本研究分為三個章節探討：第一部份是建立液相層析螢光檢測方法同步分析雞肉、豬肉、魚及蝦中11種喹諾酮類抗菌劑殘留(marbofloxacin、norfloxacin、ciprofloxacin、lomefloxcain、danofloxacin、enrofloxacin、sarafloxacin、difloxacin、oxolinic acid、nalidixic acid、flumequine)。樣品以0.3％偏磷酸：氰甲烷(1：1, v/v)萃取，經減壓濃縮去除氰甲烷後注入HLB固相萃取匣淨化。液相層析分析條件使用以symmetry column C18 (250 x 4.5 mm i.d., 5 μm)管柱分離，配合三段式程式螢光偵檢器偵測，移動相由0.1％甲酸水溶液及氰甲烷組成進行梯度沖堤。空白肌肉組織添加3種濃度(25、50及250 ng/g；除了danofloxacin添加濃度為6.25, 12.5 及62.5 ng/g)建立線性、偵測極限、定量極限、精密度及精確度之確效試驗。11種喹諾酮抗菌劑之添加試驗之平均回收率為71.7至105.3%，定量極限為5.0至28.0 ng/g。結果顯示本方法簡單、快速、靈敏且適合例行性分析工作。
第二部份是建立液相層析-電噴灑-串聯式質譜儀方法檢測牛奶、雞肉、豬肉、魚及蝦中18種喹諾酮抗菌劑殘留，此方法能篩檢及確認包括12種兩性的喹諾酮抗菌劑 (marbofloxacin、norfloxacin、enrofloxacin、ciprofloxacin、desethylene ciprofloxacin、lomefloxacin、danofloxacin、sarfloxacin、difloxacin、ofloxacin、orbifloxacin、enoxacin)及6種酸性的喹諾酮抗菌劑 (oxolinic acid、nalidixic acid、flumequine、cinoxacin、piromidic acid、pipemidic acid)。樣品之萃取液為含1％甲酸之氰甲烷溶液，經減壓濃縮後以10%氰甲烷定容，再以正己烷去脂。高效能液相層析分析條件為XDB C8 (150 x 4.6 mm, 5μm)分離管柱，移動相由20 mM甲酸銨、0.1％甲酸水溶液及氰甲烷組成進行梯度沖堤，質譜儀使用正離子多重反應(MRM)模式。CCα及CCβ之測定乃參考歐盟2002/657/EC 指令及ISO 11843號標準，使用禁用物質之模式。本實驗條件下所測得之CCα範圍為0.18至0.68 ng/g ，CCβ範圍為0.24至0.96 ng/g。
第三部份是研究吳郭魚體內恩氟喹諾酮羧酸（enrofloxacin；ENR）及其代謝物(ciprofloxacin；CIP及des-CIP)藥物動力學，吳郭魚以口服、血管給藥單一劑量分別為10及2.5 mg/kg魚重，給藥後定時採樣(0.25、0.5、1、2、4、8、16、24、48、72、96、120、144、168 小時採樣)，每一採樣點採4隻魚體，使用LC/MS/MS分析其全血及主要臟器組織（肝、腎、胆汁及肌肉）中ENR及其代謝物（CIP, des-CIP）殘留量，LOQ 為0.01 μg/g。口服及血管兩種給藥途徑後，吳郭魚的藥物動力學過程符合一級吸收二室性開放模式。血管給ENR藥的主要藥物動力學參數為：血中濃度-時間曲線下面積(AUC) 、消除半衰期(t1/2β)、最高血中濃度(Cmax )、清除率(Cltot)及表現分佈容積(Vdss)分別為109.618 ± 31.333 μg.h/mL、55.17 ± 22.84 h、4.70 ± 0.36 μg/mL 、0.148 ± 0.004 L/h/kg 、 1.111 ± 0.226 L/kg。口服給ENR藥的主要藥物動力學參數為： AUC 、消除半衰期、 最高血中濃度出現的時間點(Tmax )、最高血中濃度(Cmax )分別為599.418 ± 76.194 μg.h/mL 、75.95 ± 12.94 h、0.601±0.06h 、9.748 ± 0.458 μg/ mL。口服給ENR藥後可在肝、腎及胆汁中測到CIP(ENR的活性代謝物)。而des-CIP(CIP的主要代謝物)僅在口服給ENR藥後第120 ∼168 h的膽汁中測到0.01 ∼0.03 μg/ g 。ENR及其代謝物在吳郭魚體內為典型的腸肝循環且會大量累積在胆汁中。這現象可以解釋吳郭魚在口服ENR後到第7天血液及肌肉尚維持在高濃度的原因。

