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系統識別號 U0007-2807201112584000
論文名稱(中文) 腎臟有機陰離子運輸蛋白1於家兔體內給予藥物交互作用之藥物動力學研究
論文名稱(英文) Pharmacokinetics studies of drug-drug interactions on renal organic anion transporter 1 in rabbits
校院名稱 臺北醫學大學
系所名稱(中) 藥學研究所
系所名稱(英) Graduate Institute of Pharmacy
學年度 99
學期 2
出版年 100
研究生(中文) 賴麒開
研究生(英文) Chi-Kai Lai
學號 M301098011
學位類別 碩士
語文別 中文
口試日期 2011-06-30
論文頁數 132頁
口試委員 指導教授-許光陽
委員-何意
委員-鮑力恆
中文關鍵字 藥物動力學,家兔,運輸蛋白,藥物交互作用 
英文關鍵字 Pharmacokinetic,rabbit,transporter,drug-drug interaction 
學科別分類
中文摘要
Indomethacin(INDO)與Ketoprofen(KETO)為非類固醇類抗發炎藥廣泛地利用在各種炎症的緩解與治療,在臨床上陸續發現其與藥物間的交互作用,以及在體外實驗中,發現其與有機陰離子運輸蛋白1(Organic anion transporter 1; OAT1)間的交互作用有關,p-Aminohippuric acid(PAH)為測量腎小管主動分泌的指標物質,且其對腎臟上OAT1具有高度的親和力與專一性,本實驗以靜脈注射的方式分別投予INDO、KETO至紐西蘭大白兔體內,並同時靜脈注射投予同莫耳數的PAH,以探討INDO以及KETO與PAH間藥物動力學上的變化,藉以瞭解其與OAT1之間的交互作用,並更進一步投予多劑量INDO與KETO,使其血中濃度達穩定狀態,分別討論其不同藥物動力學情況下的變化。
本實驗所得到的檢體經前處理後,以逆向高效液相層析法進行分析,其血中濃度的檢定,在濃度範圍內皆具有良好的線性關係、準確度以及精密度。單一劑量的KETO、INDO、PAH分別單獨給予至家兔體內,已觀察其個別的藥物動力學,隨後進行合併給藥實驗,合併給予單一劑量的INDO及PAH或是KETO及PAH,再進行多劑量投予INDO或是KETO,待其血中濃度達穩定狀態後,同時給予單一劑量的PAH加上KETO或是INDO;所得到的檢體經分析後,將血中濃度經計算所得到的藥物動力學參數,進行統計分析,結果顯示在合併給予單一劑量KETO時,兩者的藥物動力學參數皆有所變化,且在KETO血中濃度達到穩定狀態時,其變化更加明顯,PAH的總清除率(clearance; CL)下降(穩定狀態10.0 ± 1.9 vs 單一劑量11.5 ± 控制組0.8 vs 16.8 ± 1.8 mL/min/kg; p < 0.01),排除半衰期延長(117.2 ± 32.1 vs 86.0 ± 12.1 vs 54.4 ± 27.1 min; p < 0.03),KETO的CL也下降(61.4 ± 5.8 vs 74.6 ± 8.7 vs 166.3 ± 18.5 mL/min/kg; p < 0.01),且排除半衰期也有延長(315.0 ± 81.0 vs 423.2 ± 100.3 vs 154.7 ± 31.3 min; p < 0.02),且兩者其他藥物動力學參數也有變化,並具統計學上意義;而在合併給予INDO下,兩者的藥物動力學也產生變化,且在INDO達到穩定狀態下,其變化愈加顯著,PAH的CL下降(6.8 ± 0.8 vs 10.0 ± 1.9 vs 16.8 ± 1.8 mL/min/kg; p< 0.01),排除半衰期延長(188.5 ± 51.9 vs 123.7 ± 23.9 vs 54.4 ± 27.1 min; p < 0.02),而INDO的CL下降(27.2 ± 2.5 vs 56.3 ± 3.6 vs 128.2 ± 12.4 mL/min/kg; p < 0.01),排除半衰期延長(912.8 ± 98.0 vs 825.8 ± 141.7 vs 229.1 ± 76.4 min; p < 0.01),兩者的其他藥物動力學參數與控制組相比,皆有統計學上之明顯差異,以上統計結果,顯示在合併給藥下,PAH、KETO、INDO會互相影響彼此的藥物動力學,進一步以公式計算其個別的淨分泌清除率,可以發現在合併給藥下,PAH的主動分泌清除率下降(合併給予KETO:3.1 ± 1.7 vs 4.4 ± 0.7 vs 9.2 ± 1.6 mL/min/kg; p < 0.05;合併給予INDO:0.2 ± 0.7 vs 3.0 ± 1.2 vs 9.2 ± 1.6 mL/min/kg; p < 0.05),而KETO(43.0 ± 4.3 vs 55.2 ± 17.6 vs 123.5 ± 37.7 mL/min/kg; p < 0.05)及INDO(10.2 ± 1.5 vs 27.4 ± 5.4 vs 70.1 ± 18.3 mL/min/kg; p < 0.05)也有相同的情形,可以推論PAH與INDO及KETO在家兔腎臟上的OAT1發生競爭的情形,而導致其藥物動力學上的變化,這樣的實驗結果也與文獻中細胞實驗的結果有相似的情形。
英文摘要 INDO and KETO are members of the non-steroidal anti-inflamma-tory drugs which are prescribe for the relief and treatment for different inflammatory syndromes. However, the interactions with other drugs and the interactions with organic anion transporter 1 (OAT1) were discovered in vivo and in vitro, respectively. This research wouLd demonstrate the experiment in New Zealand rabbits via administration of INDO or KETO which wouLd help understanding the relationship between the OAT1 and INDO or KETO and the effects on pharmacokinetic.
