Isoferulic acid 在家兔體內之藥物動力學研究
Pharmacokinetic studies of isoferulic acid in rabbits
中文摘要
Isoferulic acid 存在於一些常見的生藥材中, 如升麻(Cimicifugae Rhizoma)及威靈 仙(Clematidis Radix), 此外, 蜂膠(Propolis)中亦含有微量的 isoferulic acid。在過去 所發表的研究報告中, 被證實具有抗發炎、鎮痛、退熱、消腫及降血糖……等作用, 不過isoferulic acid 在藥物動力學方面卻無相關的研究報告發表, 為了對 isoferulic acid 在生物體內的藥物動態有更深一層的了解, 本實驗以家兔為對象, 給予靜脈 注射及口服投與兩種方式投與isoferulic acid, 以觀察 isoferulic acid 在家兔體內的 藥物動力學表現。
本實驗之分析方法乃利用逆相高效液相層析管柱配合波長320 nm 之紫外光檢測。
在血漿濃度範圍為每毫升0.01 至 50 微克間, 呈現良好的線性關係( r2 =0.9997) ; 同次間分析之變異係數為1.88 13.51%, 異次間分析之變異係數為 1.39 14.04%。而尿液濃度範圍為每毫升 0.05 至 100 微克間, 亦呈現良好的線性關係 ( r2 =0.9978) ; 同次間分析之變異係數為 1.22 11.06%, 異次間分析之變異係數 為1.08 8.98%, 顯示此兩者皆為良好之分析方法。
本實驗中在isoferulic acid 的安定性方面, 由實驗結果顯示, 於室溫中(25C)不同 酸鹼值下(pH2.66 9.60), isoferulic acid 均非常安定, 而無降解的現象發生; 此外, 在全氧狀態下, 尿液中 isoferulic acid 亦表現非常安定而無降解情形。
在動物實驗方面, 本實驗先以三種不同劑量 2 mg/kg、5 mg/kg、25 mg/kg 之 isoferulic acid 靜脈投與至六隻家兔, 分析其血漿中濃度變化情形, 結果顯示 isoferulic acid 於家兔體內的藥物動態符合二室性藥物動力學模式。而在此劑量範 圍下呈現does-independent 之藥物動力學特性, 藥物動力學參數 half-life, half- life, K10, K12, K21, Vd, ClT 並無統計學上之差異; 排除半衰期( half-life)分別為 13.883.95 , 13.331.91 , 14.000.95 分鐘, 清除率(ClT)別為 23.754.83 , 20.92
2.13 , 21.332.87 ml/min ; 其曲線下面積(AUC)分別為 88.6022.78 , 266.5436.86 , 1382.67172.19 gmin/ml, 與劑量之間呈現良好的線性比例關係(Y = 1.04X + 1.30 , r2 = 0.9805)。
以口服投與劑量25 mg/kg 之 isoferulic acid 於六隻家兔, 分析其結果, 發現其血漿 中isoferulic acid 之動態與靜脈注射投與之結果不甚相同, 屬於一室性藥物動力學 或二室性藥物動力學模式, 而其曲線下面積(AUC)為 306.9024.22 gmin/ml 與 靜脈注射25 mg/kg 之 isoferulic acid 之數據相比較, 獲得口服投與 isoferulic acid 之絕對生體可用率(FP.O.)為 0.220.03。
另一方面, 由實驗結果顯示, isoferulic acid 經由腎臟排出的比例非常低(小於 1%), 但在與glucuronic acid 進行抱合反應的生成比例上卻高達 37.4912.25 %, 由此推 論, 腎臟並非 isoferulic acid 的主要排除途徑, 而首途效應及其他器官的代謝才是 isoferulic acid 的主要代謝管道。
英文摘要
Isoferulic acid is the major constituent of Cimicifugae rhizoma and Clematidis radix.
In previous papers, isoferulic acid has been demonstrated to have anti-inflammatory, hypothermic, antipyretic, antiedematous, and anti-hyperglycemic effects. Although isoferulic acid has several pharmacological actions, the pharmacokinetics of isoferulic acid has not been studied. The aim of this studies was to investigate the
pharmacokinetics of isoferulic acid in the rabbits.
An accuracy, simple and specific high performance liquid chromatographic (HPLC) method was developed to detect the isoferulic acid in biological sample firstly. A C18 reverse phase column with UV detection at 320 nm was used in chromatographic separation. The calibration curve of plasma sample shows good linearity within the concentration range of 0.01 to 50 g/ml ; the calibration curve of urine sample also shows good linearity within the concentration range of 0.05 to 100 g/ml. The coefficients of variation (C.V.) of the within-run and between-run validation are all within 15%.
The stability of isoferulic acid in various pH buffer solutions were investigated. The result shows that isoferulic acid was very stable in pH 2.66 9.60 at room
temperature (25C), and there was no degradation of isoferulic acid. Besides, the stability of isoferulic acid in urine under air was also very stable and no degradation.
The pharmacokinetics of isoferulic acid was studied by intravenous administration of three different doses (2, 5, 25 mg/kg) in six rabbits, respectively. The plasma
concentration-time profiles of isoferulic acid could be descried by a bi-exponential equation with each dose. The elimination half-life are 13.883.95, 13.331.91, 14.000.95 minutes , and systemic clearance(ClT) are 23.75 4.83, 20.922.13, 21.332.87 ml/min. There are no significant difference in elimination half-life and systemic clearance of isoferulic acid under these three doses. The area under the curves (AUCs) calculated from time zero to infinite are 88.6022.78, 266.5436.86, 1382.67172.19 gmin/ml. It is proportional to the dose administrated. It indicated that isoferulic acid may be have dose-independent pharmacokinetics between 2 ~ 25 mg/kg IV injection.
In addition, 25 mg/kg of isoferulic acid was oral administration to six rabbits. The concentration-time profiles of plasma could be fitted by one-compartment model or two-compartment model. The area under the curves (AUCs) was 306.9024.22
gmin/ml. Comparing with that of intravenous administration in the dose of 25 mg/kg , the absolute bioavailability of isoferulic acid was 0.220.03 through the oral administration.
On the other hand, the ratio of isoferulic acid excreted from kidney was less than 1%,
but percentages of glucuronidation for isoferulic acid is more than 37.4912.25%. It shows that first-pass effect of liver and other tissue were major pathway of
metabolism for isoferulic acid instead of kidney.
