臺灣博碩士論文加值系統

1-[4-(furo[2,3-b]-quinolin-4-ylamino)phenyl]ethanone（PK-L1）及其同類物1-[4-(3-chlorofuro[2,3-b]-quinolin-4-ylamino)phenyl]ethanone（PK-L4）屬於最近新研發之4-anilino[2,3-b]quinoline類抗癌化合物，而此二化合物PK- L1和PK-L4在分子構造僅差一個氯原子取代。經由體外試驗顯示其可抑制大多數腫瘤細胞之生長，包括液態腫瘤及固態腫瘤。但是PK-L1及PK-L4目前仍處於體外試驗階段，尚未有任何相關之血漿分析方法及體內動態試驗之報告。因此，本實驗目的在於發展PK-L1及PK-L4之血漿分析方法，以及將其投予正常大白鼠體內來進一步探討其藥物動力學。
本實驗採用高效能液相層析法（HPLC）分析血漿藥物含量。另外，分別靜脈注射投予8.4、4.2、2.1 mg/kg之PK-L1及9.4、4.7、2.35及1.175 mg/kg之PK-L4於正常大白鼠後，以二室模式來探討其藥物動力學。
結果顯示，本實驗之分析方法具高度準確性及精密度。此外，在以靜脈注射投藥後，PK-L1及PK-L4在高劑量時（PK-L1及PK-L4分別為高於4.2及4.7 mg/kg）皆呈現非線性之藥物動力學特性；在較低劑量時（PK-L1及PK-L4分別為2.1-4.2 mg/kg及1.175-4.7 mg/kg）則皆依循線性之藥物動力學；但PK-L1及PK-L4在等莫耳劑量投予後，分子構造上多了一個氯原子取代之PK-L4呈現較大之濃度曲線下面積值（AUC0�_∞）及較低之血漿清除率（Clp），但二者之排除半衰期（t1/2 (��)）並無顯著差異，平均值分別為1.5及1.1小時。

1-[4-(furo[2,3-b]-quinolin-4-ylamino)phenyl]ethanone (PK-L1) and its analogue, 1-[4-(3-chlorofuro[2,3-b]-quinolin-4-ylamino)phenyl]ethanone (PK- L4), both these 4-anilino[2,3-b]quinoline derivatives are presently new synthetic anti-tumor compounds. These two compounds, PK-L1 and PK-L4, are just different in one chlorine replacement on the structure. In vitro study showed that they could inhibit most tumor cell growth, including liquid and solid tumors. PK-L1 and PK-L4, however, were passed only through in vitro study and had yet neither related plasma drug analytical method nor in vivo study report. Therefore, the purpose of this study was to develop a plasma drug analytical method and explore the pharmacokinetics after administration of drug to normal rats.
In this study, we used high performance liquid chromatography (HPLC) to determine the drug content in plasma. In addition, we explored the pharmaco- kinetics with two-compartment model after intravenous administration of PK-L1 at doses of 8.4, 4.2 and 2.1 mg/kg and PK-L4 at doses of 9.4, 4.7, 2.35 and 1.175 mg/kg.
The results showed that the analytical method in this study provided both high accuracy and precision. Besides, after administration of drugs, both PK-L1 and PK-L4 represented non-linear pharmacokinetics at high doses above 4.2 and 4.7 mg/kg for PK-L1 and PK-L4, respectively; and both represented linear pharmacokinetics at lower doses, 2.1-4.2 mg/kg and 1.175-4.7 mg/kg for PK-L1 and PK-L4, respectively. In addition, the same molar doses of PK-L4, the compound with one chlorine replacement on the structure, produced higher area under the curve (AUC�~�_�V) and lower plasma clearance (Clp) but not the elimination half-life (t1/2 (��)). The mean t1/2 (��) values of PK-L1 and PK-L4 were 1.5 and 1.1 h, respectively.

