呋喃唑酮在草鱼体内的药代动力学及残留检测的研究
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摘要
本论文对呋喃唑酮的药效及其药代动力学与残留检测进行了系列研究。首先进行了呋喃唑酮对三种草鱼致病菌ST_(78-3-3)，58-20-9，56-12-10的体外抑菌效果实验，测得该药对三种致病菌的最小抑菌浓度分别为：8μg／ml，128μg／ml，128μg／ml。
其二，建立了测定草鱼血浆及组织中呋喃唑酮的高效液相色谱法(HPLC)，该法灵敏、简便、准确。血浆、肌肉、肝脏、肾脏中呋喃唑酮平均相对回收率分别为89.2％、85.7％、70.9％、72.1％。其日内与日间相对偏差分别为(5.87±3.12)％、(6.12±4.18)％，可满足呋喃唑酮药代动力学研究。以引起两倍基线噪音的药量为最低检测限，本法最低检出浓度为0.002μg／g，可满足药物残留检测要求。
其三，在25±0.5℃水温条件下，按60mg／kg的剂量给平均体重为65±10g的草鱼单次和多次灌服呋喃唑酮，用高效液相色谱法检测用药后不同时间血浆、肝脏、肌肉、肾脏中药物浓度，采用MILLEMNIUM~(32)工作站处理原始数据，然后用MCPKP药代动力学软件处理药时数据，对药物的吸收、分布、消除及组织残留进行研究。结果表明：1)单剂量口服呋喃唑酮在草鱼体内的药时数据符合一级速率吸收开放性二室模型，在血液中主要药代动力学参数为：AUC 3.7569μg.h／ml，Cmax 0.5176μg／ml,T_(1/2α)1.5249h，T_(1/2β)22.8632h，Tpeak 2.2296h，K_(10)1.0158h~(-1)，K_(12) 0.1249h~(-1)，K_(21) 0.0654h~(-1)，给药后72小时在肌肉与血浆中检测不到药物；2)多剂量口服呋喃唑酮在草鱼体内的药时数据符合一级速率吸收一室开放模型，其主要药动学参数为：AUC 2.3182μg.h／ml，Cmax 0.850μg／ml，Ka0.5515h~(-1)，K 0.0936 h~(-1)，T_(1/2ka)1.2565h，T_(1/2k)7.4308h,Tp 2.8732h，药物在血浆、肌肉、肝脏、肾脏中消除时间分别为：3d、15d、20d、20d。
本研究结果表明，呋喃唑酮对引发草鱼常见病的三种致病菌药效低而在鱼体内残留时间长，这为我国在水产养殖中禁用呋喃唑酮提供了理论支持。
A series of experiments were carried out for studies on pharmacokinetics and residues determination of furazolidonum .At first, in vitro, inhibitory efficacies of furazolidonum were tested on three strains pathogenic bacteria from grass carp (Ctenopharyngodon idellus) : 8X78-3-3 , 58-20-9 , 56-12-10. The minimum inhibitory concentration to the three strains was 8 g /ml, 128 g /ml, 128 g /ml respectively.
Secondly, a sensitive, simple and accurate high performance liquid chromatograph (HPLC) method for the analysis of the concentration of furazolidonum in the grass carp in vivo had been set up. The average relative recoveries of furazolidonum in the plasma , muscle, liver and kidney were 89.2%, 85.7%, 70.9%, 72.1%, respectively. The within-a-day and interday cofficient of variations of the analytical method were (5.87 3.12)%, (6.12 4.18)% respectively,so the method can meet for the pharmacokinetics study.The limit of detection(LOD) which is calculated as two times the signal to noise ratio is 0.002 g /g, which can meet for the residue determination.
Thirdly ,under 25 0.5 ,pharmacocinetics and residues of orally administered at single and multiple dose of furazolidonum (60mg/kg) were investigated in grass crap, concentration of furazolidonum in Tissues(plasma, muscle, liver, kidney) were measured using HPLC and processed with MILLEMNIUM32 work station. The plasma concentration-time data was analyzed with MCPKP practical pharmacokinetics software.The results showed that: 1) The plasma profiles of furazolidonum in grass carp were best described by a two-compartment open model with the first order absorption following single dosing administration . The main parameters in the blood of grass carp were: AUC 3.7569 g /ml, Cmax 0.5176 g /ml, T1/2 1.5249h, T1/2 22.8632h, Tpeak 2.2296h, K10 1.0158h-1,K12 0.1249h-1,K21 0.0654h-1. At seventy-two hours after administration ,the residues of furazolidonum in plasma and muscle can not be detected. 2) At multiple dosing administration , the Concentration-Time curve of furazolidonum in grass carp blood was in accordance
with one-compartment open model with first order absorption . The main parameters were: AUC 2.3182 g.h/ml, Cmax 0.850 g /ml, Ka 0.5515h-1, K 0.0936 h-1, T1/2ka
1.2565h, T1/2k 7.4308h, Tp 2.8732h. The depletion of furazolidonum from plasma .muscle, Liver and kidney took 3d, 15d, 20d, 20d, respectively .
