复方新诺明和恩诺沙星在两种水产动物体内的药物代谢动力学及残留研究
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摘要
本文分为两个部分，第一部分研究了22℃C±3℃和16℃±2℃水温条件下，多次口服给药后，复方新诺明(磺胺甲(口恶)唑SMZ／甲氧苄啶TMP=5／1)在花鲈的肌肉、血液、肝脏、肾脏四种组织中的残留和消除规律，并比较了不同温度下残留和消除规律的差别。第二部分研究了22.5℃±1℃水温条件下，以10mg／kg的剂量肌肉注射给药，恩诺沙星及其活性代谢物环丙沙星在中国对虾肌肉、血液、肝胰脏三种组织内的代谢情况，并设计出了合理的给药方案。各组织中药物浓度由高效液相色谱法测得。以上研究在国内均属首次。
研究结果表明：与TMP相比，SMZ在花鲈体内残留量较小，且消除较快。以22℃±3℃下肌肉中的残留情况为例，停药一天后SMZ和TMP在花鲈肌肉组织内的残留量分别为9.4和30.1μg／ml；消除半衰期T_(1/2)β分别为0.37d和1.98d。温度对SMZ和TMP在花鲈体内的吸收和消除均有影响，温度对于吸收的影响主要体现于TMP，22℃±3℃和16℃±2℃温度下，停药一天后TMP在肌肉、血液、肝脏、肾脏四种组织中的浓度分别为30.1，8.47，18.8，100.9μg／ml和12.9，5.6，8.27，23.2μg／ml，数据显示较高温度下，TMP在花鲈体内的吸收率较高；温度对SMZ的吸收率则无明显影响。温度对SMZ和TMP在花鲈组织内的消除速度的影响可从下列数据看出：22℃±3℃水温条件下，SMZ和TMP在肌肉、血液、肝脏、肾脏四种组织中的T_(1/2)β分别为0.37，0.47，0.72，0.48d和1.98，2.09，1.63，5.53d；16℃±2℃下的分别为0.72，0.95，1.90，1.11d和3.48，3.92，3.43，7.8d。说明两种药物在花鲈组织内的消除速度随温度的升高而加快，并且，SMZ的消除速度受温度影响更明显。综合两种药物在鱼体内的残留情况，建议花鲈在16℃和22℃水温条件下口服复方新诺明的休药期应为26d和32d。
中国对虾肌注恩诺沙星后，血液中药物浓度即刻达到峰值，并迅速向组织中分布，血药经时过程符合一级吸收二室开放模型，主要药动学参数为：T_(1/2)α0.094h、T_(1/2)β7.03h、AUC39mg／L.h、K_(12)3.59h~(-1)、K_(21)3.69h~(-1)，CLB0.25L／kg.h，药物在血液中的药-时
复方新诺明和恩诺沙星在两种水产动物体内药物代谢动力学及残留研究
曲线方程为c血液=3.93扩·38t+3.83e一01‘。药物在肌肉、肝胰脏内的经时过程亦符合
一级吸收二室开放模型，主要药代参数分别为AUC73和320m叭.h、T，。KA 0.03和
0 .06h、T，二刀19.7和597h，参数显示药物在这两种组织中分布广泛，药物向组织中运转
的速度较快，消除速度较慢。药物在组织中的药一时曲线方程分别为C肌l、=4 .379e一04‘
+2.57e一003‘一6.949e一22’3‘、e。，。，=8.99e一0·142‘+3.44e一o，’3，·6.949e一l”5‘。恩诺沙星的代
谢物环丙沙星在三种组织中均能测到，其在肌肉，血液，肝胰脏中的主要参数分
别为:Cn、a、0.009、0.023、0.183林咖U，AUC 0.139、0.466、7.2 mg/L.h，T，。K^0.17、
0.x4、2.34h，TI/2K一0.3、13.3、Zo.7h，从数据可以看出环丙沙星在各组织中生成
比较迅速，消除较慢，在肝胰脏中浓度最大。根据本试验结果，按照多计量给药
原理，则中国又创吓肌注恩诺沙星合适的给药方案应为:6 .4mg瓜g的剂量，每日一次给药。
This article could be divided into two parts, one part first reports the residual characteristics of SMZ and TMP in perch at different temperature following oral administration for 5 consecutive days. The concentrations of medicament were determined by High Performance Liquid Chromatography. The results indicated that The velocity of elimination and absorptivity changed at different temperature. They will increase when the temperature increase. The withholding period for perch after oral
administration at dose of 40mg kg-1 with mixture of SMZ and TMP (5/l)for 5 consecutive days should be 26d and 30d at water temperature 22℃ and 16℃.