The study felld into three sections. The first section that a liquid chromatography method with fluorescence detection was developed for simultaneous determination of 11 quinolones (QNs; marbofloxacin, norfloxacin, ciprofloxacin, lomefloxacin, danofloxacin, enrofloxacin, sarafloxacin, difloxacin, oxolinic acid, nalidixic acid and flumequine) in chicken, pork, fish and shrimp. The analytes were extracted with 0.3% metaphosphoric acid: acetonitrile (1:1, v/v), followed by a HLB cartridge clean-up procedure. The HPLC separation was carried out on a symmetry column C18 (250 mm x 4.5 mm i.d., 5 μm) with linear gradient elution of 0.1% formic acid: acetonitrile as mobile phase and programmable fluorescence detection. The method was validated by spiking blank animals tissues at three different levels (25, 50 and 250 ng/g; except 6.25, 12.5 and 62.5 ng/g for DAN) and linearity, detection limit, quantification limit, precision and accuracy were checked. Mean recoveries of 11 QNs from edible animal tissues were 71.7-105.3%. The limits of quantification in different muscle tissues ranged from 5.0 to 28.0 ng/g. The results showed it was simple, rapid, sensitive and suitable for routine test.
The second section that a LC-ESI-MS/MS method was developed for determining 18 (fluoro)quinolone (QNs) residues in milk, chicken, pork, fish and shrimp. This method is capable of screening and confirming the presence of 12 amphoteric QNs (marbofloxacin, norfloxacin, enrofloxacin, ciprofloxacin, desethylene ciprofloxacin, lomefloxacin, danofloxacin, sarfloxacin, difloxacin, ofloxacin, orbifloxacin and enoxacin) and 6 acidic QNs (oxolinic acid, nalidixic acid, flumequine, cinoxacin, piromidic acid and pipemidic acid). The drugs were extracted from matrix using acetonitrile with 1% formic acid, diluted in 10% acetonitrile and defatted by extraction with hexane. The LC separation was conducted on a XDB C8 (150 x 4.6 mm, 5μm) column with gradient elution of 20 mM ammonium formate with 0.1% formic acid–acetonitrile as the mobile phase. Mass spectral acquisition was completed in the positive ion mode by applying multiple reaction mode (MRM). The decision limit (CCα) and detection capability (CCβ) stated in the Decision No. 2002/657/EC and the ISO standard No.11843, has been calculated in the case of the nonauthorized substance. The values of CCα ranged from 0.18 to 0.68 ng/g and CCβ ranged from 0.24 to 0.96 ng/g under specified conditions.
