臺灣博碩士論文加值系統

運輸蛋白(transporter)是一種在細胞膜上掌控物質進出的蛋白質，近年來許多臨床上發生的藥物交互作用被認為可能與其有關。本實驗的目的為以單劑量與多劑量兩種不同的合併給藥方式來探討兔子腎臟上有機陰離子運輸蛋白ü85;體I(Organic anion transporter I, OATI)進行交互作用時的藥物動力學變化
本實驗藥物p-Aminohippuric acid (PAH)、Ibuprofen (IBU)及Indomethacin (INDO)在血漿中濃度的分析方法皆採用逆向高效液相層析法，其血中濃度檢量線在本實驗濃度範圍內具有良好的線性關係以及準確性與精確性。
口服同莫耳單一劑量的IBU(21.38mg/kg)或INDO(37.08mg/kg)至家兔體內，並同時靜脈注射等莫耳數之PAH(20mg/kg)，可得單劑量給藥後結果。實驗顯示：(1) INDO血中濃度曲線下面積(AUC)及最高血中濃度(Cmax)相較於對照組有8.42至11.33倍顯著差異(p<0.01)；清除率(clearance,CL)有6.94倍的顯著下降(p<0.01)。(2) PAH之AUC及CL有稍微上升及下降。(3) IBU的AUC稍微上升且CL下降了3.56倍(p<0.01)。(4) PAH在與IBU單劑量合併使用時，AUC些微上升。
多劑量IBU或INDO口服給藥後發現：(1) INDO的AUC及Cmax有15.02至20.93倍之顯著上升(p<0.01)；CL下降了19.66倍(p<0.01)。(2) PAH與INDO合併給藥時，其AUC有2.07倍的顯著上升(p<0.01)；CL有1.94倍的顯著下降(p<0.01)。(3) IBU的AUC上升且CL下降了5.53倍(p<0.01)。(4) PAH在與IBU多劑量合併使用時，AUC及CL都有上升及下降。INDO經由腎排除的比例有60%，IBU則約45%~75%，但因IBU在腎小管的主動分泌比例只有約1%，而INDO則將近34.4%，故在評估OATI對於IBU與INDO的影響時須考慮此因素。由實驗結果可知，OATI上發生藥物交互作用時會改變藥物彼此間的排除。

Carrier-mediated processes, often referred to as transporters which located on the membrane, play key roles in the reabsorption and secretion of many endogenous and xenobiotic compounds by the kidney. In recent years, the specific roles of such transporters in drug disposition and drug-drug interactions become more important. The purpose of this study is to estimate the interaction of drugs with the organic anion transporter I (OATI) in the kidney.
An accuracy, precision, simple and specific HPLC method was developed to detect the concentration of p-aminohippuric acid (PAH), ibuprofen (IBU) and indomethacin (INDO) in plasma.
The drug-drug interaction evaluating of OATI was determined by combining dosing with same molar dose of I.V. of PAH (20mg/kg) and P.O. administration of single or multiple dose of IBU (21.38mg/kg) and INDO (37.08mg/kg) to rabbits. During single dose of INDO or IBU administration, the results were shown below: (1) INDO: significantly increased the AUC and Cmax by 8.42 to 11.33 fold (p<0.01) and decreased the CL by 6.94 fold (p<0.01). (2) PAH: slightly increased the AUC and slightly decreased the CL. (3) IBU: slightly increased the AUC and Cmax but significantly decreased the CL by 3.56 fold (p<0.01). (4) PAH: combination dosing with IBU slightly increased the AUC.
In multiple dose studies, the results were shown below: (1) INDO: significantly increased the AUC and Cmax by 15.02 to 20.93 fold (p<0.01) and decreased the CL by 19.66 fold (p<0.01). (2) PAH: significantly increased the AUC by 2.07 fold (p<0.01) and decreased the CL by 1.94 fold (p<0.01). (3) IBU: slightly increased the AUC and Cmax but significantly decreased the CL by 5.53 fold (p<0.01). (4) PAH: slightly increased the AUC and slightly decreased the CL. The excretion of IBU in kidney (45%-75%) is equal with INDO (60%), but the tubular excretion of IBU was only 1% compared with 34.4% of INDO.This may result the difference of OATI effect.
In comparison between single and multiple dose administration, the results showed the higher competition level in drug-drug interaction when INDO or IBU multiple administration. The OATI effect the elimination of IBU and INDO.

