臺灣博碩士論文加值系統

本研究團隊在過去的研究中合成了一系列anthranilic acid衍生物，包括DSM-RX 116 (Ethyl 2-(2-fluorobenzamido)benzoate)、DSM-RX 78 (Methyl 2-(2-fluorobenzamido)benzoate)及兩者之代謝產物SMP-3 (2-(2-fluorobenzamido)benzoic acid)等；其中DSM-RX 116及DSM-RX 78具有良好的抗發炎活性，可以抑制活化的嗜中性球產生超氧化陰離子(superoxide anion, O2.−)的生成，其IC50為0.17和0.65 M。此外，靜脈投予此兩者化合物有效的改善了接受trauma-hemorrhagic (T/H) shock的大白鼠所引起的多重性器官衰竭。因此研究之目的為建立DSM-RX 116、DSM-RX 78及SMP-3之分析方法並監測大白鼠體內靜脈與口服之藥物動力學的變化，以及其分佈與毒性研究。經確效後實際應用至血漿濃度分析及藥物動力學的實驗。體外實驗顯示DSM-RX 116及 DSM-RX 78會受到esterase的影響而被水解為SMP-3，且此兩者化合物均會與血漿中白蛋白100 %結合，無游離態的化合物存在，而其代謝產物SMP-3蛋白質結合率也高達99 %。動物實驗方面，分別投予Sprague Dawley rats DSM-RX 116、DSM-RX 78及SMP-3靜脈劑量1.0 mg/kg，口服劑量40.0 mg/kg；其藥物動力學參數顯示靜脈給予DSM-RX 116、DSM-RX 78及SMP-3其半衰期（t1/2）為8.98、8.77及23.99分鐘；清除率（CL）為24.57、22.31及2.24 mL/min/kg；曲線下面積（AUC0-）為41.76，48.03及486.44 min∙mg/L。口服給予DSM-RX 116及DSM-RX 78後，分析結果顯示血液中未含有原始的化合物，但可偵測到其水解產物SMP-3，因此三者藥物動力學參數非常相近。急性毒性實驗進行了7天累積劑量（3 mg/kg）及24小時單一高劑量（45 mg/kg）靜脈給予SMP-3、DSM-RX 78及DSM-RX 116，結果顯示僅高劑量投予化合物會對SD大白鼠產生肝臟毒性，引起浸潤型淋巴球的聚集與膠原蛋白的沉積，其毒性為DSM-RX 78最大，而在其他的組織切片中並沒有發現明顯被破壞、發炎及免疫系統被活化的現象。

The anthranilic acid derivatives, DSM-RX 116 (Ethyl 2- (2- fluorobenzamido) benzoate), DSM-RX 78 (Methyl 2-(2-fluorobenzamido)benzoate), and their hydrolysis compound, SMP-3 (2-(2-fluorobenzamido)benzoic acid), were synthesized. In previous study, DSM-RX 78 and DSM-RX 116 showed inhibitory effects on fMLP-induced superoxide anion generation in neutrophil with IC50 value of 0.65 and 0.17 μM. Furthermore, i.v. administration of DSM-RX 78 and DSM-RX 116 in rats subjected to trauma - hemorrhagic (T/H) shock caused a significant improvement in multiple organ dysfunctions. In present study, the experimental of plasma concentrations and pharmacokinetic analysis of DSM-RX 116, DSM-RX 78 and SMP-3 were determined by HPLC analysis. The pharmacokinetics, distributions and toxicitys of intravenously (1.0 mg/kg) and oral (40.0 mg/kg) administered SMP-3、DSM-RX 116 and DSM-RX 78 were also determined in Sprague Dawley rats. The in vitro experiments showed that DSM-RX 116 and DSM-RX 78 will hydrolysis to SMP-3 by esterase, and the protein binding ratio of SMP-3 was 100%. In addition, the protein binding ratio of the hydrolysis product SMP-3 was up to 99%. Mean kinetic parameters of DSM-RX 116, DSM-RX 78 and SMP-3 via i.v. administration as follows: elimination half-life (t1/2) 8.98, 8.77 and 23.99 min; clearance (CL) 24.57, 22.31 and 2.24 mL/min/kg; AUC0- 41.76, 48.03 and 486.44 min∙mg/L. Since DSM-RX 116 and DSM-RX 78 were hydorlyzed to SMP-3 through oral administration, they with similar kinetic parameters in oral administration. The toxicity of SMP-3, DSM-RX 78 and DSM-RX 116, including cumulative dose (3 mg/kg/day for 7 days) and single dose (45 mg/kg/day), were evaluated using intravenously administration. In single dose experimental, the histology analysis showed there were no toxicity to heart, brain, kidney, and lung; but they may exhibit liver toxicity.

