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| 題名: | 液相層析串聯質譜分析法定性及定量生物檢體內毒藥物成分 |
| 作者: | 劉秀娟 |
| 貢獻者: | 藥學系(博士班) |
| 關鍵詞: | 液相層析串聯質譜分析法 定性分析 定量分析 毒藥物 |
| 日期: | 2010 |
| 上傳時間: | 2010-10-20 12:53:06 (UTC+8) |
| 摘要: | 近年來隨著液相層析質譜分析法的技術進展，有許多不同類組合的液相層析串聯質譜儀，可以提供開發更具專一性分析方法的機會，尤其是在使用單一種分析方法來達成毒藥物篩驗及確認的雙重檢測目標的可能性上。本研究首先使用液相層析電灑離子阱質譜儀，樣品經層析管分離、離子阱質譜儀選取母離子(M+H)，以線性增加碰撞能量技術將母離子碰撞為子離子，選取子離子之二次質譜圖及滯留時間，建立800種包含鴉片類、安非他命類、鎮靜安眠藥、抗憂鬱劑、農藥及一般常見藥物等毒藥物標準正電離子模式二次質譜圖資料庫，此一創新的離子斷裂模式及擁有豐富離子訊息之毒藥物二次質譜圖資料庫經歷六個月之長期測試結果，顯示質譜的再現性及比對率極佳。同時我們亦採用大量死亡案件解剖取得生物檢體及美國病理學會能力測試檢體，經液相-液相或固相萃取法處理後，注入儀器檢測，配合分析軟體進行圖譜資料搜尋比對，結果確認分析方法對於毒藥物成分的鑑別率極高，且在待測物滯留時間內並沒有明顯的干擾物質存在，此一方法與傳統二步驟之免疫分析法及氣相層析質譜分析法相比較，在檢測毒藥物的能力方面在檢出率與檢驗時效已有重大突破及明顯提昇。
本研究進一步應用液相層析三段四極柱串聯質譜儀建立靈敏度及專一性高的分析方法，以氘化物為內標準品、正電離子模式電灑游離法(ESI)配合多重反應偵測(MRM)同時定量分析頭髮及唾液內安非他命、甲基安非他命、嗎啡、可待因、乙醯嗎啡及乙醯可待因等6種成分。頭髮分析部分係以50 mg空白頭髮配製濃度為100-10000 pg/mg等7種不同濃度之日內及日間精準度(CV%)安非他命為1.03-5.06%、甲基安非他命為1.90-5.56%、嗎啡為0.95-7.41%、可待因為1.01-7.62%、乙醯嗎啡為2.23-4.01%、乙醯可待因為1.29-8.21%；在此濃度範圍內具有良好之線性關係 (r2>0.998)；最低可偵測濃度(LOD) 為10 pg/mg；最低可定量濃度(LOQ)為50 pg/mg。以此方法對監所86位接受觀察勒戒女子之頭髮進行安非他命類及鴉片類成分定量分析，探討國內此二類毒品併用之比例及成分間之比值相關性。在唾液分析部分係將10 ?尳之唾液以直接注入儀器分析之方式，同時定量分析唾液內安非他命類及鴉片類6種成分，因減少檢體前處理及萃取濃縮等步驟，可縮短分析之時間，在濃度1-500 ng/mL範圍內具有良好之線性關係 (r2>0.990)；以5種濃度檢測日內及日間精準度(CV%)，安非他命為1.02-4.24%、甲基安非他命為1.00-8.16%、嗎啡為0.85-11.38%、可待因為1.67-9.62%、乙醯嗎啡為0.92-3.50%、乙醯可待因為2.75-12.89%。最低可偵測濃度及最低可定量濃度均為1 ng/mL，亦成功以此方法應用於接受毒品減害替代療法的34位測試者之唾液中所含安非他命類及鴉片類成分定量分析。
Recent advances in liquid chromatography-tandem mass spectrometry (LC-MS/MS) technology have provided an opportunity for the development of more specific approaches to achieve the screen and confirmation goals in a single analytical step. For this purpose, this study adapts the electrospray ionization ion trap LC-MS/MS instrumentation for the screening and confirmation of over 800 drugs and toxic compounds in biological specimens. An LC-MS/MS database, including 800 drug and toxic compounds, has been constructed, featuring information-rich MS/MS spectra derived from a novel fragmentation approach incorporating voltage ramping and broadened mass window for activation. The resulting spectra are rich in high- and low-mass fragment ions, highly effective for matching and proven reproducible over a 6 month test period. Coupled to effective sample preparation protocols, the database searching process greatly improved the identification of drugs in postmortem specimens and external proficiency test samples provided by College of American Pathology by the LC-electrospray ionization (ESI)-MS/MS technology. No significant interference was found at the retention time expected of the targeted compounds. This method has significantly improved the efficiency of our routine laboratory operation that was based on a two-step (fluorescence polarization immunoassay and gas chromatography/mass spectrometry) approach in the past.