目次

中文摘要…………………………………………………………………I
Abstract…………………………………………………………………II
目次………………………………………………………………………III
表目錄…………………………………………………………………VIII
圖目錄……………………………………………………………………XII
縮寫表……………………………………………………………………XIV
第一章緒論
壹、 前言……………………………………………………………1
貳、 研究背景………………………………………………………3
一、 腎臟於藥物排除之角色………………………………………3
1. 腎臟之基本功能…………………………………………………3
2. 腎絲球過濾………………………………………………………8
3. 腎小管主動分泌…………………………………………………9
4. 腎小管再吸收…………………………………………………110
二、 離子運輸蛋白於腎臟排除上的角色………………………111
1. 腎臟上運輸蛋白基本性質與功能……………………………111
2. 腎臟上有機陰離子運輸蛋白的分類…………………………116
3. 腎臟上有機陰離子運輸蛋白在腎臟上的分布………………112
4. 腎小管上的有機陰離子運輸蛋白担體I…………………… 24
5. 經由腎臟上有機陰離子運輸蛋白担體I排除之物質……… 28
6. 腎臟上有機陰離子運輸蛋白担體I與非類固醇類止痛藥…30
7. 離子運輸蛋白在臨床上的影響………………………………34
8. OATI與紐西蘭大白兔的研究關連……………………………35
三、 腎臟功能之測量……………………………………………36
1. 利用p-aminohippuric acid評估腎小管分泌與有機陰離子
運輸蛋白I的運輸能力…………………………………… 36
2. p-Aminohippuric acid之基本物化性質…………………36
3. p-Aminohippuric acid之分析方法…………………………37

四、 腎小管上有機陰離子運輸蛋白担體I的受質………………38
1. 經由有機陰離子運輸蛋白担體I運輸之物質……………… 38
2. Ibuprofen之基本物化性質……………………………………38
3. Ibuprofen之藥物動力學特性…………………………………39
4. Indomethacin之基本物化性質………………………………40
5. Indomethacin之藥物動力學特性……………………………41
五、 研究動機與目的……………………………………………42

