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研究生:楊禮綺
研究生(外文):Li-ChiYang
論文名稱:以Mosapride預測大鼠體內酵素相關藥物交互作用的可能性
論文名稱(外文):Feasibility of Mosapride to predict enzyme-based drug-drug interactions in rats
指導教授:周辰熹周辰熹引用關係鄭靜玲鄭靜玲引用關係
指導教授(外文):Chen-Hsi ChouChen-Hsi Chou
學位類別:碩士
校院名稱:國立成功大學
系所名稱:臨床藥學與藥物科技研究所
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:2012
畢業學年度:100
語文別:中文
論文頁數:97
中文關鍵詞:mosapride細胞色素3A探針性試藥藥品交互作用體內體外相關性
外文關鍵詞:mosaprideCYP3A probedrug-drug interactionin Vitro-in Vivo correlation
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簡介
Cytochrome P450(CYP450)為人類及大鼠主要的代謝酵素之一類,其中又以亞族(subfamily)CYP3A所佔含量最多,主要分布在肝臟細胞及腸道上皮細胞。由於其廣泛代謝藥物及天然物的特性,有鑑於目前臨床治療方法的選擇多元性,多種藥物併用引起交互作用的風險的可能性增加,因此與CYP3A相關的藥物交互作用研究在近年來也漸漸受到許多藥政相關單位的重視。Mosapride為serotonin 5HT4促進劑,臨床上主要用於消化器官蠕動異常所引起的不適症狀,於人體內主要經由肝臟細胞色素CYP3A4代謝成des-4-fluorobenzyl mosapride。在本實驗室過去的相關研究中發現,以大白鼠動物模式靜脈注射及口服給予mosapride分別可觀察到肝臟及腸道中CYP3A酵素含量和清除率成高度相關性,能夠反應出酵素活性,且mosapride和廣為使用的探針性試藥midazolam在清除率上有顯著的一致性,更加強了mosapride作為CYP3A體內探針性試藥的可行性。
研究目的
為進一步將mosapride的應用範圍擴大於藥物動力學臨床前試驗,本研究利用大白鼠肝臟微粒體進行體外培養試驗以了解mosapride的酵素動力學特性及對CYP3A酵素抑制劑的反應程度,配合大鼠體內藥物交互作用試驗進行體內體外相關性研究,探討mosapride作為探針性試藥預測大鼠體內交互作用的可能性。
研究方法
體外試驗首先建立mosapride及midazolam體外酵素動力學模式,分別確立酵素動力學參數,再以目前常用的探針性試藥midazolam標定mosapride之抑制動力學參數,了解其本身對其他受質的抑制機轉。另外選擇不同抑制機轉的CYP3A抑制劑,以mosapride作為探針性試藥,求得體外抑制參數,並將此試驗結果利用In Vitro-In Vivo Extrapolation(IVIVE)公式作大鼠體內藥物交互作用的預測。同時配合大鼠活體試驗,觀察控制組及投予CYP3A抑制劑ketoconazole後mosapride的藥物動態改變情形,與體外試驗預測的結果以模式進行相關性研究。
研究結果
以大鼠肝臟微粒體進行體外試驗結果mosapride主要藉由CYP3A subfamily代謝,且mosapride本身除了為CYP3A受質外,對於典型的CYP3A探針性試藥midazolam也有抑制代謝的情形(Ki = 3.8 μM)。另外,利用mosapride作為體外探針性試藥能夠敏感反映出不同抑制機轉的CYP3A酵素抑制劑之抑制反應,其中臨床常見的抑制劑ketoconazole以mixed type型式對mosapride的代謝反應呈現強效抑制(Ki = 0.247 μM),並且在體內交互作用試驗中隨著劑量增加,對mosapride代謝有顯著的抑制作用。在體內體外相關性試驗中,配合公式及肝臟清除率模式(well-stirred model、parallel tube model、dispersion model)預估大鼠體內併用CYP3A抑制劑ketoconzazole的mosapride清除率變化,預測結果與體內交互作用試驗結果皆呈高度相關。
研究結論
Mosapride在大鼠模式中以體外或體內試驗皆能反應出CYP3A酵素活性受抑制的程度,且本試驗利用公式及肝臟清除率模式進行體內體外相關性試驗研究,預測臨床常見CYP3A抑制劑ketoconazole的抑制反應結果與體內試驗呈高度相關,因此mosapride作為CYP3A活性探針性試藥,應用在臨床上CYP3A相關的藥物交互作用評估或藥品研發、中西藥交互作用等應具有相當的潛力。
Introduction
CYP3A is one of the most important and most abundant subfamily expressed in the liver and small intestine. The use of selected drugs as “probes” to assess in vivo CYP activity has been the subject of intense interest for over a decade. Among many CYP3A probes, midazolam is the most accepted CYP3A probe used in human, but it’s use is limited.
Mosapride, a new prokinetic agent, undergoes N-dealkylation metabolism to form des-4-fluoro-benzyl metabolite (M-1) mediated by CYP3A enzymes.After intravenous and oral administration of mosapride, the hepatic and intestinal CYP3A contents showed strongly correlation with mosapride, therefore, mosapride clearance can be used to reflect the in vivo CYP3A activity,on the other hand, strong correlation between the clearance of mosapride and midazolam supports the applicability of mosapride as a probe to assess hepatic CYP3A activity in rats.