The other part part first reports pharmacoknetics of enroflxacin and its activated metabolite ciprofloxacin in Penaeus chinensis. after intramuscular injection. The concentration of medicament were determined by High Performance Liquid Chromatography. The data were analyed with the pharmacoknetics computer program MCPKP. The pharmacyoknetic showed that the concentration-time course of enroflxacin in plasma after intramuscular injection can be described by a two-compartment open model. The main pharmacoknetics parameters were as follows: T,/2 a 0.094h, T1/2B 7.03h, AUC 39 Mg/L.h, K12 3.59 h-1 , K21 3.69h-1. The theoretical equation was C血液 =3.93e-738t+3.83 e-0.1t. the concentration-time course of enrofioxacin in muscle and liver can be described by a two-compartment open model too. The main pharmacoknetics parameters were as follows: AUC 73 and 320 Mg/L.h > T1KA 0.03
and 0.06h, T1/2 B 19.7 and 59.7h. The theoretical equation was C 肌肉 =4.379e-0.4t+2.57
e-0.03tt-6.949e--22.73t, C 肝胰脏=8.99e-0.142t+3.44e-0.013t-6.949e-11.95t, Ciprofloxacin, The metab -olite of enrofioxacin can be detected in all three tissue. The values of main pharmacoknetics parameters Cmax(ug/ml),AUC(mg/L.h),T1/2KA(h)and T1/2K(h) were as follows: 0.009,1.26,0.17 and 10.3 for muscle, respectively, 0.023,0.95,0. 14and 13.3 for blood, respectively, 0.183,18.7,2.34 and 20.7 for liver, respectively. Base on the data above, we suggest dosage regimen of enrofioxacin is that Penaeus chinensis can take enrofioxacin once one day by intramuscular injection (6.4 mg/kg)
研究结果表明：与TMP相比，SMZ在花鲈体内残留量较小，且消除较快。以22℃±3℃下肌肉中的残留情况为例，停药一天后SMZ和TMP在花鲈肌肉组织内的残留量分别为9.4和30.1μg／ml；消除半衰期T_(1/2)β分别为0.37d和1.98d。温度对SMZ和TMP在花鲈体内的吸收和消除均有影响，温度对于吸收的影响主要体现于TMP，22℃±3℃和16℃±2℃温度下，停药一天后TMP在肌肉、血液、肝脏、肾脏四种组织中的浓度分别为30.1，8.47，18.8，100.9μg／ml和12.9，5.6，8.27，23.2μg／ml，数据显示较高温度下，TMP在花鲈体内的吸收率较高；温度对SMZ的吸收率则无明显影响。温度对SMZ和TMP在花鲈组织内的消除速度的影响可从下列数据看出：22℃±3℃水温条件下，SMZ和TMP在肌肉、血液、肝脏、肾脏四种组织中的T_(1/2)β分别为0.37，0.47，0.72，0.48d和1.98，2.09，1.63，5.53d；16℃±2℃下的分别为0.72，0.95，1.90，1.11d和3.48，3.92，3.43，7.8d。说明两种药物在花鲈组织内的消除速度随温度的升高而加快，并且，SMZ的消除速度受温度影响更明显。综合两种药物在鱼体内的残留情况，建议花鲈在16℃和22℃水温条件下口服复方新诺明的休药期应为26d和32d。
中国对虾肌注恩诺沙星后，血液中药物浓度即刻达到峰值，并迅速向组织中分布，血药经时过程符合一级吸收二室开放模型，主要药动学参数为：T_(1/2)α0.094h、T_(1/2)β7.03h、AUC39mg／L.h、K_(12)3.59h~(-1)、K_(21)3.69h~(-1)，CLB0.25L／kg.h，药物在血液中的药-时
复方新诺明和恩诺沙星在两种水产动物体内药物代谢动力学及残留研究
曲线方程为c血液=3.93扩·38t+3.83e一01‘。药物在肌肉、肝胰脏内的经时过程亦符合
一级吸收二室开放模型，主要药代参数分别为AUC73和320m叭.h、T，。KA 0.03和
0 .06h、T，二刀19.7和597h，参数显示药物在这两种组织中分布广泛，药物向组织中运转
的速度较快，消除速度较慢。药物在组织中的药一时曲线方程分别为C肌l、=4 .379e一04‘
+2.57e一003‘一6.949e一22’3‘、e。，。，=8.99e一0·142‘+3.44e一o，’3，·6.949e一l”5‘。恩诺沙星的代
谢物环丙沙星在三种组织中均能测到，其在肌肉，血液，肝胰脏中的主要参数分
别为:Cn、a、0.009、0.023、0.183林咖U，AUC 0.139、0.466、7.2 mg/L.h，T，。K^0.17、
