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研究生:林俊翰
研究生(外文):Chun-Han Lin
論文名稱:類風濕性關節炎對於脂溶性他汀類藥物在大鼠上藥動學影響之探討:從基礎研究到以生理學為基礎之藥動學模式
論文名稱(外文):The effects of rheumatoid arthritis on the pharmacokinetics of lipophilic statins in rats: From bench works to physiologically based pharmacokinetics (PBPK) modeling
指導教授:林君榮
指導教授(外文):Chun-Jung Lin
口試日期:2017-07-25
學位類別:碩士
校院名稱:國立臺灣大學
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:2017
畢業學年度:105
語文別:中文
論文頁數:100
中文關鍵詞:藥動學他汀類藥物類風溼性關節炎以膠原蛋白誘發之關節炎大鼠以生理學為基礎之藥動學模式
外文關鍵詞:pharmacokineticsstatinsrheumatoid arthritiscollagen-induced arthritis ratphysiologically based pharmacokinetics (PBPK)
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他汀類藥物是常用於類風溼性關節炎之心血管合併症的降血脂藥物。我們先前的研究結果顯示脂溶性他汀類藥物fluvastatin、atorvastatin及simvastatin在以膠原蛋白誘發關節炎大鼠的血中濃度顯著高於對照組。本研究進一步評估類風濕性關節炎對肝臟代謝活性之影響,並分別藉由靜脈注射及以生理學為基礎之藥動學模式(PBPK modeling)來探討關節炎對於這些他汀類藥物藥動學的影響。由我們的結果得知,關節炎大鼠肝臟微粒體的Cyp2c及Cyp3a酵素的最大反應速率明顯低於對照組。在給予靜脈速注後, simvastatin在關節炎大鼠的全身藥物暴露量為對照組的三倍。相反地, fluvastatin或atorvastatin的血中濃度在關節炎大鼠及其對照組間無差異。在關節炎大鼠上,simvastatin的微粒體代謝清除率顯著下降,然而肝細胞攝取清除率卻沒有改變。先前體外試驗之結果被納入PBPK模式中並成功預測fluvastatin及atorvastatin在關節炎大鼠及其對照組的血中濃度時間曲線。這些結果顯示類風溼性關節炎對於脂溶性他汀類藥物有不同的影響。
Statins are lipid-lowering agents widely used in rheumatoid arthritis (RA) patients with concurrent cardiovascular diseases. Previously, we have demonstrated that the blood concentrations of orally administered lipophilic statins (i.e. fluvastatin, atorvastatin, and simvastatin) were significantly changed in rats with collagen-induced arthritis (CIA). In the present study, we further investigated the impact of RA on the pharmacokinetics of these statins. Accordingly, the effect of RA on metabolic activities of hepatic microsomes was evaluated. Also, the pharmacokinetics of lipophilic statins were examined following intravenous administrations and by physiologically based pharmacokinetics (PBPK) modeling approach. The results showed that maximal metabolic activities (Vm) of Cyp2c and Cyp3a were reduced in liver microsomes of CIA rats, compared with control rats. After single intravenous bolus, the systemic exposure of simvastatin increased by 3-fold in CIA rats, compared with the controls; in contrast, there were no differences in the plasma levels of fluvastatin and atorvastatin between CIA rats and control rats. The microsomal metabolic clearance of simvastatin but not hepatic uptake clearance was significantly decreased in CIA rats. Results from previous in vitro experiments were incorporated into the established PBPK model and the concentration-time profiles of fluvastatin and atorvastatin were successfully reproduced in either control rats or the CIA rats. These findings show the differential influence of RA in the pharmacokinetics of lipophilic statins.
