臺灣博碩士論文加值系統

Amsacrine為治療acute adult leukemia及lymphoma之抗癌藥物，屬於Topoisomerase II inhibitor。本實驗兩種模式藥，分別為PK-A2與PK-A3，乃以Amsacrine結構加以修飾並做官能基取代而得之具抗癌活性之新化合物。PK-A2及PK-A3兩藥物親脂性皆大於Amsacrine，而且PK-A2及PK-A3兩藥物之結構差異僅在官能基團上的-OH與-OCH3。在抗癌活性方面，兩藥物均對腎臟癌細胞與皮膚癌細胞具有很大的抑制生長作用。由於其為新合成之藥物，並無相關體內藥物動力學特性之資料，本研究在最初嘗試建立PK-A2與PK-A3之分析條件及並比較血液中的藥物萃取方法，之後將藥物以靜脈注射方式投予至190∼220克重之Wistar大白鼠體內，經時收集血液檢品並以Dichlomethane作為藥物萃取之溶媒，以HPLC分析藥物濃度，探討PK-A2及PK-A3兩藥物在動物體內之藥物動力學特性。分析結果顯示兩藥物均可得到不錯的檢量線線性關係。藥物血液中萃取率方面，PK-A2可達90％以上，PK-A3則可達80％以上。實驗結果顯示，PK-A2在大白鼠體內之排除半衰期平均為1.69小時，PK-A3則為1.61小時，但統計上並無明顯差異。另一方面，PK-A2及PK-A3兩者皆呈現線性藥物動力學特性，且兩藥物比較之下，PK-A3則具有較大之分佈體積。

Amsacrine is an antitumor drug against acute adult leukemia and lymphoma. The two model drugs, PK-A2 and PK-A3, are new antitumor compounds and synthesized from the substitution and modification of the main chemical structure of amsacrine. So far, there is no data to describe the pharmacokinetic characters of the two model drugs. In this study, drugs were administered by IV bolus into Wistar rats weighted 190 to 220 g. The blood samples were extracted with dichlomethane and then analyzed by HPLC method. Finally, we discussed the individual pharmacokinetic characters and also compared the difference between PK-A2 and PK-A3. The fine linear relationships of the calibration curve were available, and the extraction ratio was upon 90 % with PK-A2 and 80 % with PK-A3. Results showed the half-life of PK-A2 was 1.69 hours and that of PK-A3 was 1.69 hours, though there was no difference statistically. Otherwise, both PK-A2 and PK-A3 revealed the character of linear pharmacokinetics, and the PK-A3 possessed the higher volume of distribution in steady state.

中文摘要--------------------------------------------------7
英文摘要--------------------------------------------------8
壹、緒論--------------------------------------------------9
一、 研究背景------------------------------------------9
二、 Furo[3,2-c]quinoline衍生物之來源--------------------13
三、 Furo[3,2-c]quinoline衍生物之概述--------------------13
四、 實驗目的-----------------------------------------16
貳、材料與方法-------------------------------------------17
一、 溶媒與試藥---------------------------------------17
二、 儀器與設備---------------------------------------18
三、 注射劑製備---------------------------------------19
四、 實驗方法-----------------------------------------21
甲、分析條件之選擇-----------------------------------21
乙、分析方法-----------------------------------------21
(1) PK-A2分析方法------------------------------21
1、 Stock solution之製備------------------------21
2、 定性方法----------------------------------21
HPLC層析條件---------------------------22
3、 定量方法----------------------------------22
檢量線製作-------------------------------22
(2) PK-A3分析方法------------------------------23
1、 Stock solution之製備------------------------23
2、 定性方法----------------------------------23
HPLC層析條件---------------------------24
3、 定量方法----------------------------------24
檢量線製作------------------------------24
丙、 溶解度------------------------------------------26
丁、 血漿中蛋白質結合率------------------------------27
戊、 血漿萃取率試驗----------------------------------28
(1) 不同萃取溶媒之比較--------------------------28
(2) 以Dichloromethane為萃取溶媒之血漿萃取率----28
己、 動物實驗----------------------------------------29
庚、 統計分析----------------------------------------30
參、結果與討論-------------------------------------------31
（1） 分析條件之選擇與探討---------------------------31
（2） PK-A2分析方法---------------------------------35
1、 HPLC層析條件------------------------------35
2、 檢量線-------------------------------------35
3、 同日間準確性及精密度-----------------------35
4、 異日間準確性及精密度-----------------------36
（3） PK-A3分析方法----------------------------------41
1、 HPLC層析條件-------------------------------41
2、 檢量線-------------------------------------41
3、 同日間準確性及精密度-----------------------41
4、 異日間準確性及精密度-----------------------42
（4） 溶解度-----------------------------------------46
（5） 血漿中蛋白質結合率-----------------------------47
（6） 不同萃取溶媒之比較 ----------------------------49
（7） 以Dichloromethane為萃取溶媒之血漿萃取率--------49
(8) 動物實驗及單一劑量給藥結果---------------------52
1、 分室模式之選擇-----------------------------52
2、 單一劑量給藥-------------------------------54
2.1 PK-A2靜脈投予及其血漿中濃度----------54
2.2 PK-A3靜脈投予及其血漿中濃度----------63
3、 藥物動力學參數之探討-----------------------72
3.1 PK-A2藥物動力學參數------------------72
3.2 PK-A3藥物動力學參數------------------75
4、 PK-A2與PK-A3結構、親脂性與藥動參數之比較
-------------------------------------------78
肆、結論-------------------------------------------------84
伍、參考文獻---------------------------------------------80

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高雄醫學大學藥學研究所博士論文：呋喃喹啉類衍生物之合成及生物活性研究 研究生陳意莉 撰