoing hepatobiliary excretion. Following treatment with cyclosporin A, the pharmacokinetic data of caffeine were not significantly difference. Although no direct transport studies were undertaken and multiple factors may affect brain penetration and hepatobiliary excretion, our results indicate that P-glycoprotein may not involve in these processes.
Evodia rutaecarpa extract and its preparation were applied for the inhibition of cytochrome P450 1A2. To assess the possible herb-drug interaction, the herbal ingredient (rutaecarpine 25 mg/kg, p.o.), ethanol extract of Evodia rutaecarpa (1 g/kg/day, p.o.) and the herbal preparation Wu-Chu-Yu-Tang (1 g/kg/day, p.o) were pretreated daily for three consecutively days and on the fourth day caffeine was administered (5 mg/kg, i.v.). The results indicate that the caffeine level was significantly decreased by the pretreatment of the extract of Evodia rutaecarpa, rutaecarpine and Wu-Chu-Yu-Tang with dose-related manner. It is suggested that the herb-drug interaction may occur through the induction of the metabolism of caffeine.
In conclusion, the pharmacokinetics of unbound caffeine appears in a dose-dependent manner at ranges of 3 to 10 mg/kg. Caffeine penetrated blood-brain barrier and underwent hepatobiliary excretion. The BBB entrance and biliary elimination of caffeine might not be affected by P-glycoprotein. In addition, our results warn the herbal medicine should be carefully used which may be a double-edge sword for the health care.
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