The third section that the pharmacokinetics of ENR and its active metabolite (CIP and des-CIP) were estimated in tilapia after intravenous (i.v.) and oral (p.o.) administration of a single dose of 2.5 and 10 mg/kg body weigh, respectively. At prefixed time points, from 0.25 h to 7 days after administration, whole blood and main tissue (liver, kidney, bile and muscle) from 4 individuals in each were collected. The concentration of ENR and its active metabolites in the main tissue were simultaneously detected by LC/MS/MS method. Limited of quantitation (LOQ) of this method were 0.01μg/g. Pharmacokinetic parameters from both routes were described to have a two- compartment open model with first-order elimination. After i.v. administration, the area under the drug concentration-time (AUC), elimination half-life (t1/2β), maximum plasma concentration (Cmax ), total body clearance (Cltot) and apparent volume of distribution at steady-state (Vss) of ENR were 109.6 ± 31.33 μg.h/mL, 55.17 ± 22.84 h, 4.70 ± 0.36 μg/mL, 14.82 ± 4.24 L/h/kg, 1105 ± 223.40 L/kg ,respectively. After oral administration, the AUC , t1/2β, Tmax , Cmax of ENR were 599.42 ± 76.19μg.h/mL , 75.95 ± 12.94 h, 0.601±0.06h, 9.75 ± 0.46μg/mL, respectively. After p.o. administration, CIP could be detected in liver, kidney and bile. Regarding des-CIP, the main active metabolite of CIP, could be detected in 120∼168 h bile among tissue. ENR and CIP had significance enterohepatic cycle in Tilapia and easily accumulated in bile. It seems reasonable to explain the phenomenon of ENR and CIP maintenance of high concentration in blood and muscle during the test time.

摘要…………………………………….…………………………………………………..Ⅰ
Abstract……………………………………………………..………………………………Ⅲ
目錄………………………………………………………..……………………………….Ⅴ
表目錄……………………………………………………………….……………………..Ⅶ
圖目錄……………………………………………………………….……………………..Ⅸ

第一章前言…………………………………………………...………….…………………1
第一節引言……………………………………………………………………1
第二節喹諾酮類藥物的特性及其用……………………………………….3
第三節、喹諾酮類藥物殘留問題.…………………………………….……..14
第四節喹諾酮類藥物殘留檢測…………………………………….………………18
第五節喹諾酮類藥物於水生生物之藥物動力學研究………………….…………25
第六節 吳郭魚之簡介……………………………………………….……….…...35
第二章 高效能液相層析螢光法分析喹諾酮類殘留之研究………………………………37
第一節引言………………………………………………………….…….....37
第二節儀器材料及方法……………………………………………..………………38
第三節結果…………………………………………………………...………………43
第四節討論……………………………………………………….….………………..54
第三章 LC-ESI/MS/MS分析喹諾酮類抗菌劑殘留之研究……………….….……………58
第一節引言……………………………………………….….….……………..58
第二節儀器材料及方法………………………………………….….……………...59
第三節結果…………………………………………………………..………………65
第四節討論………………………………………………………………….………..75
第四章 恩氟喹諾酮羧酸及其代謝物在吳郭魚體內的藥物動力學之研究………………79
第一節引言.................................................………………………………………….79
第二節儀器材料及方法…………………………………………………………...81
