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研究生:曾宣凱
研究生(外文):Hsuan-Kai Tzeng
論文名稱:評估對胺基水楊酸次微米化促進生體可用率之研究
論文名稱(外文):Improve the Bioavailability of p-Aminosalicylic Acid by Submicronization
指導教授:許光陽許光陽引用關係
指導教授(外文):Kuang-Yang Hsu
學位類別:碩士
校院名稱:臺北醫學大學
系所名稱:藥學研究所
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:2008
畢業學年度:96
語文別:中文
論文頁數:157
中文關鍵詞:對胺基水楊酸次微米化粒子生體可用率
外文關鍵詞:p-aminosalicylic acidsubmicron particlesbioavailability
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對胺基水楊酸( p-Aminosalicylic acid, PAS)為抗肺結核藥品,因溶解度不佳及首渡效應強烈導致口服生體可用率低而退居為第二線。
本實驗目的在於評估以超重力沉澱法所製成之次微米化PAS 粒子
(Higee, 平均粒徑: 1 μm)投與至家兔體中是否具有提升生體可用率
的效果。
本實驗血漿中PAS 及其代謝物乙醯胺基水楊酸(N-AcPAS)的濃度
分析方法乃以逆向高效液相層析法為之。PAS 及N-AcPAS 之檢量線
在本實驗濃度範圍內具有良好之線性關係及準確性與精確性。
兔子乙醯代謝型之篩選乃利用Sulfadiazine (10 mg/kg)靜脈投與於8 隻家兔體內定之,其中5 隻為快速乙醯化代謝型,3 隻為慢速
乙醯化代謝型。
將10、30、50 mg PAS 靜脈投與至家兔(n=8)後,PAS 之藥動學參數呈現清除率隨著劑量增加而降低(p<0.01),血中濃度曲線下面積
(AUC)也不呈現等比例上升之現象,顯示在此劑量範圍內PAS 具有非
線性藥物動力學特性。
將10、30、50 mg 之PAS(平均粒徑: 10 μm)及Higee 口服投與至家兔後,在(1)10 mg 劑量:Higee 之AUC、生體可用率及最高血中濃度相較於對照組均沒有顯著差異。(2)30 mg 劑量: Higee 之AUC
(p<0.01)、生體可用率(p<0.01)及最高血中濃度(p<0.05)相較於對照組均呈現1.6~1.7 倍之顯著差異。(3) 50 mg 劑量: Higee 之AUC (p<0.05)、生體可用率(p<0.05)及最高血中濃度(p<0.05)相較於對照組也呈現1.5~1.6 倍之顯著差異。由此可知Higee 於中高劑量PAS 下對於家兔之生體可用率有顯著之增進。
將PAS 口服給藥與乙醯代謝型結果相互比較後,在50 mg 劑量
下,Higee 均可增進快速或慢速乙醯代謝型之生體可用率( p<0.05 );且在Higee,慢速乙醯代謝型之AUC 顯著大於快速乙醯代謝型
(p<0.05)。由此推論Higee 在快速溶離後可能會快速飽和慢速乙醯代
謝型家兔之乙醯化反應而使PAS 生體可用率增加;在30 mg 劑量條
件下亦有相似結果。
中文摘要.......................................I
Abstract.....................................III
目次..........................................IV
表目錄......................................VIII
圖目錄........................................XI
縮寫表.......................................XIV
第一章緒論.....................................1
壹、前言.......................................1
貳、研究背景...................................2
一、肺結核.....................................2
1. 致病原及致病機轉............................3
2. 病理學......................................4
3. 傳播........................................5
4. 臨床徵照...................................10
5. 診斷.......................................12
6. 治療指引...................................16
7. 抗藥性肺結核...............................19
二、對胺基水楊酸..............................22
1. PAS 之化學特性.............................22
2. PAS 之抗菌機轉.............................24
3. PAS 之藥物動力學...........................26
三、乙醯化代謝酵素............................36
四、微粒化製藥技術及超重力再結晶法............46
參、研究目的..................................59
第二章實驗材料與方法..........................61
壹、實驗儀器及材料............................61
一、實驗試藥..................................61
二、實驗儀器..................................63
三、試藥之配製................................64
1. PAS 儲備溶液之配製.........................64
2. N-AcPAS 儲備溶液之配製.....................64
3. SDZ 儲備溶液之配製.........................64
貳、分析方法..................................66
一、PAS 及N-AcPAS 分析方法....................66
1. 分析條件...................................66
2. 動物檢品處理方法...........................68
3. 檢量線配製方法.............................70
4. 分析方法確效試驗...........................71
二、SDZ 分析方法..............................73
1. 分析條件...................................73
2. 動物檢品處理方法...........................75
3. 檢量線配製方法.............................77
4. 分析方法再確效試驗.........................77
參、動物實驗方法..............................78
一、篩選家兔乙醯化代謝型方法..................79
二、靜脈注射實驗方法..........................80
三、口服投與實驗方法..........................81
四、定量乙醯化代謝比例實驗....................82
肆、動物實驗數據處理..........................83
伍、統計方法..................................87
第三章實驗結果與討論..........................89
壹、分析方法結果與討論........................89
一、PAS 分析方法結果與討論....................89
1. 分析條件...................................89
2. 檢量線.....................................90
3. 同次及異次確效試驗.........................91
二、SDZ 分析方法結果與討論....................99
1. 分析條件...................................99
2. 檢量線.....................................99
3. 分析方法再確效.............................99
貳、動物實驗結果與討論.......................104
一、SDZ 篩選乙醯化代謝型結果與討論...........104
二、靜脈注射PAS 結果與討論...................106
三、口服實驗結果與討論.......................110
四、比較代謝型與次微米化粒子口服生體可用率
結果與討論...................................123
五、乙醯化代謝比例結果與討論.................143
第四章結論...................................148
參考文獻.....................................152
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