Furthermore, in this study, we developed a sensitive and specific method for simultaneous quantitation of amphetamine, methamphetamine, morphine, codeine, 6-acetylmorphine and 6-acetylcodeine in human hair and oral fluid by LC-MS/MS. Calibration, with deuterated internal standards, was performed by linear regression analysis. Mass spectrometric analysis was performed in positive-ion mode, applying multiple reaction monitoring using appropriate collision energy for each precursor ion. When applied to the analysis of drug-free hair specimens fortified with 100-10000 pg/mg, the overall protocol achieves the following inter-day and intra-day precision ranges: 1.03-5.06%, 1.90-5.56%, 0.95-7.41%, 1.01-7.62%, 2.23-4.01% and 1.29-8.21%, for amphetamine, methamphetamine, morphine, codeine, 6-acetylmorphine, and 6-acetylcodeine, respectively. Good linearity (r2 > 0.998) and detection and quantitation limits (10 and 50 pg/mg) were routinely observed. Data derived from the analysis of amphetamines and opiates in hair samples collected from 86 self-reported drug abusers were evaluated to understand the drug use pattern among this population. For oral fluid analysis, 10-?尳 aliquots were injected directly onto the LC-MS/MS system. Linearity was established in the concentration range of 1-500 ng/mL. The limits of detection and quantitation were 1 ng/mL for these 6 analytes. The precision and accuracy were determined by spiking oral fluid samples at five concentration levels. For all analytes, the relative standard deviations of intra- and inter-day precision were 0.85-6.41% and 1.00-12.89%, respectively. With practically no sample preparation requirement, this method substantially reduced total analysis time and was successfully applied to the analysis of 34 oral fluid specimens collected from patients participating in a substitution therapy program. |
| 關聯: | 224頁 |
| 描述: | (一)論文目次
第一章 緒論………………………………………………………………1
第一節 前言…………………………………………………………2
第二節 法醫毒物及臨床毒物分析流程簡介………………………2
壹、分離…………………………………………………………2
貳、初步篩驗………………………………………………… 3
參、確認檢驗………………………………………………… 3
肆、定量分析………………………………………………… 4
第三節 研究動機及目的………………………………………… 4
第四節 液相層析質譜儀儀器原理……………………………… 6
壹、進樣系統………………………………………………… 7
貳、離子源…………………………………………………… 7
一、電灑游離法…………………………………………… 8
二、大氣壓化學游離法…………………………………… 11
參、質量分析器……………………………………………… 12一、四極柱質量分析器…………………………………… 12
二、離子阱質量分析器…………………………………… 14
肆、偵測器…………………………………………………… 15
伍、資料處理系統…………………………………………… 16
陸、串聯質譜分析法………………………………………… 16
一、子離子掃描…………………………………………… 18
二、母離子掃描…………………………………………… 18
三、中性丟失掃描………………………………………… 19
四、選擇反應偵測………………………………………… 19
五、多重反應偵測………………………………………… 19
第五節 研究內容概述…………………………………………… 20
第二章 以液相層析離子阱質譜儀建立二次質譜資料庫以篩驗及確認生物檢體內未知毒藥物成分………….………………………… 21
第一節 前言…………………………….………………………… 22
第二節 實驗材料與方法………………………………………… 24
壹、實驗材料.. ………………………………………………… 24
貳、實驗儀器……………………………….………………… 24
參、檢體來源……………………..…………………………… 26
一、生物檢體…………………………..………………… 26
二、非傳統性檢體…………………..…………………… 26
三、美國病理學會盲績效檢體…………………………… 26
肆、實驗方法…………………….………….………………… 26
一、建立資料庫………………………….…….………… 26
二、固相萃取…………………………..………………… 26
三、液相-液相萃取…………………..…………………… 27
四、頭髮及指甲萃取……………………………………… 27
五、資料庫搜尋比對……………………………………… 27
第三節 結果與討論……………………………………………… 29
壹、線性增加碰撞能量技術評估…………………………… 29
貳、ESI-MS/MS之圖譜資料庫……………………………… 29
參、資料庫搜尋……………………………………………… 30
肆、偵測極限之評估………………………………………… 30
伍、標準二次質譜再現性評估……………………………… 30
陸、分析方法耐變性評估…………………………………… 31
柒、二次質譜資料庫應用實例……………………………… 40