第三節結果………………………………………………………………………...89
第四節討論…………………………………………………………………………103
第五章 總結……………………………………………………………………………..105
參考文獻…………………………………………………………………………………109
附錄一、圖1∼19……………………………………………………………………….118
附錄二、個人簡歷………………………………………………………………………137
表目錄
頁次
表1-1 台灣、日本、歐盟之喹諾酮類藥最大殘留容許量（MRL）……….………..15
表1-2 喹諾酮類合成抗菌劑殘留分析方法………………………………………….23
表1-3 氟滅菌使用規範……………………………………………………………….27
表1-4 歐索磷酸用規範……………………………………………………………….28
表1-5 吳郭魚特性…………………………………………………………………….36
表2-1 分析11種QNs移動相之梯度設定……………………………………………42
表2-2 螢光偵測器激發/放射波長設定……………………………………………...42
表2-3 14種喹諾酮類抗菌劑其紫外光及螢光最佳偵測波長………………………44
表 2-4 比較3種萃取方法之回收率…………………………………………………46
表2-5 11種喹諾酮類抗菌劑標準曲線之線性方程式及相關係數………………..46
表2-6 添加組織11 種喹諾酮類抗菌劑之回收率…………………………………..49
表2-7 添加喹酮類抗菌劑之精密度確效試驗……………………………………….50
表2-8 添加喹酮類抗菌劑於魚肉之LOD 及LOQ……………………………………..51
表2-9 烏骨雞肉中ENR 及 CIP 殘留………………………………………………..51
表3-1分析18種QNs移動相之梯度設定………………………………..…………..64
表3-2最佳化二次質譜MRM 之參數設定…………………………………………….64
表3-3 相對離子強度之最大可容許範圍…………………………………………….68
表3-4 18種喹諾酮抗菌劑的質譜碎片相對離子強度比……………………………68
表3-5 18種QNs 於吳郭魚(魚片)之基質效應與絕對回收率……………………...72
表3-6 18種QNs於牛奶、魚、蝦、豬肉、雞肉之CCα及CCβ值………………73
表3-7 LC-ESI /MS/MS及 HPLC-FLD方法檢測FAPAS能力試驗結果………………73
表4-1分析ENR、CIP及des-CIP藥物移動相之梯度設定…………………………82
表4-2最佳化二次質譜MRM 之參數設定…………………………………………….82
表4-3 3種喹諾酮類抗菌劑標準曲線之線性方程式及相關係數…………………..90
表4-4 全血添加ENR、CIP、des-CIP回收率及方法精密度……………………….90
表4-5 魚肉添加ENR、CIP、des-CIP回收率及精密度…………………………….90
表4-6 口服給藥後血、腎、肝、胆汁及肉中ENR 的濃度…………………………92
表4-7口服給藥後血、腎、肝、胆汁及肉中CIP的濃度…………………………..92
表4-8 血管注射血、腎、肝、胆汁及肉中 ENR 的濃度……………………………93
表4-9 血管注射 ENR血、腎、肝、胆汁及肉中 CIP濃度…………………………93
表4-10 口服給藥ENR在各組織中CIP轉換率………………………………………94
表4-11 血管注射ENR在各組織中CIP轉換率……………………………………….94
表4-12口服給藥ENR在吳郭魚體內的藥物動力學參數……………………………102
表4-13血管注射給藥ENR在吳郭魚體內的藥物動力學參數………………………102
圖目錄
頁次
圖1-1 18種喹諾酮類藥物結構式……………………………………………………..8
圖1-2 喹諾酮類藥物污染環境可能之途徑……………………………….………….17
圖2-1.11種喹諾酮類抗菌劑 HPLC層析圖…………………………………….…….44
圖2-2 HPLC層析圖(A)空白魚肉 (B)魚肉添加250 ng/g喹酮類抗菌劑…….……48
圖2-3白蝦殘留CIP (21 ng/g)及ENR (368 ng/g) HPLC層析圖..………….…….52
圖2-4烏骨雞殘留CIP (16 ng/g)及ENR (428 ng/g) HPLC層析圖.………….…..52
圖2-5烏骨雞肉LC-MS/MS 層析圖……………………………………………………53
圖3-1 Norfloxacin 之二級質譜圖及質譜碎片可能之裂解途徑……………….….67
圖3-2 NAL於吳郭魚之基質效應………………………………………………….…..69
圖3-3能力試驗魚肉樣品OXO 及FLU之LC/MS/MS離子層析圖……………………74
圖4-1吳郭魚以尾部血管進行注射給藥……………………………………….……..85
圖4-2吳郭魚以塑膠軟管口服投藥…………………………………………….……..85
圖4-3吳郭魚採樣組織(肌肉、肝臟、胆汁及腎臟)…………………………….…..86
圖4-4口服第5天膽汁ENR、CIP及des-CIP 之LC/MS/MS層析圖…………….….97
圖4-5吳郭魚口服給藥(0至24小時)各組織中ENR濃度變化……………….…….98
圖4-6吳郭魚口服給藥(0至168小時)各組織中ENR濃度變化……………………98
圖4-7吳郭魚血管給藥(0至24小時)各組織中ENR濃度變化……………….…….99
圖4-8血管給藥後(0至168小時)組織中ENR濃度變化……………………………99
圖4-9吳郭魚血管給藥ENR後血藥濃度變化…………………………..……………100
圖4-10以WinNonlin預測吳郭魚血管給藥ENR後在血液內的分佈……………..101
圖4-11以WinNonlin預測吳郭魚口服給藥ENR後在血液內的分佈……………..101

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