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研究生:鄭羽含
研究生(外文):Yu-Han Cheng
論文名稱:以分散式液液微萃取結合表面輔助雷射脫附游離質譜法偵測人類尿液與血清中利伐沙班
論文名稱(外文):Determination of Rivaroxaban in Human Urine and Serum by Surface-Assisted Laser Desorption/Ionization Mass Spectrometry with Dispersive Liquid-Liquid Microextraction
指導教授:張玉珍張玉珍引用關係
指導教授(外文):Yu-Chen Chang
學位類別:碩士
校院名稱:國立高雄師範大學
系所名稱:化學系
學門:自然科學學門
學類:化學學類
論文種類:學術論文
論文出版年:2015
畢業學年度:103
語文別:中文
論文頁數:110
中文關鍵詞:表面輔助雷射脫附游離質譜法分散式液液微萃取法利伐沙班
外文關鍵詞:SALDI-MSDLLMERivaroxaban
相關次數:
  • 被引用被引用:1
  • 點閱點閱:125
  • 評分評分:
  • 下載下載:13
  • 收藏至我的研究室書目清單書目收藏:2
本研究是以分散式液液微萃取法(Dispersive Liquid-Liquid Microextraction, DLLME)結合表面輔助雷射脫附游離質譜法(Surface-Assisted Laser Desorption Ionization Mass Spectrometry, SALDI-MS)偵測生物樣品中的抗凝血藥物-利伐沙班(Rivaroxaban, RIV)。50 μL之氯仿(萃取劑)與260 μL四氫呋喃(分散劑)混合溶液快速注入1 mL樣品溶液中,使其形成雲霧狀態(Cloudy state)。萃取步驟完成後,以膠體鈀作為SALDI-MS之基質進行RIV之偵測。在最佳萃取及偵測條件下,RIV之偵測極限為2 nM。當萃取樣品溶液及萃取後回溶液體的體積比為200,RIV之濃縮倍率為141。此方法更成功應用在人類尿液及血清中的偵測,尿液樣品的線性範圍為0.02-1 μM;血清樣品之線性範圍為0.2-5.0 μM,在尿液與血清中的偵測極限分別為6和60 nM,RIV在尿液及血清中的回收率分別為50.6%及29.8%;在尿液及血清中Intra-day與Inter-day的精密度與準確度皆小於8%(n=5)。此方法提供了簡單、快速、低成本與高再現性去偵測人類尿液與血清樣品中RIV。
  A method for the determination of rivaroxaban (RIV) using dispersive liquid-liquid microextraction (DLLME) coupled to surface-assisted laser desorption/ionization mass spectrometric (SALDI-MS) detection was developed. A mixture of 50 μL of chloroform (extraction solvent) and 260 μL of tetrahydrofuran (dispersive solvent) was injected rapidly into the aqueous sample to form a cloudy solution. After the extraction, RIV was detected through SALDI-MS using colloidal Pd as SALDI matrix. Under optimum conditions, the limits of detection (LOD) at a signal-to-noise ratio of 3 was 2 nM for RIV. With a sample-to-extract volume ratio of 200, the enrichment factor for RIV was calculated to be 141. This developed method was successfully applied to the determination of RIV in human urine and serum samples. The linear ranges were 0.02-1μM for urine sample and 0.2-5.0 μM for serum sample. The LODs for urine and serum were 6 and 60 nM, respectively. Recoveries of RIV in urine and serum sample were 50.6% and 29.8%, respectively. This method provides simplicity, rapidity, low cost, and high reproducibility for the determination of RIV in human urine and serum sample.