第二章 實驗材料與方法……………………………………43
壹、 實驗儀器與材料………………………………………43
一、 實驗試藥品……………………………………………43
二、 實驗儀器………………………………………………44
三、 實驗試藥之配置………………………………………45
1. p-Aminohippuric acid儲備液之製備…………………45
2. Ibuprofen儲備液之製備………………………………45
3. Indomethacin儲備液之製備……………………………45
4. p-Aminobenzoic acid儲備液之製備……………………46
5. Mefenamic acid儲備液之製備…………………………46
貳、 分析條件……………………………………………………47
一、 p-Aminohippuric acid分析方法…………………………47
1. p-Aminohippuric acid 之HPLC分析條件………………47
2. p-Aminohippuric acid血漿檢品之處理…………………48
3. p-Aminohippuric acid檢品標準檢量線配置方法………49
二、 Ibuprofen分析方法…………………………………………50
1. Ibuprofen之HPLC分析條件……………………………50
2. Ibuprofen血漿檢品之處理………………………………51
3. Ibuprofen檢品標準檢量線配置方法……………………52
三、 Indomethacin分析方法……………………………………53
1. Indomethacin之HPLC分析條件………………………53
2. Indomethacin血漿檢品之處理…………………………54
3. Indomethacin檢品標準檢量線配置方法………………55
參、 分析方法之確效實驗……………………………………56
一、 p-Aminohippuric acid分析方法之確效實驗…………56
1. 專一性試驗………………………………………………56
2. 同次(Within-run)分析之精確性(precision)與準確性
(accuracy)………………………………………………56
3. 異次(Between-run)分析之精確性(precision)與準確性
(accuracy)………………………………………………56
二、 Ibuprofen分析方法之確效實驗………………………58
1. 專一性試驗………………………………………………58
2. 同次(Within-run)分析之精確性(precision)與準確性
(accuracy) ……………………………………………58
3. 異次(Between-run)分析之精確性(precision)與準確性
(accuracy) ……………………………………………58
三、 Indomethacin分析方法之確效實驗…………………59
1. 專一性試驗………………………………………………59
2. 同次(Within-run)分析之精確性(precision)與準確性
(accuracy) ………………………………………………59
3. 異次(Between-run)分析之精確性(precision)與準確性
(accuracy) ………………………………………………59
肆、 動物實驗方法…………………………………………60
一、 實驗動物之準備工作……………………………………60
二、 篩選家兔腎臟有機陰離子運輸蛋白I substrates的方
法…………………………………………………………61
三、 靜脈注射p-aminohippuric acid之實驗………………62
1. 單一劑量測定p-aminohippuric acid於家兔體內之
藥物動力學實驗……………………………………………62
四、 口服投與ibuprofen與indomethacin之實驗……………63
1. 單一劑量測定ibuprofen與indomethacin於家兔體內之
藥物動力學實驗……………………………………………63
五、 合併靜脈注射與口服投與之實驗方法……………………65
1. 單一劑量靜脈注射p-aminohippuric acid合併單一劑量
口服投與ibuprofen與indomethacin之藥物動力學研究
-- 測定同時給予單劑量ibuprofen與p-aminohippuric
acid於家兔體內之藥物動力學…………………………65
-- 測定同時給予單劑量indomethacin與
p-aminohippuric acid於家兔體內之藥物動力學……65
2. 單一劑量靜脈注射p-aminohippuric acid合併多劑量
口服ibuprofen與indomethacin之藥物動力學研究
-- 測定同時給予多劑量ibuprofen與p-aminohippuric
acid於家兔體內之藥物動力學………………………68
-- 測定同時給予多劑量indomethacin與
p-aminohippuric acid於家兔體內之藥物動力學……70
六、 動物實驗之藥物動力學數據處理與分析……………71
1. 靜脈注射p-aminohippuric acid之數據處理………71
2. 口服投與ibuprofen以及indomethacin之數據處理……71
3. 合併靜脈注射p-aminohippuric acid與口服投與
ibuprofen、indomethacin之數據處理…………………72
七、 統計方法………………………………………………73

第三章 實驗結果與討論………………………………………75
壹、 分析方法之結果與討論分析…………………………75
一、 p-Aminohippuric acid分析結果與討論……………75
1. 檢品分析結果……………………………………………75
2. 標準檢量線………………………………………………75
3. 同次及異次之確效試驗…………………………………75
4. 分析方法討論………………………………………………76
二、 Ibuprofen與indomethacin分析結果與討論……………81
1. 檢品分析結果………………………………………………81
2. 標準檢量線…………………………………………………81
3. 同次及異次之確效試驗……………………………………81
4. 分析方法討論………………………………………………82
貳、 動物實驗結果與討論……………………………………93
一、 靜脈注射p-aminohippuric acid結果與討論…………93
二、 口服實驗結果與討論……………………………………96
三、 合併靜脈注射與口服投與之結果與討論………………102
1. 單一劑量靜脈注射p-aminohippuric acid合併單一劑量口服
投與ibuprofen……………………………………………102
2. 單一劑量靜脈注射p-aminohippuric acid合併單一劑量口服
投與indomethacin……………………………………………108
3. 單一劑量靜脈注射p-aminohippuric acid合併多劑量口服投
與 ibuprofen………………………………………………114
4. 單一劑量靜脈注射p-aminohippuric acid合併多劑量口服投
與indomethacin………………………………………………124
5. 比較單劑量與多劑量間ibuprofen與indomethacin彼此的
藥物動力學變化………………………………………………136
6. 比較OATI於體內實驗與體外實驗時對ibuprofen與
indomethacin的藥物動力學變化……………………………146
7. OATI對ibuprofen代謝物的影響……………………………147
8. OATI之研究與動物模式的關連………………………………149

第四章 結論………………………………………………………150
參考文獻…………………………………………………………………152

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