目錄
指導教授推薦書..........................................................................................
口試委員會審定書......................................................................................
授權書..........................................................................................................
致謝..........................................................................................................Ⅳ
中文摘要..................................................................................................Ⅵ
英文摘要..................................................................................................Ⅷ
目錄..........................................................................................................Ⅹ
圖目錄…………………………………………………..................……Ⅸ
表目錄……………………………………………..…………………ⅩⅣ
第一章 緒論……………………………………………………..…...….1
第一節 前言……………………………………………..……….….1
第二節 發炎反應…………..………………………………….…….2
第三節 藥物動力學…………………………………..………….….7
第二章 研究背景與動機………………………...........….16
第三章 實驗材料與方法………………………………………...…….20
第一節 實驗材料………………………………………..…………20
第二節 實驗設計與方法………………………………..…………24第四章 結果與討論……………………………………………...…….47
第一節 DMS-RX 116、DSM-RX 78及SMP-3之分析.…………...48
第二節 血漿檢品分析………..…………………………..……..…59
第三節 Esterase體外水解實驗……………………………..……..65
第四節 體外DSM-RX 116與血漿蛋白結合率……………..…....72
第五節 體內蛋白質結合率……………………………………..…72
第六節 藥物動力學………………………………………………73
第七節 大白鼠各器官中化合物之分析…….……….……....…101
第八節 毒性實驗……………………………..…………….…108
第五章 結論………………………………………...…………..…….124
參考文獻………………………………………………………...…….129



圖目錄
Fig.1 嗜中性白血球吞噬細菌後引發呼吸爆裂反應..............................4
Fig.2 超氧化陰離子形成路徑………………………………………..…5
Fig.3 藥物於體內分佈、代謝、排泄途徑................................................12
Fig.4 一室模式圖形………………..…………………………..……..13
Fig.5 二室模式圖形……………………………………………..……..14
Fig.6 （A）瞿麥植株（B）中藥瞿麥圖.......................................................16
Fig.7 化合物HPW-01結構式……………….………………………….16
Fig.8 The structure of DSM-RX 78 and DSM-RX 116……………...…17
Fig.9 SMP-3 UV譜圖………………………………………….……….25
Fig.10 SMP-3 IR譜圖…………………………………………………..25
Fig.11 SMP-3 1H NMR譜圖……………………………………………26