目錄
謝誌 Ⅰ
摘要 Ⅱ
Abstract Ⅲ
目錄 Ⅳ
圖目錄 Ⅷ
表目錄 XⅠ
一、緒論 1
1-1抗凝血劑-利伐沙班(Rivaroxaban)簡介 1
1-1-1作用機轉 3
1-1-2藥物動力學 5
1-1-3治療範圍及生物毒性 5
1-1-4分析方法整理 6
1-2基質輔助雷射脫附游離法(MALDI)簡介 9
1-2-1 MALDI發展歷程 9
1-2-2 MALDI原理機制 11
1-2-3 MALDI有機基質之特性與應用 12
1-3表面輔助雷射脫附游離法(SALDI)簡介 15
1-3-1 SALDI基質之特性與應用 16
1-3-2 SALDI於小分子之應用 19
1-4分散式液液微萃取法 24
1-5研究動機與目的 28
二、實驗部分 29
2-1實驗藥品 29
2-2儀器設備 32
2-3實驗方法及步驟 33
2-3-1溶液配置 33
2-3-2尿液樣品採樣及前處理 35
2-3-3血清樣品採樣及前處理 35
2-3-4 DLLME步驟 36
2-3-5 SALDI樣品製備 36
2-3-6質譜操作條件 38
三、 結果與討論 39
3-1 表面輔助雷射脫附游離法偵測 39
3-1-1基質之選擇 39
3-1-2基質濃度之探討 44
3-1-3添加磷酸鈉緩衝溶液之探討 46
3-2 分散式液液微萃取最佳萃取條件分析 48
3-2-1萃取劑之選擇 48
3-2-2分散劑之選擇 51
3-2-3分散劑體積之探討 53
3-2-4萃取劑體積之探討 55
3-2-5待萃取樣品溶液pH值之探討 57
3-2-6添加鹽類之探討 59
3-2-7震盪時間之探討 61
3-3標準溶液之檢量線與偵測極限 64
3-3-1直接分析之檢量線與偵測極限 64
3-3-2經分散式液液微萃取之檢量線與偵測極限 66
3-3-3 分散式液液微萃取之濃縮倍率與萃取回收率 68
3-4尿液樣品之定量分析 70
3-4-1尿液樣品之檢量線與偵測極限 74
3-4-2尿液樣品之回收率 77
3-4-3尿液樣品之精密度與準確度 78
3-4-4尿液樣品之選擇性 80
3-5血清樣品之定量分析 87
3-5-1血清樣品前處理探討 87
3-5-2血清樣品之檢量線與偵測極限 91
3-5-3血清樣品之回收率 94
3-5-4血清樣品之精密度與準確度 95
3-5-5血清樣品之選擇性 96
四、 結論 103
五、 參考文獻 104
圖目錄
圖1 利伐沙班(Rivaroxaban)結構圖 2
圖2 凝血連鎖反應(coagulation cascade)與RIV作用位置 4
圖3 不同劑量RIV(BAY 59-7939)血漿濃度對時間曲線 6
圖4 基質輔助雷射脫附游離機制圖 11
圖5 分散式液液微萃取之流程圖 25
圖6 分散式液液微萃取(DLLME)結合表面輔助雷射脫附游離法
(SALDI)樣品製備步驟 37
圖7 不同基質對於RIV游離效率之質譜圖 41
圖8 Colloidal Pd之UV-visible吸收光譜圖 43
圖9 (A)與(B)為Colloidal Pd之TEM圖 43
圖10 不同Colloidal Pd濃度對於RIV游離效率之影響 45
圖11 不同磷酸系統緩衝溶液濃度對RIV游離效率之影響 47
圖12 不同萃取劑種類對於RIV萃取效率之影響 50
圖13 不同分散劑種類對於RIV萃取效率之影響 52
圖14 分散劑體積對於RIV萃取效率之影響 54
圖15 萃取劑體積對於RIV萃取效率之影響 56
圖16 pH值對於RIV萃取效率之影響 58
圖17 鹽類添加(NaCl)對於RIV萃取效率之影響 60
圖18 萃取時間對於RIV萃取效率之影響 62
圖19 RIV以SALDI直接分析之檢量線 65
圖20 RIV以分散式液液微萃取結合SALDI之檢量線 67
圖21 尿液樣品空白及添加RIV以SALDI-TOF MS偵測之圖譜 72
圖22 尿液樣品中添加RIV經分散式液液微萃取,不同回溶溶劑
條件SALDI-TOF MS偵測之圖譜 73
圖23 尿液樣品中添加RIV經分散式液液微萃取之檢量線 75
圖24 尿液樣品A以SALDI-TOF MS偵測之圖譜 81
圖25 尿液樣品B以SALDI-TOF MS偵測之圖譜 82
圖26 尿液樣品C以SALDI-TOF MS偵測之圖譜 83
圖27 尿液樣品D以SALDI-TOF MS偵測之圖譜 84
圖28 尿液樣品E以SALDI-TOF MS偵測之圖譜 85
圖29 尿液樣品F以SALDI-TOF MS偵測之圖譜 86
圖30 血清樣品前處理實驗經DLLME萃取後以SALDI-TOF MS
偵測之質譜圖 89
圖31 血清樣品添加RIV以SALDI-TOF MS偵測之質譜 90
圖32 血清樣品中添加RIV經分散式液液微萃取之檢量線 92
圖33 血清樣品A以SALDI-TOF MS偵測之圖譜 97
圖34 血清樣品B以SALDI-TOF MS偵測之圖譜 98
圖35 血清樣品C以SALDI-TOF MS偵測之圖譜 99
圖36 血清樣品D以SALDI-TOF MS偵測之圖譜 100
圖37 血清樣品E以SALDI-TOF MS偵測之圖譜 101
圖38 血清樣品F以SALDI-TOF MS偵測之圖譜 102
表目錄
表1傳統有機酸基質與適用分析物類型 13
表2 SALDI於小分子應用之文獻整理 22
表3 MALDI-TOF MS之操作參數 38
表4各種萃取劑之密度及溶解度 49
表5分散式液液微萃取之萃取最佳化條件 63
表6 RIV直接分析與經分散式液液微萃取之定量分析結果 69
表7 RIV於尿液樣品中經DLME結合SALDI之定量分析結果 76
表8 RIV於尿液樣品中之精密度與準確度 79
表9 RIV於血清樣品中經DLME結合SALDI之定量分析結果 93
表10 RIV於血清樣品中之精密度與準確度 95

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