0.x4、2.34h，TI/2K一0.3、13.3、Zo.7h，从数据可以看出环丙沙星在各组织中生成
比较迅速，消除较慢，在肝胰脏中浓度最大。根据本试验结果，按照多计量给药
原理，则中国又创吓肌注恩诺沙星合适的给药方案应为:6 .4mg瓜g的剂量，每日一次给药。
This article could be divided into two parts, one part first reports the residual characteristics of SMZ and TMP in perch at different temperature following oral administration for 5 consecutive days. The concentrations of medicament were determined by High Performance Liquid Chromatography. The results indicated that The velocity of elimination and absorptivity changed at different temperature. They will increase when the temperature increase. The withholding period for perch after oral
administration at dose of 40mg kg-1 with mixture of SMZ and TMP (5/l)for 5 consecutive days should be 26d and 30d at water temperature 22℃ and 16℃.
The other part part first reports pharmacoknetics of enroflxacin and its activated metabolite ciprofloxacin in Penaeus chinensis. after intramuscular injection. The concentration of medicament were determined by High Performance Liquid Chromatography. The data were analyed with the pharmacoknetics computer program MCPKP. The pharmacyoknetic showed that the concentration-time course of enroflxacin in plasma after intramuscular injection can be described by a two-compartment open model. The main pharmacoknetics parameters were as follows: T,/2 a 0.094h, T1/2B 7.03h, AUC 39 Mg/L.h, K12 3.59 h-1 , K21 3.69h-1. The theoretical equation was C血液 =3.93e-738t+3.83 e-0.1t. the concentration-time course of enrofioxacin in muscle and liver can be described by a two-compartment open model too. The main pharmacoknetics parameters were as follows: AUC 73 and 320 Mg/L.h > T1KA 0.03
and 0.06h, T1/2 B 19.7 and 59.7h. The theoretical equation was C 肌肉 =4.379e-0.4t+2.57
e-0.03tt-6.949e--22.73t, C 肝胰脏=8.99e-0.142t+3.44e-0.013t-6.949e-11.95t, Ciprofloxacin, The metab -olite of enrofioxacin can be detected in all three tissue. The values of main pharmacoknetics parameters Cmax(ug/ml),AUC(mg/L.h),T1/2KA(h)and T1/2K(h) were as follows: 0.009,1.26,0.17 and 10.3 for muscle, respectively, 0.023,0.95,0. 14and 13.3 for blood, respectively, 0.183,18.7,2.34 and 20.7 for liver, respectively. Base on the data above, we suggest dosage regimen of enrofioxacin is that Penaeus chinensis can take enrofioxacin once one day by intramuscular injection (6.4 mg/kg)
引文
1．冯洪辉．兽医药物代谢动力学．北京：科学出版社，1987．
2．李涛．兽医药物动力学．哈尔滨：东北农学院出版社，1985．
3．高清芳，冯克玉，张晓友．现代临床药学．北京：人民军医出版社，1997．34-37．
4．姜立英．动物药理学．中国人民解放军军牧大学，1996．
5. Chang Y L, Chou M H, Lin M F, et al. Determination and pharmacokinetic study of unbound cefepime inrat bile by iquidchromatography with on-line microdialysis. J Chromatogr A, 2001,914:77-82.
