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研究生:黃偉勛
研究生(外文):Wei-hsun Huang
論文名稱:Oxethazaine之誤用與在運動藥檢中檢測 mephentermine及phentermine之可能相關性
論文名稱(外文):Detection of mephentermine and phentermine in doping control and a possible link of these drugs to oxethazaine misuse
指導教授:曾應龍曾應龍引用關係邱鐵雄邱鐵雄引用關係
指導教授(外文):Ying-lung TsengTED H Chiu
學位類別:碩士
校院名稱:慈濟大學
系所名稱:藥理暨毒理學研究所
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:2008
畢業學年度:96
語文別:中文
論文頁數:86
中文關鍵詞:氣相層析質譜儀運動藥檢
外文關鍵詞:GC-MSdopingmephenterminephentermineoxethazaine
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在最近之全國性運動比賽期間, 慈濟大學運動藥物檢驗中心在進行藥物檢測時,曾發現多個尿液檢體中皆含有mephentermine 及 phentermine兩種運動禁藥成份。隨後在運動禁藥會議上,有一位選手提供其在比賽期間因治療胃痛所服用之處方,經實驗室檢測該運動員所提供之處方中所含之藥物後,發現了Stoin之藥物。 Stoin內含oxethazaine,在臨床上常用來做局部麻醉使用。Oxethazaine在體內會代謝出mephentermine及phentermine此兩種藥物。而這兩種藥物皆為世界反運動禁藥組織(WADA )在比賽期間所禁止使用的。
為了區別運動員在尿液檢測中之藥物是否來自服用oxethazaine或mephentermine及phentermine, 我們進行人體代謝實驗。五位健康的志願者在不同的時間中分別口服了5mg oxethazaine、10mg phentermine及10mg mephentermine; 藥物服用間隔為一個星期。在不同的時間點收集尿液後,以氣相層析質譜儀進行分析。結果顯示:(1) mephentermine在質譜之base peak為m/z 168,其餘特徵離子為m/z 110、91;phentermine的base peak為m/z 154,其餘特徵離子為m/z 132、91。(2) 代謝之趨勢圖顯示,在服用mephentermine後所產生之mephentermine及phentermine代謝峰在2小時至24小時之間;而服用oxethazaine所產生的代謝峰趨勢則是在2小時至12小時之間。(3)服用mephentermine、oxethazaine及phentermine所顯示出的phentermine代謝峰分別為24小時、2小時至12小時及2小時至24小時。(4)服用mephentermine所產生之mephentermine代謝物累積量濃(9.3±4.9 mg ; mean±S.D.)高過於代謝物phentermine之濃度(2.7±2.1 mg)。然而在服用oxethazaine後所產生的結果則相反,其mephentermine代謝物濃度為(0.5±0.3 mg),phentermine代謝物濃度為(1.2±0.8 mg)。 (5)當服用phentermine時,在尿液中只發現未改變的藥物本體。依據這些研究結果、運動員之尿液結果及使用oxethazaine後之代謝成分,我們推斷該運動員在比賽期間所服用之藥物很可能來自oxethazaine之誤用。
In a recent national sport competition in Taiwan, our laboratory found several positive cases on mephentermine and phentermine. One of the athletes claimed that medications had been taken for treating stomach pain prior to the game and the medications were presented to the doping control authority. Results of laboratory investigation found that Stoin was contained in one of the medications administered by the athlete. Stoin contains oxethazaine and has been used clinically as a topical anesthetic. Oxethazaine may convert to mephentermine and phentermine by the body’s metabolism. These drugs are prohibited in sports by the World Anti-Doping Agency.
