摘要
咖啡酸為屬於天然多酚類化合物中的酚酸類（phenolic acid）。酚酸類化合物相當常見於食物，而以咖啡酸含量最多，常以酯類型態存在，例如與qunic acid結合形成chlorogenic acid。在生理功用上主要具有清除自由基，抗發炎、過敏反應，此外也是許多中藥裡的藥理活性成分，因此近來愈來愈多致力於咖啡酸等類似化合物的相關研究。然而咖啡酸在大白鼠藥物動力學的部分多半以體外模式研究，較少體內模式的研究，其原因可能來自於定量分析上的不易及其本身安定性的問題。
因此本研究目的為 (1) 開發一個可定量在生物體液中咖啡酸濃度之毛細管電泳配合螢光偵測器的分析方法。(2) 以靜脈及口服投予咖啡酸於大白鼠評估其體內之動力學。(3) 投予與咖啡酸的運輸載體有關的臨床用藥probenecid和simvastatin，分別探討其交互作用。
實驗結果已成功開發並確效一毛細管電泳分析方法用來定量咖啡酸在動物體液內之濃度，且實際應用至大白鼠體內動力學研究。試驗發現咖啡酸在大白鼠體內有劑量依性的關係，推測可能在排除機轉牽涉載體媒介（carrier-mediated）或主動分泌現象。口服投與結果得知其生體可用率約16﹪。在交互作用方面，靜脈注射咖啡酸與probenecid併用之下，血漿濃度經時變化則未見明顯改變，而膽汁排除似乎有受到抑制的現象；但由於皆無顯著差異，故只能初步推測probenecid可能抑制了咖啡酸由膽汁分泌運輸載體，譬如MRP2。然而這還需要進一步的實驗證實。至於口服併用臨床用藥simvastatin時，其血中濃度經時變化圖有觀察到雙峰現象，但對整體藥動參數並無影響。
整體而言，咖啡酸在大白鼠體內藥物動力學呈現非線性，因此可能在代謝或排泄具有飽和現象。藥物交互作用的探討則顯示咖啡酸的膽汁排除可能會受probenecid抑制，因此推測咖啡酸的膽汁排除可能與MRP2相關。另外在口服併用monocarboxylate transporter受質simvastatin後並未觀察到顯著差異，然而其中可能牽涉劑量與投與途徑的關係，因此二者間的交互作用需要做進一步研究才可能釐清。

Abstract
Introduction. Caffeic acid is a natural phenolic compound, found abundant in foods. It usually exists in the form of ester, most frequently as caffeoyl ester, which is known as chlorogenic acid. The physiological benefits of caffeic acid include free radical scavenging, anti-inflammation, and anti-allergic effects. Recently, it is also identified as the active component in many Chinese herbal medicines and has diverse biological effects. Therefore, it is of great importance to assess the pharmacokinetics of caffeic acid. However, kinetic studies of caffeic acid has been limited mainly to in vitro rather than in vivo investigations, due to the lack of quantification methods for caffeic acid.

Purpose. The aim of this study was to develop an analytical method for caffeic acid using capillary electrophoresis (CE) coupled with laser induced fluorescence (LIF) detection, and to apply the method to evalute the pharmacokinetics of caffeic acid in rats following intravenous and oral administration. The effects of probenecid and simvastatin on the disposition and absorption kinetics of caffeic acid were also examined.

Results. A simple and sensitive CE-LIF method for the analysis of caffeic acid in biological fluids was developed and validated. The method was applied successfully to pharmacokinetic studies of caffeic acid. The disposition of caffeic acid in rats displayed dose-dependency. The nonlinearity of clearance suggested that carrier-mediated transport might be involved in the disposition of caffeic acid. The absolute bioavailability of caffecic acid was about 16%. Co-administration with probenecid intravenously did not alter the plasma concentration-time profile of caffeic acid, nevertheless, its biliary excretion appeared to be inhibited by probenecid, an inhibitor of MRP2. When simvastatin, a substrate of monocarboxylate transporter (MCT), was co-administered orally with caffeic acid, the maximal plasma concentration of caffeic acid was decreased and its plasma profiles showed distinct double peak phenomena.

Conclusion. In summary, the disposition kinetics of caffeic acid in rats was non-linear. In rats, the oral bioavailability of caffeic acid was 16%. Co-administration with probenecid, a potent inhibitor of transporter MRP2 reduced the levels of caffeic acid in bile, indicating that the bile secretion of caffeic acid might be mediated by this drug transporter. On the other hand, although simvastatin altered the plasma levels of caffeic acid, the effect did not reach statistical significance. Therefore, the role of MCT on the pharmacokinetics of caffeic acid remained to be clarified.

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