Fig.12 SMP-3 13C NMR譜圖………………………...………….……...26
Fig.13 DSM-RX116於Ultraviolet Spectroscopy之全波長掃描………48
Fig.14 DMS-RX 116 HPLC層析圖（波長230 nm，濃度100 g/mL，流速1.0 mL/min，注射量20 L，移動相d.d. water：methanol＝1：4）……………………….………………………………….33
Fig.15 DMS-RX 78 HPLC層析圖（波長230 nm，濃度100g/mL，流速1.0 mL/min，注射量20 L，移動相d.d. water：methanol＝1：4）…………………………………………………………….…51
Fig.16 SMP-3 HPLC層析圖（波長230 nm，濃度100 g/mL，流速1.0 mL/min，注射量20 L，移動相0.5 % TFA in d.d. water：methanol＝1：4）…………………………………………………….….....51
Fig.17 SMP-3 HPLC層析圖（波長230 nm，濃度0.7813 g/mL，流速1.0 mL/min，注射量40 L，移動相0.5 % TFA in d.d. water：methanol＝1：4）…………………………………………....…...52

Fig.18 SMP-3 HPLC層析圖（波長230 nm，濃度0.7813 g/mL，流速1.0 mL/min，注射量40 L，移動相0.3 % TFA in d.d. water：methanol＝1：3）………………………………………………..52
Fig.19 DSM-RX116樣品溶液於0.3 % TFA in d.d. water：methanol＝1：3分析條件下之檢量線RUNⅠ、Ⅱ、Ⅲ………………………..54
Fig.20 DSM-RX 78樣品溶液於0.3 % TFA in d.d. water：methanol＝1：3分析條件下之檢量線RUNⅠ、Ⅱ、Ⅲ…………………….......56
Fig.21 SMP-3樣品溶液於0.3 % TFA in d.d. water：methanol＝1：3分析條件下之檢量線RUNⅠ、Ⅱ、Ⅲ…………..………………..58
Fig.22 DSM-RX 116於血漿內之HPLC層析圖…………………....….59
Fig.23 DSM-RX 116於血漿分析之檢量線RUNⅠ、Ⅱ、Ⅲ………...…60
Fig.24 SMP-3於血漿內之HPLC層析圖………………………………61
Fig.25 SMP-3於血漿分析之檢量線RUNⅠ、Ⅱ、Ⅲ…………………..62
Fig.26 DSM-RX 78於血漿內之HPLC層析圖……………….…...…63
Fig.27 DSM-RX 78於血漿分析之檢量線RUNⅠ、Ⅱ、Ⅲ…………….64
Fig.28 DSM-RX 78加入3 unit esterase於各時間點的殘留率………70
Fig.29 DSM-RX 78分別加入12 unit、6 unit、3 unit esterase後於各時間點的殘留百分比平均值………………………………..........70
Fig.30 DSM-RX 116加入3 unit esterase於各時間點的殘留率………71
Fig.31 DSM-RX 78與DSM-RX 116加入3 unit esterase於各時間點的差異性………………………………………………………….71
Fig.32 DSM-RX 116於血漿中之HPLC層析圖譜………………..…74
Fig.33 靜脈給予1.0 mg/kg DSM-RX 116其血液濃度對時間之曲線.76
Fig.34口服給予40.0 mg/kg DSM-RX 116其代謝產物SMP-3血液濃度對時間之曲線圖……………………………………..…………78
Fig.35 DSM-RX 78於血漿中之HPLC層析圖譜……………….……...79
Fig.36 靜脈給予1.0 mg/kg DSM-RX 78其血液濃度對時間之曲線...81
Fig.37 口服給予40.0 mg/kg DSM-RX 78其代謝產物SMP-3血液濃度對時間之曲線圖…………………………………..……………82
Fig.38 SMP-3於血漿中之HPLC層析圖譜……………………………84
Fig.39 靜脈給予1.0 mg/kg SMP-3其血液濃度對時間之曲線圖…....85
Fig.40 口服給予40.0 mg/kg SMP-3其血液濃度對時間之曲線圖…..86
