以改良式QuEChERS法開發具快速、簡單與低污染之樣品前處理技術，並結合液相層析電噴灑串聯式質譜儀進行魚肉組織14種磺胺類藥物殘留分析，建立具綠色化學、高選擇性與高靈敏度之微量分析方法。磺胺類藥物典型分子離子碎片分別為156 m/z、108 m/z 與92 m/z。層析條件為逆相HC-C18管柱，移動相A為5 mM醋酸銨水溶液(以甲酸調製pH值為3.5)、移動相B為甲醇。分析方法回收率為80.2–93.5%，變異係數為3.82–8.71%，最低偵測極限為0.43–1.22 μg kg-1，定量極限為1.27–3.71 μg kg-1，基質干擾效應為-18.2–18.4%。本研究方法應用於藥物動力學之分析，以吳郭魚口服單一劑量每公斤體重100 mg磺胺一甲氧嘧啶，其觀察藥物在體內之吸收、分布與排除，藥物濃度與時間之曲線關係以非房室模式進行分析。研究顯示磺胺一甲氧嘧啶在肝臟與膽囊有較高含量，肌肉含量相對較低。磺胺一甲氧嘧啶於吳郭魚體體內主要代謝物為乙醯化磺胺一甲氧嘧啶，其中體內乙醯化轉化率高達45%。乙醯化磺胺一甲氧嘧啶代謝物在血液中半衰期為46.2小時，較磺胺一甲氧嘧啶的21.7小時長。磺胺一甲氧嘧啶在96-120小時及乙醯化磺胺一甲氧嘧啶代謝物在48-72小時均出現再吸收情況，此為典型腸肝循環之現象。最後，將藥物動力學數據結合抑菌藥效學分析，磺胺一甲氧嘧啶血液中最高濃度為 9.6 mg kg-1，高於Aeromonas salmonicida subsp. Salmonicida 之MIC (3.12 mg kg-1), Vibrio anguillarum MIC (3.12 mg kg -1) 與 Vibrio harveyi MIC (6.25 mg kg -1)，實驗顯示磺胺一甲氧嘧啶對此三種水產細菌病原體有抑菌效果，然而Pseudomonas fluorescens 和 Yersinia ruckeri在高劑量時(>100 μg kg-1)乃無抑菌成效。

A rapid and efficient multiresidue method that involves using improved QuEChERS method and LC–ESI–MS/MS was developed to measure trace levels of sulfonamides in fish tissues. This proposed method was proven to be a powerful, highly sensitive, and environmentally friendly analytical tool that requires minimal sample preparation. The typical MS/MS fragmentation patterns of the [M+H]+ were 156 m/z, 108 m/z, and 92 m/z. Separation was performed on HC-C18 columns with a gradient elution by using methanol and 5 mM ammonium acetate aqueous solution (adjusted to pH 3.5 with formic acid). This method was validated and exhibited favorable performance as well as acceptable accuracy (80.2–93.5%), precision (3.82–8.71%), sensitivity (limits of detection (LODs) 0.43–1.22 μg kg-1 and limits of quantification (LOQs) 1.27–3.71 μg kg-1), and an acceptable matrix effect (-18.2–18.4%). This methodology has been successfully applied in analyzing various fish tissue from local markets.
The pharmacokinetics of sulfamonomethoxine (SMM) were estimated after single oral administration (100 mg/kg body weight) to the tilapia at 25.0 °C and drug concentration–time profiles for blood and tissues were described by the non–compartmental model. In the pharmacokinetics studies, the results indicated high levels of SMM appeared usually in the well perfused tissues, such as liver and bile, whereas low levels of SMM were generally found in the poorly perfused tissues, such as muscle. Acetylation of SMM in tilapia following oral administration was 45% and N4-acetyl sulfamonomethoxine (AC-SMM) was the major acetylated metabolite observed. T1/2 of AC-SMM (46.2 h) was longer than of SMM (21.7 h) in blood. Redistribution occurred in blood SMM from 96 h to 120 h and in blood AC-SMM from 48 h to 72 h. With regard to the drug excretion pathway, it was concluded that SMM and AC-SMM were excreted mainly by the biliary in the tilapia. Moreover, bile excretion may result in enterohepatic cycling and to some extent retard drug elimination.
In the PK–PD modeling of SMM study, the Cmax (9.6 mg kg-1) was above MIC value of Aeromonas salmonicida subsp. Salmonicida (3.12 mg kg-1), Vibrio anguillarum (3.12 mg kg -1) and Vibrio harveyi (6.25 mg kg -1). These results illustrated that SMM can inhibit the growth of certain aquatic bacterial pathogens.

