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研究生:林怡君
研究生(外文):Yi-Chun Lin
論文名稱:抗細胞增殖藥品Methylglyoxal-bis-guanylhydrazone於老鼠體內之動態研究
論文名稱(外文):Disposition of an Antiproliferative Agent Methylglyoxal-bis-guanylhydrazone in Rats
指導教授:鄭靜玲鄭靜玲引用關係周辰熹周辰熹引用關係
指導教授(外文):Ching-Ling ChengChen-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:2002
畢業學年度:90
語文別:中文
論文頁數:102
中文關鍵詞:MGBG藥品動態學
外文關鍵詞:MGBGdisposition
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Methylglyoxal-bis-guanylhydrazone (MGBG) 為抗細胞增殖的藥品。正常生理pH下呈現有機陽離子狀態,為多胺類生合成酵素之抑制劑。其結構與本實驗室之前研究藥品metformin類似。MGBG開發之初因對其藥動認識不清,臨床上曾因給藥頻次過高而造成毒性累積的致死病例產生。已有文獻對其藥動研究極少,MGBG於體內主要分佈於肝臟,可能沒有代謝且不與血漿蛋白結合。文獻中MGBG分析方法多耗時且繁複,所需血漿體積大,使得分析方法應用至體液濃度定量及動物藥動學試驗上困難度增加。
本研究目的為開發一簡單、快速、靈敏之分析方法並實際應用至血漿中MGBG之濃度分析;測定MGBG與血漿蛋白之結合比率並觀察各種生理因素對其影響;藉由離體肝臟灌流模式探討MGBG在老鼠肝中排除及分佈情形;研究藥品於老鼠活體內之動態。並將所得之藥動性質與metformin比較。
實驗結果已開發一分析方法,經確效後實際應用至MGBG之血漿濃度分析與藥動學實驗。體外實驗顯示,MGBG與血漿蛋白結合比率不高,且不隨藥品濃度而變化,但會受到pH值及血漿蛋白濃度的影響。MGBG於老鼠肝中抽提率低、分佈廣且呈現穿透速限的特性。肝分佈體積與穿透率表面積乘積隨著劑量增加而漸趨飽和,與metformin相類似,此現象可能隱含了細胞載體對於MGBG在肝細胞中運輸的角色,但並無法得知是否與調控metformin攝入肝細胞的有機陽離子載體相關。MGBG於老鼠體內清除率大於腎絲球過濾速率,且呈現劑量越高,清除率逐漸下降至平緩的趨勢,具有飽和的現象。
本研究的結論為MGBG雖肝抽提率低,但似乎有載體調控其進出肝細胞,在體內可能經由腎臟以主動分泌的方式排除,且劑量越高,清除漸達飽和。故在劑量調整時需要小心,以避免腎臟或體內蓄積的危險性。
Introduction. Methylglyoxal-bis-guanylhydrazone (MGBG) is an antiproliferative agent. The structure of MGBG is similar to polyamines and it inhibits the biosynthesis pathway of polyamines. Studies on the pharmacokinetics of MGBG are rare. Due to its long half-life, initial clinical studies using once daily regimen showed severe toxicity of MGBG in patients. MGBG distributed widely into the body, especially in the liver. However, there are no reports on the hepatic extraction and disposition of MGBG, and the extent of its plasma protein binding remains unknown. To address all these issues, a simple and sensitive assay for MGBG in biological fluids is needed.
Objectives. The aim of this study is to develop a simple, rapid, and sensitive high-performance liquid chromatography (HPLC) method to quantitate the concentration of MGBG in plasma; to determine the unbound fraction of MGBG in plasma using ultrafiltration, and examining the effects of physiologic factors on the protein binding of MGBG; to characterize the disposition of MGBG in isolated perfused rat liver; and to investigate the pharmacokinetics of MGBG in rats.
Results. A new validated HPLC method for the analysis of MGBG in plasma was developed, and was applied successfully to pharmacokinetic studies. Binding of MGBG to plasma proteins is low with an unbound fraction greater than 77%, and is constant within the concentration range (0.5-50 mg/mL) studied. The unbound fraction decreased as the concentration of serum albumin increased from 0.1 to 4 %. The extent of protein binding increased with the increase of the pH of plasma, and a linear relationship was found between binding and the percentage of un-ionized form of MGBG in plasma. The hepatic extraction ratio of MGBG is low. The disposition kinetics of MGBG in the liver was permeability-rate limited and showed dose-dependency, suggesting that hepatic uptake of MGBG could be carrier-mediated. The disposition of MGBG in rats displayed two-compartmental characteristics, and its clearance was dose-dependent.
Conclusion. In summary, the binding of MGBG to plasma protein is low. As the hepatic extraction of MGBG is low, it seems that the major elimination organ is kidney. The clearance of MGBG in rats is dose-dependent, thus one should be very careful when adjusting the dosage of MGBG to avoid its accumulation.
摘要i
Abstractiii
致謝v
目錄vi
表目錄x
圖目錄xi
縮寫表xiii
第壹章 緒論1
第一節 多胺類1
一﹑組成及分佈1
二﹑生理功能1
三﹑體內濃度調控2
四﹑臨床重要性及應用4
第二節 MGBG簡介5
一﹑物化性質5
二﹑藥動特性5
三﹑作用機轉6
四﹑臨床應用6
五﹑毒性及副作用7
第三節 MGBG與Metformin7
一﹑前言7
二﹑物化及藥動性質比較8
第四節 MGBG分析方法之文獻回顧8
第貳章 研究目的13
第一節 分析方法及確效13
第二節 體外血漿蛋白結合率測定14
第三節 離體灌流老鼠肝中動態14
一﹑穩定灌流實驗14
二﹑瞬間注射動力學14
第四節 體內藥物動力學15
第參章 實驗材料、儀器及方法16
第一節 實驗材料16
一﹑實驗動物16
二﹑藥品與試劑16
三﹑常用緩衝溶液配方18
第二節 實驗儀器18
一﹑高效液相層析系統18
二﹑高速過濾離心系統19
三﹑灌流系統19
四﹑放射線標定系統20
五﹑插管手術及檢品處理20
六﹑繪圖及藥動分析軟體21
第三節 實驗方法22
一﹑藥品定量分析22
二﹑高速過濾離心法23
三﹑離體肝臟灌流實驗24
四﹑插管手術27
五﹑實驗設計28
六﹑數據解析31
第肆章 實驗結果42
第一節 分析方法及確效42
一﹑HPLC層析圖譜42
二﹑校正曲線42
三﹑確效評估42
第二節 體外血漿蛋白結合率測定43
一﹑濃度依性試驗43
二﹑不同pH值影響43
三﹑不同牛血清白蛋白濃度影響43
四﹑應用44
第三節 離體灌流老鼠肝中動態44
一﹑穩定灌流實驗44
二﹑瞬間注射動力學45
第四節 體內藥物動力學46
一﹑劑量依性實驗46
第伍章 討論68
第一節 分析方法及確效68
第二節 體外血漿蛋白結合率測定68
第三節 離體灌流老鼠肝中動態70
第四節 體內藥物動力學72
第陸章 結論73
參考文獻74
附錄85
自述87
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