附圖目錄 --------------------------------------------------------------------------------------------- Ⅰ
附表目錄 --------------------------------------------------------------------------------------------- Ⅳ
中文摘要 --------------------------------------------------------------------------------------------- 1
英文摘要 --------------------------------------------------------------------------------------------- 2
壹、 緒論 ------------------------------------------------------------------------------------------ 3
貳、 材料與方法 --------------------------------------------------------------------------------- 9
一、 藥品與化學試劑 --------------------------------------------------------------------- 9
二、 儀器 ------------------------------------------------------------------------------------ 10
三、 實驗方法 ------------------------------------------------------------------------------ 11
甲、 PK-L1 --------------------------------------------------------------------------------- 11
1. 定量分析 --------------------------------------------------------------------------- 11
1.1 HPLC層析條件 -------------------------------------------------------------- 11
1.2 萃取率 -------------------------------------------------------------------------- 11
1.3 檢量線之製作 ----------------------------------------------------------------- 12
1.4 分析方法之確效 -------------------------------------------------------------- 12
1.5 蛋白質結合率 ----------------------------------------------------------------- 13
2. PK-L1之體內試驗 ---------------------------------------------------------------- 14
2.1 注射劑之製備 ------------------------------------------------------------------ 14
2.2 動物實驗 ------------------------------------------------------------------------ 15
（1） 動物 --------------------------------------------------------------------- 15
（2） 投藥 --------------------------------------------------------------------- 15
（3） 血漿檢品之分析 ------------------------------------------------------ 15
（4） 體內藥物動力學研究 ------------------------------------------------ 16
（5） 統計分析 --------------------------------------------------------------- 16
乙、 PK-L4 ------------------------------------------------------------------------------- 16
1. 定量分析 --------------------------------------------------------------------------- 16
1.1 HPLC層析條件 --------------------------------------------------------------- 16
1.2 萃取率 -------------------------------------------------------------------------- 17
1.3 檢量線之製作 ----------------------------------------------------------------- 17
1.4 分析方法之確效 -------------------------------------------------------------- 18
1.5 蛋白質結合率 ----------------------------------------------------------------- 19
2. 體內試驗 ---------------------------------------------------------------------------- 19
2.1 注射劑之製備 ----------------------------------------------------------------- 19
2.2 動物實驗 ----------------------------------------------------------------------- 20
（1） 動物 ------------------------------------------------------------------- 20
（2） 投藥 ------------------------------------------------------------------- 20
（3） 血漿檢品之分析 ---------------------------------------------------- 20
（4） 體內藥物動力學研究 ---------------------------------------------- 21
（5） 統計分析 ------------------------------------------------------------- 21
參、 結果與討論 --------------------------------------------------------------------------------- 22
甲、 PK-L1 ---------------------------------------------------------------------------------- 22
1. 定量分析方法之建立 ------------------------------------------------------------ 22
1.1 HPLC檢量線 ------------------------------------------------------------------ 27
1.2 分析方法之確效 -------------------------------------------------------------- 30
1.3 蛋白質結合率 ----------------------------------------------------------------- 31
2. PK-L1之動物體內試驗 ---------------------------------------------------------- 32
2.1 PK-L1於不同給予劑量下經時血中濃度變化 -------------------------- 33
2.2 三組不同劑量之比較 -------------------------------------------------------- 43
乙、 PK-L4 ---------------------------------------------------------------------------------- 49
1. 定量分析方法之建立 ------------------------------------------------------------ 49
1.1 HPLC檢量線 ----------------------------------------------------------------- 54
1.2 分析方法之確效 -------------------------------------------------------------- 57
1.3 蛋白質結合 -------------------------------------------------------------------- 58
2. PK-L4之動物體內試驗 --------------------------------------------------------- 59
2.1 PK-L4於不同給予劑量下經時血中濃度變化 -------------------------- 61
2.2 四組不同劑量之比較 -------------------------------------------------------- 74
丙、 PK-L1與PK-L4之比較 ------------------------------------------------------------- 80
肆、 結論 ------------------------------------------------------------------------------------------ 83
伍、 參考文獻 ------------------------------------------------------------------------------------ 85

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