Abstract (Chinese) ii
Abstract iii
Chapter 1 Introduction 1
1.1 Background of sulfonamides 1
1.1.1 Physicochemical properties of sulfonamides 1
1.1.2 Chemotherapy and mechanism of antimicrobial activity of SAs 3
1.1.3 Side effect, toxicity and risks of sulfonamide residues 6
1.1.4 Legislation 8
1.2 Analytical strategies of SAs in biological samples 10
1.2.1 Introduction of the concept of green analytical chemistry 10
1.2.2 Reviews on the instrumental analysis in SAs 14
1.2.3 Reviews on the sample pretreatment technique in SAs 19
1.3 The properties of pharmacokinetics in SAs 23
1.3.1 Absorption and distribution 24
1.3.2 Metabolism 28
1.3.3 Excretion 31
1.3.4 Non-compartmental analysis 33
1.3.5 Review on pharmacokinetics properties in aquatic animals 35
1.4 Pharmacokinetics–pharmacodynamics (PK–PD) modeling of antimicrobial drugs in MIC study 38
1.4.1 Bacterial pathogens in fish and antimicrobial activity of drugs 38
1.4.2 PK–PD parameter relationships for antibiotics 41
1.5 Motivation and specific aims 47
Chapter 2 Establishment and validation of green analytical method for determining SAs in fish sample 49
2.1 Introduction 49
2.2 Materials and methods 51
2.2.1 Chemicals and reagents 51
2.2.2 HPLC–ESI–MS/MS instrumentation and conditions 53
2.2.3 Sample collection 54
2.2.4 Improved QuEChERS method 55
2.2.5 Validation of the analytical procedure 57
2.2.6 Matrix effects test 59
2.3 Results and discussion 60
2.3.1 Optimizing the HPLC–ESI–MS/MS condition 60
2.3.2 Sample preparation protocol based on modified QuEChERS 68
2.3.3 Validation 72
2.3.4 Matrix effect 77
2.3.5 Comparison of analytical methods of SAs in biological matrices 79
2.3.6 Application of the improved QuEChERS to real samples 82
2.4 Conclusions 84
Chapter 3 Pharmacokinetics of sulfamonomethoxine and its N4-acetyl metabolite in tilapia after oral administration 85
3.1 Introduction 85
3.2 Materials and methods 87
3.2.1 Chemicals and reagents 87
3.2.2 HPLC–ESI–MS/MS conditions 88
3.2.3 Experimental fishes 88
3.2.4 Drug administration and sampling 88
3.2.5 Sample preparation 90
3.2.6 Pharmacokinetics analysis 91
3.3 Results and discussion 92
3.3.1 AC-SMM method validation 92
3.3.2 The mean concentrations of SMM versus time in blood and other tissues 97
3.3.3 Pharmacokinetics parameters of SMM after administration to tilapia 102
3.3.4 Absorption and distribution of SMM in tilapia 104
3.3.5 Excretion of SMM in tilapia after oral administration 108
3.3.6 Metabolism of SMM in tilapia after oral administration 111
3.4 Conclusions 117
Chapter 4 Evaluation of the antibacterial activities of sulfamonomethoxine and
PK–PD modeling analysis 118
4.1 Introduction 118
4.2 Materials and methods 121
4.2.1 Bacterial strains and growth conditions 121
4.2.2 MIC determinations 122
4.2.3 PK–PD modeling analysis 123
4.3 Results and discussion 124
4.4 Conclusions 126
Chapter 5 Comprehensive comments 127
References 129
Appendix 143

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