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研究生:謝緯賢
研究生(外文):Wei-Hsien Hsieh
論文名稱:TW01之藥物動力學研究
論文名稱(外文):Pharmacokinetic Studies on TW01
指導教授:王惠珀王惠珀引用關係
指導教授(外文):Hui-Po Wang
學位類別:碩士
校院名稱:長庚大學
系所名稱:天然藥物研究所
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:2003
畢業學年度:91
語文別:中文
論文頁數:54
中文關鍵詞:TW01藥物動力學cremophor EL生體可用率半衰期清除率口服靜脈注射
外文關鍵詞:TW01pharmacokineticcremophor ELbioavailabilityhalf-lifeclearanceoralintravenous
相關次數:
  • 被引用被引用:6
  • 點閱點閱:217
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  • 下載下載:0
  • 收藏至我的研究室書目清單書目收藏:0
目前臨床上所使用之抗癌藥,均屬細胞毒藥物 (cytotoxic agents),治療癌症之外的副作用極大,且效果並不理想。本實驗室合成一系列抗癌新化合物,其中TW01於in vitro藥理活性篩選時顯示其顯著地抑制多種癌細胞株的活性,此外TW01於in vivo之藥理實驗,對裸鼠之血管增生有顯著地抑制作用。鑒於尋得藥物動力學最適化的配方將可促進藥效活性,因此本實驗之目的為建立TW01之分析方法並進行藥物動力學之研究。
於本實驗中,我們以高壓液相層析儀建立TW01之分析方法。本實驗分析方法之回收率為96.36 ± 7.31 %,最低可偵測濃度 (LOD)為3.90 ng/mL,最低可定量濃度 (LOQ) 為7.81 ng/mL,分析方法之確效藉由評估同日內、異日間實驗之精密度與準確度而完成,實驗之變異係數於15 %以內,相對誤差於20 %以內。
分析方法建立以後,分別給予Wistar大白鼠口服30 mg/Kg及尾靜脈注射0.7 mg/Kg之TW01,並建立個別之藥物血漿濃度-時間之資料,然後將藥物血漿濃度-時間之資料輸入WinNonlin軟體並選擇非室模式計算藥物動力學參數。本實驗中,TW01經靜脈注射 (將3.6 mg 的TW01溶於7.5 mL 之Cremophor EL : ethanol = 1 : 1溶媒中,使成為濃度0.48 mg/mL之溶液) 後的曲線下面積 (AUC) 為1.31 ± 0.56 hr.μg/mL,最高血中濃度 (Cmax) 為1.58 ± 0.67 μg/mL,清除率為768.62 ± 373.91 mL/hr/Kg,分佈體積為1384.54 ± 709.60 mL/Kg,半衰期 (t1/2) 為2.34 ± 1.31小時,平均滯留時間為1.78 ± 0.40小時。以 (Cremophor EL : ethanol = 1 : 1) : H2O = 19 : 1為溶媒口服投予TW01後,曲線下面積 (AUC) 為0.52 ± 0.14 hr.μg/mL,於口服後1.06 ± 0.33小時 (Tmax) 達到最高血中濃度 (Cmax) 0.18 ± 0.09 μg/mL,清除率為677.86 ± 359.20 mL/hr/Kg,分佈體積為1991.92 ± 927.07 mL/Kg,半衰期 (t1/2) 為2.70 ± 1.54 hr,平均滯留時間為3.16 ± 1.26 hr,口服投予TW01 (30 mg/Kg) 之生體可用率為1.14 ± 0.61 ﹪。
由實驗的結果顯示,TW01以口服的途徑投予動物體內,其生體可用率不佳,造成此結果的原因,可能與未找到適當之媒液以增加TW01之溶解度有關。然而罹患HA22T腫瘤之裸鼠口服10 mg/Kg之TW01卻有顯著之抗腫瘤活性,因此有必要尋找更適當的媒液增加TW01之溶解度,使得在藥物動力學方面之結果達到最適化。
Anti-cancer drugs currently used are classified as cytotoxic agents. These drugs not only caused side effects but also showed low efficacy. TW01, a compound synthesized in our laboratory showed profound in vitro anticancer activities against a variety of human tumor cell lines. This compound also showed significant anti-angiogenesis effect in mice. As optimized formulation of drug pharmacokinetic (PK) profile can improve drug pharmacodynamic activity, this study aims to establish the analytical method to investigate the PK profile of TW01.
In this study, assay method for analyzing TW01 in biological fluid was first established by HPLC. Under this method, the recovery rate was 96.36 ± 7.31 %. The limit of detection (LOD) and the limit of quantitation (LOQ) were 3.90 ng/mL and 7.81 ng/mL, respectively. Validation was made by the evaluation of the intra-day and inter-day precision and accuracy. The coefficient of variation was 15 % and the relative error was 20 %.
TW01 was then administered orally (30 mg/Kg) or injected intravenously (0.7 mg/Kg) into the tail vein of Wistar rats. Plasma concentration-time profile of TW01 was established. The pharmacokinetic parameters were determined by calculation with WinNonlin program based on the noncompartment model from the plasma concentration-time data. After i.v. injection of TW01 (0.48 mg/mL, a solution of 3.6 mg TW01 in 7.5 mL of Cremophor EL : ethanol = 1 : 1 solvent), the AUC was 1.31 ± 0.56 hr.μg/mL . The maximum blood concentration (Cmax) was 1.58 ± 0.67 μg/mL. The clearance was 768.62 ± 373.91 mL/hr/Kg and the volume of distribution was 1384.54 ± 709.60 mL/Kg. The half-life was 2.34 ± 1.31 hours and the mean residue of time (MRT) was 1.78 ± 0.40 hours. The AUC after oral administration of TW01 (a suspension of 57.8 mg TW01 in 36.0 mL of (Cremophor EL : ethanol = 1 : 1) : H2O = 19 : 1 solvent) was 0.52 ± 0.14 hr.μg/mL. The maximum blood concentration of TW01 (Cmax) was 0.18 ± 0.09 μg/mL and the time to reach maximal concentration (Tmax) was 1.06 ± 0.33 hours. The clearance was 677.86 ± 359.20 mL/hr/Kg and the volume of distribution was 1991.92 ± 927.07 mL/Kg. The half-life was 2.70 ± 1.54 hours and the mean residue of time was 3.16 ± 1.26 hours. Oral bioavailability of TW01 (30 mg/Kg) was calculated to be 1.14 ± 0.61 %.
The low oral bioavailability might be due to the low solubility of TW01 in Cremophor EL : ethanol = 1 : 1 vehicle. As low dose (10 mg/Kg) of TW01 showed promising antitumor activity in nude mice bearing HA22T hepatoma, it is necessary to seek for vehicles to improve the solubility of TW01 and optimize the pharmacokinetic profile.
目錄......................................................i
圖表目錄................................................iii
中文摘要................................................vii
英文摘要.................................................ix
壹、研究動機及背景........................................1
貳、研究方向..............................................3
參、實驗內容..............................................4
一、儀器與材料............................................4
二、溶液的配置............................................5
三、動物實驗..............................................8
四、分析方法的確認.......................................10
五、數據分析與統計方法...................................11
肆、結果與討論...........................................20
一、TW01分析條件之尋找...................................20
二、內部標準品之尋找.....................................23
三、檢品製備方法之最適化研究.............................26
四、TW01於Wistar大白鼠之藥物動力學實驗...................39
伍、結論.................................................49
陸、參考文獻.............................................51
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