p-Aminohippuric acid (PAH) is the index compound for estimating the active excretion of the proximal tubule, and highly specific to OAT1. We administrated PAH intravenously with or without INDO or KETO as the same mole as PAH contemporarily. We could explore the interaction between INDO, KETO, PAH and OAT1 via observing the variation on pharmacokinetic parameters.
A simple HPLC-based method with good linearity, accuracy and precision was developed for detecting the concentration of INDO, KETO and PAH in rabbit plasma. First, single-dose of PAH, KETO and INDO were administrated to rabbits for determining their pharmacokinetic(PK) parameters as control, and the following data was collected for comparison to the control. Second, a single-dose of PAH was administrated with a single-dose of KETO or INDO simultaneously, separately. Third, the KETO and INDO were administrated as multiple dosing for reaching steady state. Then a single-dose of PAH was administrated with a single-dose of KETO or INDO simultaneously, separately. After co-administrated with KETO, compared to control, the clearance(CL) of PAH decreased(steady state: 10.0 ± 1.9 vs single-dose: 11.5 ± control: 0.8 vs 16.8 ± 1.8 mL/min/kg; p < 0.01), and the elimination half-life prolonged(117.2 ± 32.1 vs 86.0 ± 12.1 vs 54.4 ± 27.1 min; p < 0.03), also the CL of KETO decreased(61.4 ± 5.8 vs 74.6 ± 8.7 vs 166.3 ± 18.5 mL/min/kg; p < 0.01), and the elimination half-life prolonged(315.0 ± 81.0 vs 423.2 ± 100.3 vs 154.7 ± 31.3 min; p < 0.02). Other PK parameters were also changed with statistically significants. After administrated with INDO, the clearance(CL) of PAH decreased(6.8 ± 0.8 vs 10.0 ± 1.9 vs 16.8 ± 1.8 mL/min/kg; p< 0.01), and the elimination half-life prolonged(188.5 ± 51.9 vs 123.7 ± 23.9 vs 54.4 ± 27.1 min; p < 0.02), also the CL of KETO decreased(27.2 ± 2.5 vs 56.3 ± 3.6 vs 128.2 ± 12.4 mL/min/kg; p < 0.01), and the elimination half-life prolonged(912.8 ± 98.0 vs 825.8 ± 141.7 vs 229.1 ± 76.4 min; p < 0.01). Other PK parameters were also changed with statistically significants. Data shown above implicate the interactions between PAH and KETO or INDO. And the net secretion clearances(CLS) were deduced and compared to the control, the CLS of PAH decreased(after administrated with KETO: 3.1 ± 1.7 vs 4.4 ± 0.7 vs 9.2 ± 1.6 mL/min/kg; p < 0.05, or INDO: 0.2 ± 0.7 vs 3.0 ± 1.2 vs 9.2 ± 1.6 mL/min/kg; p < 0.05). Meanwhile, the CLS of KETO and INDO decreased(KETO: 43.0 ± 4.3 vs 55.2 ± 17.6 vs 123.5 ± 37.7 mL/min/kg; p < 0.05, and INDO: 10.2 ± 1.5 vs 27.4 ± 5.4 vs 70.1 ± 18.3 mL/min/kg; p < 0.05), respectively, which were statistically significant and implied the interactions on the secretion via OAT1, and altered the PK parameters of PAH, INDO and KETO significantly.