Purpose
In this project, it is aimed to characterize the in vitro microsome kinetics of mosapride itself and inhibition kinetics with other known CYP3A inhibitors. Finally, to evaluate the feasibility of mosapride to predict CYP3A-mediated drug-drug interactions in rats.
Methods
In vitro experiment, the incubation system and kinetic parameters of the substatrates(Km, Vmax)will be established,.The inhibition constant(Ki or IC50) of typical CYP450 inhibitors will be determined and compared with reference values. In vitro/in vivo extrapolation(IVIVE)equation and in vitro/in vivo scaling technique were used to predict the decrease in CL of mosapride after ketoconazole IV infusion treatment. Thus to evaluate the feasibility of mosapride to predict enzyme inhibition effect of ketoconazole by comparing the prediction from in vitro data with in vivo drug-drug interactions data.
Results
From in Vitro studies it comfirmed that mosapride is primarily metabolized by CYP3A subfamily in rats. We found mosapride is not only the substrate but also acts as an inhibitor on midazolam metabolism(Ki =3.8 μM).And as a probe substrate, mosapride reflected enzymes activity well in inhibition conditions. Finally, clearance of mosapride affected by ketoconazole is well-predicted by using IVIVE equation and IVIV scaling technique.
Conclusions
Results in this studies provide more evidence on the applicability of mosapride as a potential in vitro and in vivo hepatic CYP3A probe used to assess aspects of drug interactions having potential clinical importance in rat model, and may helpful to evaluate CYP3A related drug-drug , drug-herb, and drug food interactions in drug development and in clinical application.
中文摘要 i
Abstract iii
縮寫表 vi
目錄 vii
圖目錄 xi
第壹章 緒論 1
第一節 細胞色素(Cytochrome P450) 1
一、 命名方式 3
二、 分布及特性 3
三、 不同物種間CYP450差異 5
第二節 代謝酵素CYP3A 8
一、 種類 8
二、 酵素受誘導、抑制的作用 10
第三節 CYP3A探針性試藥 13
一、 探針性試藥定義 14
二、 理想探針性試藥條件: 14
三、 現行已知的CYP3A體內探針性試藥介紹 15
第四節 體內體外相關性試驗 19
第五節 Mosapride簡介 23
一、 物化性質 23
二、 作用機轉 23
三、 藥動特性 23
四、 藥物交互作用 28
五、 Mosapride作為探針性試藥的相關研究 29
第貳章 研究目的 32
第一節 探討Mosapride在酵素動力學的表現 32
第二節 Mosapride作為體外探針性試藥之應用 33
第三節 大白鼠體內藥物交互作用研究 33
第四節 體內體外相關性之研究 33
第參章 實驗材料、儀器及方法 34
第一節 實驗材料 34
一、 實驗動物 34
二、 藥品與試劑 34
第二節 實驗儀器 37
一、 紫外光/可見光分光光度計 37
二、 螢光分光光度計 37
三、 高效能液相層析系統 ( HPLC system ) 37
四、 微粒體製備系統 38
五、 微粒體體外培養系統 38
六、 動物實驗手術及檢品處理 38
七、 繪圖及藥動分析軟體 39
第三節 實驗方法 40
一、 藥品配製與定量分析 40
二、 大白鼠肝臟微粒體製備 42
三、 大白鼠肝臟微粒體之蛋白質含量測定:Lowry method 43
四、 Mosapride在大白鼠之藥物動態試驗 44
五、 實驗設計 47
六、 數據解析 56
第肆章 實驗結果 58
第一節 探討Mosapride在酵素動力學的表現 58
一、 Mosapride在大白鼠代謝之定性試驗 58
二、 體外肝臟微粒體培養試驗條件的確立 60
三、 酵素動力學參數之確立 63
第二節 Mosapride作為體外探針性試藥之應用 69
一、 不同機轉抑制劑之抑制反應 69
二、 受質與酵素鍵結機制之探討 69
第三節 大白鼠體內藥物交互作用研究 74
一、 控制組中靜脈輸注mosapride之藥物動力學 74
二、 CYP3A酵素抑制下mosapride之藥品動態 74
第四節 體內-體外相關性之研究 77
一、 模式使用參數 77
二、 模式適配 78
1. Well-stirred model 78
2. Parallel tube model 79
3. Dispersion model 80
第伍章 討論 81
第一節 Mosapride在酵素動力學的表現 81
一、 Mosapride在大白鼠代謝之定性試驗 81
二、 體外肝臟微粒體培養試驗條件的確立 82
三、 酵素動力學參數之確立 82
第二節 Mosapride作為體外探針性試藥之應用 83
一、 不同機轉抑制劑之抑制反應 83
二、 受質與酵素鍵結機制之探討 84
第三節 大白鼠體內藥物交互作用研究 85
一、 控制組 85
二、 抑制組 86
第四節 體內-體外相關性之研究 87
一、 模式參數影響 87
二、 模式適配度 88
第陸章 結論 90
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