Excretion studies were carried out on five healthy volunteers who orally consumed oxethazaine (5 mg), mephentermine (10 mg) and phentermine (10 mg) at different times with one week apart. Urine samples were collected at various times and analyzed using gas chromatography-mass spectrometry (GC-MS). The results were as follows: (1) The mass spectrum of mephentermine showed a base peak of m/z 168 with characteristic ions at m/z 110 and 91; phentermine showed a base peak of m/z 154 with characteristic ions at m/z 132 and 91. (2) The metabolic profiles showed that the concentrations of mephentermine and phentermine reached a peak between 2 hr to 24 hr when mephentermine was ingested and between 2 hr to 12 hr when oxethazaine was administrated. (3) The metabolic profiles revealed that the concentrations of phentermine reached a peak at approximately 24 hr, between 2 hr to 12 hr and between 2 hr to 24 hr following administration of mephentermine, oxethazaine and phentermine, respectively. (4) The cumulative amount of mephentermine metabolite (mean±S.D. = 9.3±4.9 mg) in urine was greater than that in phentermine (mean±S.D. = 2.7±2.1 mg), when mephentermine was administrated. However, this relationship was reversed with phentermine (mean±S.D. = 1.2±0.8 mg) greater than mephentermine (mean±S.D. = 0.5±0.3 mg), when oxethazaine was administrated. (5) When phentermine was ingested, only the unchanged parent drug was found in the urine. (6) According to this investigation, it was very likely that the athletes had taken oxethazaine-contained medication prior to the competitions.
1. 緒論 (Introduction)
1.1 背景介紹-----------------------------------------------------------1
1.1.1 Oxethazaine簡介----------------------------------------------------4
1.1.2 Oxethazaine之藥理作用----------------------------------------------4
1.1.3 Oxethazaine在人體的代謝--------------------------------------------5
1.1.4 Mephentermine及phentermine 簡介及藥理作用--------------------------5
1.1.5 Mephentermine及phentermine代謝-------------------------------------7
1.1.6 Mephentermine及phentermine偵測分析之文獻探討-----------------------9
1.2 萃取方法----------------------------------------------------------10
1.2.1 液相-液相萃取法之原理---------------------------------------------10
1.2.2 液相-液相萃取法之優缺點-------------------------------------------10
1.3 化學衍生法--------------------------------------------------------11
1.3.1 化學衍生法之目的--------------------------------------------------11
1.3.2 化學衍生法之原理及種類--------------------------------------------11
1.3.3 化學衍生劑之選擇--------------------------------------------------13
1.4 氣相層析質譜法----------------------------------------------------13
1.5 研究目的----------------------------------------------------------14

2. 實驗 (Experimental)
2.1 藥品--------------------------------------------------------------15
2.1.1 標準品------------------------------------------------------------15
2.1.2 試劑與溶劑--------------------------------------------------------15
2.1.3 實驗室自行製備----------------------------------------------------15
2.2 尿液檢體與取樣時間------------------------------------------------16
2.3 樣品之前處理------------------------------------------------------16
2.3.1 樣品之前處理步驟--------------------------------------------------17
2.4 氣相層析質譜儀的設定條件------------------------------------------19
2.5 方法確效性--------------------------------------------------------20
2.5.1 偵測極限及定量極限------------------------------------------------20
2.5.2 檢量線------------------------------------------------------------20
2.5.3 回收率------------------------------------------------------------21
2.5.4 準確性與精確性----------------------------------------------------23
2.5.4.1 分析內精確性與準確性----------------------------------------------23
2.5.4.2 分析間精確性與準確性----------------------------------------------23

3. 結果 (Results)
3.1 特徵離子和強度----------------------------------------------------25
3.2 Oxethazaine、mephentermine、phentermine 在尿液中代謝產物之鑑定----25
3.3 偵測極限與定量極限------------------------------------------------29
3.4 檢量線------------------------------------------------------------29
3.5 回收率之評估------------------------------------------------------32
3.6 準確性與精確性之評估----------------------------------------------33
3.7 人體代謝實驗------------------------------------------------------36
3.7.1 Mephentermine 尿液中濃度變化與代謝情形----------------------------36
3.7.2 Oxethazaine尿液中濃度變化與代謝情形-------------------------------38
3.7.3 Phentermine在尿液中之濃度變化與代謝情形---------------------------40
3.7.4 Mephentermine 、 phentermine與 oxethazaine在尿液中之代謝累積量----42
3.7.5 Mephentermine 、 phentermine及 oxethazaine在尿液中各個時間點代謝物濃度之比值---------------------------------------------------------------------46
3.7.6 運動員尿液mephentermine及phentermine在尿液中之代謝分析------------49
3.7.6.1 運動員尿液Mephentermine及phentermine的濃度與(MP/Ph)之比值---------50
4. 討論 (Discussion)-------------------------------------------------51
5. 結論 (Conclusion)-------------------------------------------------56
6. 參考文獻 (References)---------------------------------------------57
7. 附件 (Appendix)---------------------------------------------------62
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