Fig.41靜脈給予1.0 mg/kg DSM-RX 116、DSM-RX 78及SMP-3其血液濃度對時間之曲線圖……………………………………...87
Fig.42 靜脈給予1.0 mg/kg DSM-RX 116、DSM-RX 78及SMP-3後其血液中DSM-RX 116與其代謝產物SMP-3之合、DSM-RX 78及其代謝產物SMP-3之合與SMP-3之濃度對時間之曲線圖..88
Fig.43口服給予40.0 mg/kg DSM-RX 116、DSM-RX 78及SMP-3其血液濃度對時間之曲線圖……………………………………89
Fig.44 分別投予3.0 mg/kg DSM-RX 116、DSM-RX 78及SMP-3 10分鐘後於各器官的分佈情形。（A）DSM-RX 116、DSM-RX 78及SMP-3（B）DSM-RX 116與其代謝出產物SMP-3之合、DSM-RX 78與其代謝出產物SMP-3之合及SMP-3…………….....................................................................106
Fig.45 分別投予3.0 mg/kg DSM-RX 116、DSM-RX 78及SMP-3 30分鐘後於各器官的分佈情形。（A）DSM-RX 116、DSM-RX 78及SMP-3（B）DSM-RX 116與其代謝出產物SMP-3之合、DSM-RX 78與其代謝出產物SMP-3之合及SMP-3………………………………………………………..107
Fig.46 SMP-3、DSM-RX 78及DSM-RX 116分別投予0.1、0.5、1、2、4 mM於HepG2細胞株之細胞存活率對濃度做圖。（n=3，＊代表p＜0.05）…………………………………………………109
Fig.47 24小時急性毒性實驗。腦組織切片以400X顯微鏡觀察下攝影，H & E 染色切片及Masson's trichrome染色切片(A)及(F)control(B)及(G)vehicle（Cermophol EL : DMSO : saline =1:1:8, ~3 ml）(C)及(H)尾靜脈投予SMP-3 45 mg/kg(D)及(I)尾靜脈投予DSM-RX 116 45 mg/kg(E)及(J)尾靜脈投予DSM-RX 78 45 mg/kg……………………………………………………112
Fig.48 24小時急性毒性實驗。肺組織切片以400X顯微鏡觀察下攝影，H & E 染色切片及Masson's trichrome染色切片(A)及(F)control(B)及(G)vehicle（Cermophol EL : DMSO : saline =1:1:8, ~3 ml）(C)及(H)尾靜脈投予SMP-3 45 mg/kg(D)及(I)尾靜脈投予DSM-RX 116 45 mg/kg(E)及(J)尾靜脈投予DSM-RX 78 45 mg/kg……………………………………………………113
Fig.49 24小時急性毒性實驗。心組織切片以400X顯微鏡觀察下攝影，H & E 染色切片及Masson's trichrome染色切片(A)及(F)control(B)及(G)vehicle（Cermophol EL : DMSO : saline =1:1:8, ~3 ml）(C)及(H)尾靜脈投予SMP-3 45 mg/kg(D)及(I)尾靜脈投予DSM-RX 116 45 mg/kg(E)及(J)尾靜脈投予DSM-RX 78 45 mg/kg………………………..…………………………114
Fig.50 24小時急性毒性實驗。肝組織切片以400X顯微鏡觀察下攝影，H & E 染色切片及Masson's trichrome染色切片(A)及(F)control(B)及(G)vehicle（Cermophol EL : DMSO : saline =1:1:8, ~3 ml）(C)及(H)尾靜脈投予SMP-3 45 mg/kg(D)及(I)尾靜脈投予DSM-RX 116 45 mg/kg(E)及(J)尾靜脈投予DSM-RX 78 45 mg/kg………………………..…………………………116
Fig.51 24小時急性毒性實驗。腎組織切片以100X顯微鏡觀察下攝影，H & E 染色切片及Masson's trichrome染色切片(A)及(F)control(B)及(G)vehicle（Cermophol EL : DMSO : saline =1:1:8, ~3 ml）(C)及(H)尾靜脈投予SMP-3 45 mg/kg(D)及(I)尾靜脈投予DSM-RX 116 45 mg/kg(E)及(J)尾靜脈投予DSM-RX 78 45 mg/kg…………………..……………………………117