一、死亡案件檢體分析…………………………………… 40
二、頭髮與指甲檢體分析………………………………… 44
三、美國病理協會準確性能力測試……………………… 46
第四節 結論……………………………………………………… 46
附表………………………………………………………………… 51
縮寫表……………………………………………………………… 61
第三章 以高分離度快速液相層析離子阱質譜儀及自動化二次質譜
資料庫搜尋方式快速分析屍體內毒藥物成分……………… 63
第一節 前言……………………………………………………… 64
壹、UPLC之原理…………………………………………… 65
貳、RRLC之原理…………………………………………… 66
參、UPLC及RRLC於毒藥物分析之應用………………… 67
第二節 實驗材料與方法………………………………………… 69
壹、實驗材料……..…………………………………………… 69
貳、實驗儀器……………………………….………………… 70
參、檢體來源……………………..…………………………… 71
一、生物檢體…………………………..………………… 71
二、非傳統性檢體…………………..…………………… 71
三、美國病理學會盲績效檢體…………………………… 71
肆、實驗方法…………………….………….………………… 71
一、建立資料庫………………………….…….………… 71
二、固相萃取…………………………..………………… 71
三、液相-液相萃取…………………..…………………… 72
四、頭髮萃取……………………………………………… 72
第三節 結果與討論……………………………………………… 72
壹、ESI-MS/MS之圖譜資料庫……………………………… 72
貳、標準二次質譜再現性評估……………………………… 73
參、偵測極限之評估………………………………………… 74
肆、死亡案件檢體分析……………………………………… 74
一、海洛因致死案例……………………………………… 74
二、司法毒物實際案例應用……………………………… 83
伍、頭髮檢體分析—古柯鹼案例…………………………… 86
陸、美國病理協會準確性能力測試………………………… 89
柒、以381件死者血液比較RRLC-MS/MS與GC/MS檢測
能力…………………………………………… 98
第四節 結論……………………………………………………… 98
第四章 以液相層析串聯質譜分析法同時定量頭髮中安非他命類及
鴉片類成分……………….…………………………………… 102
第一節 前言…………………………….………………………… 103
壹、毛髮之結構與生理…………….………………………… 105
貳、藥物進入毛髮的機轉………….………………………… 106
參、頭髮中毒品成分研究文獻回顧………………………… 107
肆、頭髮中毒品成分釋出之方法…………………………… 109
伍、本研究之動機與目的……….…………………………… 110
第二節 實驗材料與方法………………………………………… 111
壹、實驗材料……..…………………………………………… 111
貳、標準品溶液的配製……………………………………… 112
一、標準品溶液的配製…………………………………… 112
二、氘內標準品溶液的配製……………………………… 112
三、頭髮檢量線溶液的配製……………………………… 112
參、實驗儀器……………………………….………………… 113
肆、檢體來源…………………………….…………………… 114
一、空白頭髮樣品………………….…………………… 114
二、吸毒者頭髮樣品……………….…………………… 114
三、頭髮分段……………………….…………………… 114
伍、實驗方法………………….………….………………… 115
一、檢體前處理方式…….………….………….………… 115
二、消化及培育方法評估……….…………….………… 115
三、分析方法的確效評估.………….………….………… 115
四、偵測極限與定量極限…………..…………………… 115
五、吸毒者頭髮中安非他命類及鴉片類成分分析……… 115
六、頭髮分段分析……………………..………………… 116
第三節 結果與討論……………………………………………… 116
壹、檢體前處理方式對於待分析物穩定性影響…………… 116
一、消化或溫浸方式對於待分析物安定性影響………… 116
二、吸毒者頭髮經消化或溫浸後溶出率之比較………… 117
貳、萃取回收率……………………………………………… 118
參、基質效應………………………………………………… 119
肆、分析方法的確效評估…………………………………… 121
伍、偵測極限與定量極限…………………………………… 135
陸、監所接受觀察勒戒者頭髮之分析……………………… 135
柒、監所接受觀察勒戒者頭髮之分段分析………………… 138
第四節 結論……………………………………………………… 138
第五章 以液相層析串聯質譜分析法直接注射方式同時定量唾液中
安非他命類及鴉片類成分………….………………………… 142
第一節 前言…………………………….………………………… 143
壹、唾液中毒藥物成分研究文獻回顧……………………… 144
貳、本研究之動機與目的…….……………………………… 146
第二節 實驗材料與方法………………………………………… 146
壹、實驗材料……..…………………………………………… 146
貳、標準品溶液的配製……………………………………… 147
一、標準品溶液的配製…………………………………… 147
二、氘內標準品溶液的配製……………………………… 147
三、唾液檢量線溶液的配製……………………………… 147
參、實驗儀器……………………………….………………… 148
肆、檢體來源…………………….………….………………… 152
一、空白唾液樣品…….……………………….………… 152
二、吸毒者唾液樣品………………..…………………… 152
伍、實驗方法…………………….………….………………… 152
一、檢體前處理方式……….………….………………… 152
二、檢體前處理方法評估….………….………………… 152
(一) 不同唾液基質對分析物波峰面積影響評估… 152
（二）唾液基質加熱處理對分析物波峰面積影響
評估……………….………….………………… 152
三、分析方法的確效評估….………….………………… 153
四、偵測極限與定量極限.………….…………………… 153
五、吸毒者唾液中安非他命類及鴉片類成分分析……… 153
第三節 結果與討論……………………………………………… 153
壹、檢體前處理方法評估…………………………………… 153
一、不同唾液基質對分析物波峰面積影響評估………… 153
二、唾液基質加熱處理對分析物波峰面積影響評估…… 154
貳、基質效應………………………………………………… 155
參、專一性評估……………………………………………… 156
肆、分析方法的確效評估…………………………………… 157
伍、偵測極限與定量極限…………………………………… 157
陸、吸毒者唾液中安非他命類及鴉片類成分分析………… 171
第四節 結論……………………………………………………… 171
第六章 總結…………………………………………………………… 174
第七章 參考文獻……………………………………………………… 175
著作選集………………………………………………………………… 190
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