Abstract i
中文摘要 ii
目錄 iii
圖目錄 vi
表目錄 viii
Chapter 1 文獻回顧 1
1.1 藥動學 1
1.1.1 代謝酵素及轉運蛋白對於藥物代謝之影響 1
1.1.2 研究藥物代謝之實驗模式 2
1.1.3 以生理學為基礎之藥動學模式 3
1.2 疾病與藥物交互作用 4
1.2.1 類風濕性關節炎 4
1.2.2 他汀類藥物 5
1.2.3 他汀類藥物用於類風濕性關節炎族群之益處與疑慮 6
Chapter 2 研究目的 15
Chapter 3 實驗材料 16
3.1 膠原蛋白誘發之關節炎大鼠動物模式之建立 16
3.2 探討關節炎對於大鼠肝臟微粒體的Cyp2c及Cyp3a酵素活性之影響 17
3.3 以靜脈速注投予statins在關節炎大鼠上之藥動學試驗 19
3.4 探討關節炎對於大鼠肝臟微粒體代謝simvastatin能力之影響 21
3.5 探討關節炎對於大鼠肝細胞攝取simvastatin能力之影響 22
3.6 建立大鼠的以生理為基礎之藥動學(PBPK)模式 24
Chapter 4 實驗方法 25
4.1 膠原蛋白誘發之關節炎大鼠動物模式之建立 25
4.2 探討關節炎對於大鼠肝臟微粒體的Cyp2c及Cyp3a酵素活性之影響 26
4.2.1 分離大鼠肝臟微粒體 26
4.2.2 微粒體的蛋白質定量分析 26
4.2.3 大鼠肝臟微粒體CYP450酵素受質之時間依賴性試驗 26
4.2.4 大鼠肝臟微粒體CYP450酵素受質之濃度依賴性試驗 27
4.2.5 液相層析串聯式質譜儀分析試驗 27
4.2.6 數據分析 28
4.3 以靜脈速注投予statins在大鼠上之藥動學試驗 28
4.3.1 大鼠之股靜脈插管 28
4.3.2 靜脈速注投予fluvastatin、atorvastatin及simvastatin 29
4.3.3 液相層析串聯式質譜儀分析試驗 29
4.3.4 數據分析 30
4.4 探討關節炎對於大鼠肝臟微粒體代謝simvastatin能力之影響 31
4.4.1 利用受質耗竭法決定肝臟微粒體代謝simvastatin之能力 31
4.4.2 液相層析串聯式質譜儀分析試驗 31
4.4.3 數據分析 31
4.5 探討關節炎對於大鼠肝細胞攝取simvastatin能力之影響 32
4.5.1 分離大鼠肝細胞 32
4.5.2 大鼠肝臟細胞懸浮液攝取simvastatin之試驗 32
4.5.3 液相層析串聯式質譜儀分析試驗 33
4.5.4 數據分析 33
4.6 建立大鼠的以生理為基礎之藥動學模式 34
4.6.1 PBPK模式的模型架構及初始參數值 34
4.6.2 PBPK模式的參數最佳化 35
4.6.3 PBPK模式的評估 36
4.6.4 PBPK模式的確效 37
4.6.5 PBPK模式之敏感度分析 37
4.6.6 PBPK 模式結合蒙地卡羅方法模擬藥物血中濃度對時間曲線 37
Chapter 5 實驗結果 46
5.1 評估膠原蛋白誘發之關節炎大鼠動物模式 46
5.2 類風溼性關節炎對大鼠肝臟微粒體Cyp2c及Cyp3a酵素活性之影響 46
5.3 以靜脈速注投予statins在大鼠上之藥動學試驗 46
5.4 探討關節炎對於大鼠肝臟攝取及代謝simvastatin能力之影響 47
5.5 建立大鼠的以生理為基礎之藥動學模式 47
5.5.1 PBPK模式的模型架構及初始參數值 47
5.5.2 PBPK模式的參數最佳化、評估及模擬 48
5.5.3 PBPK模式的確效 48
5.5.4 PBPK模式對於各參數的敏感度分析 49
5.5.5 PBPK模式結合蒙地卡羅方法模擬藥物血中濃度對時間曲線 50
Chapter 6 結果討論 70
Chapter 7 結論 74
Chapter 8 參考文獻 75
Chapter 9 附錄 87
9.1 Mass balance equations 87
9.1.1 Model 1 and Model 2 87
9.1.2 Model 3 89
9.2 Berkeley Madonna™原始程式碼 89
9.2.1 Model 1&2 (以fluvastatin為例) 89
9.2.2 Model 3 (以atorvastatin為例) 94
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