Fig.52 七天毒性實驗。腦組織切片以400X顯微鏡觀察下攝影，H & E 染色切片及Masson's trichrome染色切片(A)及(F)control(B)及(G)vehicle（Cermophol EL : DMSO : saline =1:1:8, ~3 ml）(C)及(H)尾靜脈投予SMP-3 3 mg/kg(D)及(I)尾靜脈投予DSM-RX 116 3 mg/kg(E)及(J)尾靜脈投予DSM-RX 78 3 g/kg……….119
Fig.53 七天毒性實驗。肺組織切片以200X顯微鏡觀察下攝影，H & E 染色切片及Masson's trichrome染色切片(A)及(F)control(B)及(G)vehicle（Cermophol EL : DMSO : saline =1:1:8, ~3 ml）(C)及(H)尾靜脈投予SMP-3 3 mg/kg(D)及(I)尾靜脈投予DSM-RX 116 3 mg/kg(E)及(J)尾靜脈投予DSM-RX 78 3 g/kg…………120
Fig.54 七天毒性實驗。心組織切片以400X顯微鏡觀察下攝影，H & E 染色切片及Masson's trichrome染色切片(A)及(F)control(B)及(G)vehicle（Cermophol EL : DMSO : saline =1:1:8, ~3 ml）(C)及(H)尾靜脈投予SMP-3 3 mg/kg(D)及(I)尾靜脈投予DSM-RX 116 3 mg/kg(E)及(J)尾靜脈投予DSM-RX 78 3 g/kg……………121
Fig.55 七天毒性實驗。肝組織切片以400X顯微鏡觀察下攝影，H & E 染色切片及Masson's trichrome染色切片(A)及(F)control(B)及(G)vehicle（Cermophol EL : DMSO : saline =1:1:8, ~3 ml）(C)及(H)尾靜脈投予SMP-3 3 mg/kg(D)及(I)尾靜脈投予DSM-RX 116 3 mg/kg(E)及(J)尾靜脈投予DSM-RX 78 3 g/kg……………122
Fig.56 七天毒性實驗。腎組織切片以100X顯微鏡觀察下攝影，H & E 染色切片及Masson's trichrome染色切片(A)及(F)control(B)及(G)vehicle（Cermophol EL : DMSO : saline =1:1:8, ~3 ml）(C)及(H)尾靜脈投予SMP-3 3 mg/kg(D)及(I)尾靜脈投予DSM-RX 116 3 mg/kg(E)及(J)尾靜脈投予DSM-RX 78 3 g/kg...............123




 
表目錄
Table 1. Inhibitory effect of compounds on superoxide anion generation by human neutrophils in response to fMLP…………………...18
Table 2. 標準曲線之HPLC分析條件…………………………………29
Table 3. 血漿檢品之HPLC分析條件…………………………………29
Table 4. Esterase體外水解實驗HPLC分析條件……………………33
Table 5. 血漿檢品之HPLC分析條件…………………………………36
Table 6. 血漿檢品之HPLC分析條件…………………………………40
Table 7. 組織檢品之HPLC分析條件…………………………………41
Table 8. DSM-RX116在不同波長下之平均峰波面積比較；流速= 1.0 mL/min，注射量20L，移動相d.d. water：methanol＝1：4..…49
Table 9. DSM-RX116樣品溶液於0.3 % TFA in d.d. water：methanol＝1：3分析條件下之再現性RUNⅠ、Ⅱ、Ⅲ（n＝6）……………….54
Table 10. DSM-RX 78樣品溶液於0.3 % TFA in d.d. water：methanol＝1：3分析條件下之再現性RUNⅠ、Ⅱ、Ⅲ（n＝6）…………56
Table 11. SMP-3樣品溶液於0.3 % TFA in d.d. water：methanol＝1：3分析條件下之再現性RUNⅠ、Ⅱ、Ⅲ（n＝6）………………58
Table 12. DSM-RX 116於血漿分析之再現性RUNⅠ、Ⅱ、Ⅲ（n＝6）..60
Table 13. SMP-3於血漿分析之再現性RUNⅠ、Ⅱ、Ⅲ（n＝6）………62
Table 14. DSM-RX 78於血漿分析之再現性RUNⅠ、Ⅱ、Ⅲ（n＝6）....64