6．邱银生．兽用喹诺酮类抗菌剂Enrofioxacin的研究概况，中国兽药杂志，1993，27(3)：52-55．
7．钟大放．药物代谢与药物动力学基础研究展望．辽宁药物与临床，2000，3(4)：145-149．
8．宋振玉．药物代谢研究—意义、方法、应用．北京：人民卫生出版社，1990．
9．钟大放．药物代谢．北京：中国医药科技出版社，1996
10．刘昌孝．药物动力学数据库．北京：中国医药科技出版社，1994．
11. Gumbleton M, Sneader W, pharmacokinetic considerrations in rational drug design. Clin Pharmacokinet, 1994, 26:161-1687.
12．李燕，朱秀媛．细胞色素P450酶系的研究．见：现代药理实验方法．张均田主编，北京医科大学中国协和医科大学联合出版社，1998，1643-1650．
13. Humphrey M J, Smith D A. Roleof metabolismand pharmacokinetics studies in the discovery of new drugs-present and future perspectives. Xenobiotica. 1992, 22:743-755.
14．李健，王群，孙修涛．噁喹酸对水生生物细菌病的防治效果及残留研究．中国水产科学，2001，8(3)：45-49
15．艾晓辉、左文功、贺路．淡水养殖鱼类细菌出血性败血病药物防治研究．中国水产科学，1997，4(3)：54-61．
16．潘连德，陈辉．药物防治的临床药理学与水产药物学问题．水产科技情报，1998，25(4)：169-174．
17．李兆新，冷凯良，李健，李晓川，王维芬．我国渔药质量状况及水产品中渔药残留监控．海洋水产研究，1994，28(3)：10-12．
18．李思发．水产苗种工程和水产种质资源研究．中国水产，1999，(3)：12-15．
19．李兆新．水生生物药物残留监控刻不容缓．中国水产，2000，(8)：8-9．
20．艾晓辉，陈正望，等．磺胺二甲嘧啶在银鲫体内的药动血及组织残留研究．淡水渔业，2001，31(6)：52-54．
21. Kleinow K M, Beilfuss W L, Jarboe H H. Pharmacokinetics, bioavailability, distribution, and
metabolism of Sulfadimethoxine in Rainbow Trout(Oncorhynchus mykiss). J Fish Aquat ANAL Sci,1992, 49:1070-1077.
22. Ryuji U. Pharmacokinetics and bioavailability of Sulfamonomethoxine in cultured Eel. Fish Pathology,1988,33(4):297-301.
23 Calvin C W, Steven A B. Extraction and enzyme immunoassay of Sulfadimethoxine residues in Channel Catfish(Ictalurus punctatus). J AOAC Int,1994,77:1460-1466.
24. Samuelsen O B, Lunestad B T, Jelmert A. Pharmacokinetics and efficacy studies on bath-administering potentiated Sulphonamides in Atlantic halibut, Hippoglossus hippogloss us. Fish Dis, 1997, 20:287-29.
25. Gupld B C, Holmes E. Quantitative structure-metabolism relationships using computational chemistry:pattern recognition analysis and Statistical prediction of phass Ⅱ conjugation reacuions of substituted benzoic acids in the rat. Xenobiotica, 1999,29:27-42.
26. Kazuaki U, Takaiko A, Ryuji U. Pharmacokinetics and metabolism of Sulfamonomethoxine in Rainbow Trout(Oncorhynchus mykiss)and yellowtail(Sariola quinqueradiata)following bolus intravascular administration Aquaculture,1997,153:1-8.
27. Joel E H, Richard D L, Rose M N, et al. Liquid Chromatographic dtermination of Sulfamethazine in Feed. J ASSOC OFF ANAL CHEM,1988,71(5):1054-1056.
28．王群，孙修涛，刘德月，等．复方新诺明在鲈鱼体内的药物代谢动力学研究．海洋科学，2001，25：35-38．
29. Samuelsen O B, Pursell L, Smith P, et al. Multiple-dose Pharmacokinetics study of Romet~(30) in Atlantic salmon(Sahno salar)and in vitro antibacterial activity against Aeromonas. Aquaculture,1997,152:287-296.