In conclusion , furazolidonum showed low efficiency in prohibition at the pathogenic bacteria from grass carp and long depletion time, which provided theoretical support for the ban of furazolidonum in aquaculture .
其二，建立了测定草鱼血浆及组织中呋喃唑酮的高效液相色谱法(HPLC)，该法灵敏、简便、准确。血浆、肌肉、肝脏、肾脏中呋喃唑酮平均相对回收率分别为89.2％、85.7％、70.9％、72.1％。其日内与日间相对偏差分别为(5.87±3.12)％、(6.12±4.18)％，可满足呋喃唑酮药代动力学研究。以引起两倍基线噪音的药量为最低检测限，本法最低检出浓度为0.002μg／g，可满足药物残留检测要求。
其三，在25±0.5℃水温条件下，按60mg／kg的剂量给平均体重为65±10g的草鱼单次和多次灌服呋喃唑酮，用高效液相色谱法检测用药后不同时间血浆、肝脏、肌肉、肾脏中药物浓度，采用MILLEMNIUM~(32)工作站处理原始数据，然后用MCPKP药代动力学软件处理药时数据，对药物的吸收、分布、消除及组织残留进行研究。结果表明：1)单剂量口服呋喃唑酮在草鱼体内的药时数据符合一级速率吸收开放性二室模型，在血液中主要药代动力学参数为：AUC 3.7569μg.h／ml，Cmax 0.5176μg／ml,T_(1/2α)1.5249h，T_(1/2β)22.8632h，Tpeak 2.2296h，K_(10)1.0158h~(-1)，K_(12) 0.1249h~(-1)，K_(21) 0.0654h~(-1)，给药后72小时在肌肉与血浆中检测不到药物；2)多剂量口服呋喃唑酮在草鱼体内的药时数据符合一级速率吸收一室开放模型，其主要药动学参数为：AUC 2.3182μg.h／ml，Cmax 0.850μg／ml，Ka0.5515h~(-1)，K 0.0936 h~(-1)，T_(1/2ka)1.2565h，T_(1/2k)7.4308h,Tp 2.8732h，药物在血浆、肌肉、肝脏、肾脏中消除时间分别为：3d、15d、20d、20d。
本研究结果表明，呋喃唑酮对引发草鱼常见病的三种致病菌药效低而在鱼体内残留时间长，这为我国在水产养殖中禁用呋喃唑酮提供了理论支持。
A series of experiments were carried out for studies on pharmacokinetics and residues determination of furazolidonum .At first, in vitro, inhibitory efficacies of furazolidonum were tested on three strains pathogenic bacteria from grass carp (Ctenopharyngodon idellus) : 8X78-3-3 , 58-20-9 , 56-12-10. The minimum inhibitory concentration to the three strains was 8 g /ml, 128 g /ml, 128 g /ml respectively.
Secondly, a sensitive, simple and accurate high performance liquid chromatograph (HPLC) method for the analysis of the concentration of furazolidonum in the grass carp in vivo had been set up. The average relative recoveries of furazolidonum in the plasma , muscle, liver and kidney were 89.2%, 85.7%, 70.9%, 72.1%, respectively. The within-a-day and interday cofficient of variations of the analytical method were (5.87 3.12)%, (6.12 4.18)% respectively,so the method can meet for the pharmacokinetics study.The limit of detection(LOD) which is calculated as two times the signal to noise ratio is 0.002 g /g, which can meet for the residue determination.
Thirdly ,under 25 0.5 ,pharmacocinetics and residues of orally administered at single and multiple dose of furazolidonum (60mg/kg) were investigated in grass crap, concentration of furazolidonum in Tissues(plasma, muscle, liver, kidney) were measured using HPLC and processed with MILLEMNIUM32 work station. The plasma concentration-time data was analyzed with MCPKP practical pharmacokinetics software.The results showed that: 1) The plasma profiles of furazolidonum in grass carp were best described by a two-compartment open model with the first order absorption following single dosing administration . The main parameters in the blood of grass carp were: AUC 3.7569 g /ml, Cmax 0.5176 g /ml, T1/2 1.5249h, T1/2 22.8632h, Tpeak 2.2296h, K10 1.0158h-1,K12 0.1249h-1,K21 0.0654h-1. At seventy-two hours after administration ,the residues of furazolidonum in plasma and muscle can not be detected. 2) At multiple dosing administration , the Concentration-Time curve of furazolidonum in grass carp blood was in accordance
with one-compartment open model with first order absorption . The main parameters were: AUC 2.3182 g.h/ml, Cmax 0.850 g /ml, Ka 0.5515h-1, K 0.0936 h-1, T1/2ka
1.2565h, T1/2k 7.4308h, Tp 2.8732h. The depletion of furazolidonum from plasma .muscle, Liver and kidney took 3d, 15d, 20d, 20d, respectively .