Table 15. DSM-RX 78分別加入12 unit、6 unit、3 unit esterase後於各時間點的殘留百分比平均值比較…………………….....…66
Table 16. DSM-RX 116加入3 unit esterase於各時間點經HPLC析分之曲線下面積、殘留百分比及其誤差值……………….…...…67
Table 17. DSM-RX 78加入3 unit esterase於各時間點經HPLC析分之曲線下面積、殘留百分比及其誤差值…………………...…68
Table 18. DSM-RX 78與DSM-RX 116加入3 unit esterase後於各時間點的殘留百分比平均值比較……………………….…...…69
Table 19. 靜脈給予1.0 mg/kg DSM-RX 116血清中DSM-RX 116濃度(g/mL)……………………………………………………….75
Table 20. 口服給予40.0 mg/kg DSM-RX 116血清中SMP-3濃度(g/mL)……………………………………………….………77
Table 21. 靜脈給予1.0 mg/kg DSM-RX 78血清中DSM-RX 78濃度(g/mL)…………………………………………………….......80
Table 22. 口服給予40.0 mg/kg DSM-RX 78血清中SMP-3濃度(g/mL)……………………………………………………...…82
Table 23. 靜脈給予1.0 mg/kg SMP-3血清中SMP-3濃度(g/mL)…………………………………………….…………..85
Table 24. 口服給予40.0 mg/kg SMP-3血清中SMP-3濃度(g/mL)…………………………………………………….…86
Table 25. 靜脈給予大白鼠1.0 mg/kg DSM-RX 116後，以二室性模式計算出之藥物動力學參數…..…………………………...…90
Table 26. 靜脈給予大白鼠1.0 mg/kg DSM-RX 78後，以二室性模式計算出之藥物動力學參數…..……………………………...…91
Table 27. 靜脈給予大白鼠1.0 mg/kg SMP-3後，以二室性模式計算出之藥物動力學參數…………………………………………92
Table 28. 靜脈給予大白鼠1.0 mg/kg DSM-RX 116、DSM-RX 78及SMP-3後，以二室性模式計算出之藥物動力學參數…….93
Table 29. 口服給予大白鼠40.0 mg/kg DSM-RX 116後，以一室性模式計算出之藥物動力學參數………………………………..94
Table 30. 口服給予大白鼠40.0 mg/kg DSM-RX 78後，以一室性模式計算出之藥物動力學參數………………………………... 95
Table 31. 口服給予大白鼠40.0 mg/kg SMP-3後，以一室性模式計算出之藥物動力學參數…………………………………...…96
Table 32. 口服脈給予大白鼠40.0 mg/kg DSM-RX 116、DSM-RX 78及SMP-3後，以一室性模式計算出之藥物動力學參數（所有數據均為SMP-3）…………………………………..……97
Table 33.靜脈投予3.0 mg/kg DSM-RX 116後各器官之DSM-RX 116及其代謝產物SMP-3濃度（n=3）………………………..…103
Table 34. 靜脈投予3.0 mg/kg DSM-RX 78後各臟器之DSM-RX 78及其代謝產物SMP-3濃度濃度（n=3）………………….……104
Table 35. 靜脈投予3.0 mg/kg SMP-3後各臟器之SMP-3濃度（n=3）…………………………………………………………105
Table 36. SMP-3、DSM-RX 78及DSMP-RX 116之粒徑大小（n=3）（polydispersity index, PdI）………………………………110
Table 37. 尾靜脈投予SD大白鼠45 mg/kg之SMP-3、DSM-RX 78、DSMP-RX 116 及vehicle 24小時後其之GOT及GPT分析……………………………………………………………111
Table 38. 尾靜脈連續七天投予SD大白鼠3 mg/kg之SMP-3、DSM-RX 78、DSMP-RX 116 及vehicle後其之GOT及GPT分析...118

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