論文目次 目次
中文摘要 6
Abstract 8
緒論 10
壹、前言 10
貳、研究背景 12
一、腎臟概觀 12
1. 生理及功能 12
2. 腎絲球過濾 17
3. 腎小管的主動分泌 19
4. 腎小管的再吸收 20
二、運輸蛋白 21
1.運輸蛋白家族 21
2. 腎臟上的有機陰離子運輸蛋白 23
3. 有機陰離子運輸蛋白 1 25
三、Substrates of OAT1 30
1. 藥物與OAT1 30
2. p-Aminohippuric acid 32
3. Non-steroidal anti-inflammatory drugs 34
A. Ketoprofen 36
B. Indomethacin 38
3. 紐西蘭大白兔與OAT1的關係 40
參、研究動機與目的 41
研究材料與方法 42
壹、實驗儀器與材料 42
一、實驗試藥品 42
二、實驗儀器 43
三、實驗試藥之配置 44
1. p-Aminohippuric acid 儲備液之製備 44
2. Ketoprofen儲備液之製備 44
3. Indomethacin儲備液之製備 44
4. p-Aminobenzoic acid儲備液之製備 45
5. Mefenamic acid儲備液之製備 45
貳、分析條件 46
一、 p-aminohippuric acid 之HPLC分析方法 46
1. p-aminohippuric acid 之HPLC分析條件 46
2. p-aminohippuric acid血漿檢品之分析前處理 47
3. p-Aminohippuric acid血漿檢品之標準檢量線配置方法 48
二、Ketoprofen之HPLC分析方法 49
1. Ketoprofen之HPLC分析條件 49
2. Ketoprofen血漿檢品之分析前處理 50
3. Ketoprofen血漿檢品之標準檢量線配置方法 51
三、Indomethacin之HPLC分析方法 52
1. Indomethacin之HPLC分析條件 52
2. Indomethacin血漿檢品之分析前處理 53
3. Indomethacin血漿檢品之標準檢量線配置方法 54
參、分析方法之確效 55
一、 p-aminohippuric acid分析方法之確效 55
1. 專一性試驗 55
2. 同次分析之精密度與準確度試驗 56
3. 異次分析之精密度與準確度試驗 57
二、Ketoprofen分析方法之確效 58
1. 專一性試驗 58
2. 同次分析之精密度與準確度試驗 59
3. 異次分析之精密度與準確度試驗 60
三、Indomethacin分析方法之確效 61
1. 專一性試驗 61
2. 同次分析之精密度與準確度試驗 62
3. 異次分析之精密度與準確度試驗 63
肆、動物實驗之方法 64
一、動物實驗之準備 64
二、觀察受質於家兔腎臟有機陰離子運輸蛋白1競爭之方法 65
三、單一劑量靜脈注射p-Aminohippuric acid之實驗 66
四、靜脈注射Ketoprofen與Indomethacin之實驗 67
1. 單一劑量靜脈注射Ketoprofen之實驗 67
2. 多劑量靜脈注射Ketoprofen之實驗 68
3. 單一劑量靜脈注射Indomethacin之實驗 69
4. 多劑量靜脈注射Indomethacin之實驗 70
五、合併靜脈注射之實驗方法 71
1. 單一劑量靜脈注射p-Aminohippuric acid合併單一劑量靜脈注射 71
Ketoprofen之實驗 71
2. 單一劑量靜脈注射p-Aminohippuric acid合併單一劑量靜脈注射 72
Indomethacin之實驗 72
3. 單一劑量靜脈注射p-Aminohippuric acid合併多劑量靜脈注射 73
Ketoprofen之實驗 73
4. 單一劑量靜脈注射p-aminohippuric acid合併多劑量靜脈注射 74
Indomethacin之實驗 74
六、藥物動力學參數計算與統計方法 75
1. 藥物動力學參數計算 75
2. 統計方法 76
實驗結果與討論 77
壹、分析方法之結果與討論 77
一、p-Aminohippuric acid之分析方法 77
1. 專一性 77
2. 標準檢量線 77
3. 確效試驗 77
二、Ketoprofen與Indomethacin之分析方法 82
1. 專一性 82
2. 標準檢量線 82
3. 確效試驗 82
貳、動物實驗之結果與討論 89
一、單一劑量靜脈注射p-Aminohippuric acid之實驗 89
二、單一劑量靜脈注射Ketoprofen之實驗 91
三、單一劑量靜脈注射Indomethacin之實驗 93
四、合併靜脈注射實驗之結果與討論 95
1. 單一劑量p-Aminohippuric acid合併單一劑量Ketoprofen之實驗結果 95
2. 單一劑量p-Aminohippuric acid合併單一劑量Indomethacin之實驗結果 99
3. 單一劑量p-Aminohippuric acid合併多劑量Ketoprofen之實驗結果 102
4. 單一劑量p-Aminohippuric acid合併多劑量Indomethacin之實驗結果 108
五、p-Aminohippuric acid合併給藥前後藥物動力學探討 114
六、Ketoprofen與Indomethacin合併給藥前後藥物動力學探討 117
結論 123
References 125
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