In conclusion , furazolidonum showed low efficiency in prohibition at the pathogenic bacteria from grass carp and long depletion time, which provided theoretical support for the ban of furazolidonum in aquaculture .
引文
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84. Echterhoff A M, Petz M. Quantitative HPLC analysis of nitrofuran residues in egg and milk after pro-chromatographic derivatization. Deutsche Lebensmittel Rundschau, 1994,90(11):341-344
85. Schreier T M. Determination of nidosmide residues in rainbow trout (Oncorhynchus mykiss) and channel catfish(Ictalurus punctatus) fillet tissue by high performance liquid. Agriculture Food Chem. 2000,48(16):2212-2215
86. Kaniou L.Zachariadis G,Kallogas G. Separation and determination of carbadox, nitrofurazone, nitrofuratoin,furazolidone,furaltadone in their mixtures by thin layer and high performance liquid chromatography. Joural of Liquid Chromatography,1994,17(6):1385-1398
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89．谢梅冬，崔艳丽．一阶导数光谱法测定中西复方制剂中呋喃唑酮的含量。中国兽药杂志，1996，30(2)：22-23
90．高振宏，臧恒昌．高效液相色谱法测定呋喃唑酮的含量及其杂质的控制。山东医大基础学院学报，2000，14(2)：121
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94．李爱华，蔡桃珍，吴玉深等，我国鱼类病原—嗜水气单胞菌的耐药性研究。微生物学通报，2001，28(1)：58-63．
95．袁宗辉．磺胺二甲嘧啶在健康和巴氏杆菌病兔单次和多次静注的动力学。畜牧兽医学报，1996，27(4)：360-365．
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76. Sas B. Contribution to the pathobiochemistry of furazolidone-induced oxidativo toxicity in chikens. Acta Veterinaria Hungarica,1993,41(1-2):103-121
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83. Galeano D T, Lopez M L. Rapid determination of nitrofurantoin,furazolidone and furaltadone in formulations feed and milk by high performance liquid chromatography. Journal of Liquid Chromatography, 1994,17(2):457-475
84. Echterhoff A M, Petz M. Quantitative HPLC analysis of nitrofuran residues in egg and milk after pro-chromatographic derivatization. Deutsche Lebensmittel Rundschau, 1994,90(11):341-344
85. Schreier T M. Determination of nidosmide residues in rainbow trout (Oncorhynchus mykiss) and channel catfish(Ictalurus punctatus) fillet tissue by high performance liquid. Agriculture Food Chem. 2000,48(16):2212-2215
86. Kaniou L.Zachariadis G,Kallogas G. Separation and determination of carbadox, nitrofurazone, nitrofuratoin,furazolidone,furaltadone in their mixtures by thin layer and high performance liquid chromatography. Joural of Liquid Chromatography,1994,17(6):1385-1398
87. Alawi M A. Analysis of furazolidone and furaltadone in chicken tissues and eggs using a modified HPLC/ELCD method. Fresenius Environmental Bulletin,2000,9(7-8):508-514
88．何倚霞．鱼用复方呋喃唑酮的含量测定。中国兽药杂志，2000，34(2)：28-29
89．谢梅冬，崔艳丽．一阶导数光谱法测定中西复方制剂中呋喃唑酮的含量。中国兽药杂志，1996，30(2)：22-23
90．高振宏，臧恒昌．高效液相色谱法测定呋喃唑酮的含量及其杂质的控制。山东医大基础学院学报，2000，14(2)：121
91．陈笑梅，鲍晓霞．HPLC法测定鳗鱼，猪肉和对虾中痢特灵残留。分析测试学报，1994，13(3)：78-80
92．夏文江．MCPKP-药物动力学分析的一种微机程序。中国药理学报，1988，9(2)：188-192
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94．李爱华，蔡桃珍，吴玉深等，我国鱼类病原—嗜水气单胞菌的耐药性研究。微生物学通报，2001，28(1)：58-63．
95．袁宗辉．磺胺二甲嘧啶在健康和巴氏杆菌病兔单次和多次静注的动力学。畜牧兽医学报，1996，27(4)：360-365．
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