Caffeic acid 及其酯類化合物在家兔體內之藥物動力學研究

Caffeic acid 為一多酚類化合物, 廣泛存於植物界中, methyl caffeate ethyl caffeate 為 caffeic acid 之酯類衍生物,三者皆具有 抑制 5-lipoxygenase 及 12-lipoxygenase 的活性, 故可抑制過敏反 應, 並且亦可抑制血小板的凝集作用。本實驗利用高效液相層析法定量, 對 caffeic acid, methyl caffeate 及 ethyl caffeate 進行安定性試 驗, 再以雄性家兔為實驗動物 , 分別靜脈注射與口服投予等莫耳數( 0.056 mmole/kg )之caffeic acid, methyl caffeate 及 ethyl caffeate, 建立三者在家兔體內的藥物動力學。實驗結果顯示,於不同 pH 值下 caffeic acid,methyl caffeate 及 ethyl caffeate 於 pH 值 2-5 具有較好之安定性.在 0℃下, caffeic acid, methyl caffeate 及 ethyl caffeate 於全血中之安定性較於 25℃好. 在 25℃下 caffeic acid, methyl caffeate 及ethyl caffeate 於酸化的血漿中,具有較好之 安定性。靜脈投予家兔每公斤體重 7.5, 10 或 15 毫克 caffeic acid, 此劑量範圍內 caffeic acid 藥物動力學呈 dose independent。口服投 予家兔每公斤體重 0.056 毫莫耳 caffeic acid,其藥物動力學呈現 flip-flop的現象.另外 caffeic acid 口服之生體可用率為 0.34±0.10.靜脈投予 methyl caffeate 或 ethyl caffeate, 代謝生成 caffeic acid 之比例分別為 0.18±0.09 及 0.63±0.12. 口服投予 methyl caffeate 或 ethyl caffeate, 代謝生成 caffeic acid 之比例 為 0.16±0.02 及 0.20±0.08 . 由此可知, 口服投予methyl caffeate 及 ethyl caffeate 並無法增加 caffeic acid 之生成, 而以靜脈投予, ethyl caffeate 水解生成 caffeic acid 比例比 methyl caffeate 多。 Caffeic acid(3,4-dihydroxycinnamic acid), a natural phenolic compound, is widely distributed in vegetable and coffee products. Methyl caffeate and ethyl caffeate are caffeic acid derivatives by esterification of caffeic acid These three compounds can inhibit the platelet aggregation and thromboxane biosynthesis. The stability of caffeic acid, methyl caffeate and ethyl caffeate was investigated. The result shows that caffeic acid, methyl caffeate and ethyl caffeate are stable in pH range 2-5. These three compound in whole blood are more stable at 0℃ than at 25℃. In addition, these compounds are more stable in acidified plasma than in unacidified plasma at 25℃. After i.v. bolus 7.5, 10 and 15 mg/kg of caffeic acid to rabbits, the pharmacokinetic parameters, systemic clearance, elimination rate constant, and volume of distribution, in the dose range show dose independent. The concentration-time curve can be fitted by two compartment model for caffeic acid, methyl caffeate and ethyl caffeate after i.v. bolus of 0.056 mmole/kg of these three compounds (equivalence to 10 mg/kg of caffeic acid) to rabbits respectively. It shows that caffeic acid after oral administration follows flip-flop pharmacokinetics. The bioavailability of caffeic acid after oral administration is 0.39±0.24. The formation fraction of caffeic acid after i.v. bolus of methyl caffeate and ethyl caffeate are 0.18±0.09 and 0.63±0.12. After oral administration of methyl caffeate and ethyl caffeate, respectively, the formation fraction of caffeic acid are 0.16±0.02 and 0.20±0.08. It shows that methyl caffeate and ethyl caffeate can't improve caffeic acid bioavailability after oral administration. After i.v. bolus, ethyl caffeate hydrolyzed to formation of caffeic acid is larger than that of methyl caffeate.