30. Harry B, Goran B. Temperature-Related absorption and excretion of Oxytetracycline in Rainbow Trout(Salmo gairdner R.). J Aquaculture.1990,84:363-372.
31. Joseph U, Daniel P, Robert A B, et al. Quantitation of Sulfamethazine in pork tissue by-Layer Chromato-graphy. JAOAC Int, 1993,77(2):335-341.
32．邱银生，兽川喹诺酮类抗菌剂 Enrofloxacin的研究概况[J]中国兽药杂忐，1993，2，7(3)：52-55
33．曾振灵，冯淇辉．氟喹诺酮类抗菌剂在畜禽体内的药物动力学研究进展[J]．中国兽药杂志，1994，28(4)：52-55．
34．王建元，刘玉年．氟喹诺酮类抗菌药在动物上的应用[J]．中国兽医学报，1996，16(3)：305-306．
35. B L broome, D L brooks, J G babish. Pharmacokinetic properties ofenrofloxacin in rabbits[J]. AM J Vet Res, 1991, 52(11):1835-1841.
36. A Anadon, M R Martinez-Larranaga, C Yelez, Pharmacokinetics of enrofloxacin and its N desethyl-and oxo-rnetabolites in broiler chickesn[J].AM J Vet Res,1998,28(3).2084-2089
37. A Anadon, M R Martinez-Larranaga, M J Diaz. Pharmacokinetics and residues of enrofloxacin in chickens[J]. AM J Vet Res,1995,56(4):501-506.
38．邱银生，朱式欧，郝玉萍．烟酸诺氟沙星在猪、鸡体内的组织残留研究[J]．中国兽药杂志 ，1994，28(3)：10-12．
39．丁焕中，冯洪辉，曾振灵，陈杖榴．沙拉沙星(sarafioxacin)在鸡体内的药动学．中国兽医学报，2000，5(20)：493-496．
40. Ueno R, Okada Y, Tatsuno T. Pharmacokinetics and metabolism of miloxacin in culturedeel. Aquaculture, 2001,193:1124.
41．胡功政，冯淇辉．恩诺沙星及其活性代谢物在鸡体内的药物动力学．中国兽医学报，1999，19(2)：171-174．
42. Mahmood I. Pharmacokinetic analysis of the absorption characteristics of diclofenac sodium in man by use of a multi-segment absorption model. J Pharm Pharmacol,1996,48(12):1260.
43. Elema M O, HoffK A, Kristensen H G. Bioavailability offlumequine after oral admihistration to Atlantic saimon(salmo salarL.).Aquaculture, 1995, 136:209-219.
44. Samuelsen O B, Ervik A.Single dose pharmacokinetics study of flumequine after intravenous,intraperitoneal and oral administration to Atlantic halibut(Hippoglossus hippoglossus)held in seawater at 9℃.Aquaculture, 1997,158:215-227.
45. Piakas S M, EI Said K R, Musser S M. Pharmacokinetics tissues distribution and metabolism of flumequine in channel catfish(Ictalurus punctatus).Aquaculture, 2000,187:1-14.
46．丁勇，血流限速生理药动学模型的平均稳态浓度．中国医学物理学杂志，1996，13(3)：146-148．
47. Chang Y L, Chou M H, Lin M F. Determination and pharmacokinetic study of unbound cefepime inrat bile by iquidchromatography with on-line microdialysis. J Chromatogr A, 2001,914:77-82.
48．黄丽．浅谈影响药效的因素．黑龙江医药，1999，12(4)：229-230．
49. Barnes A C, Hastings T S, Amyes S G B. Aquaculture antibacterials are antagonised by seawater cations, J Fish Dis, 1995,18:463-465.
50．朱秋华，钱国英．3种药物在甲鱼体内的残留研究．中国水产科学，2001，8(3)：50-53．
51．陈文银，印春华．诺氟沙早在中华鳖体内的药代动力学研究．水产学报，1997，21(4)：434-436．
52．杨先乐、刘至治、横山雅仁盐酸环丙沙星在中华绒鳌蟹体内约物代谢动力学研究．鱼类病害研究，2001，23(3)：89．
53．房文红、邵锦华、施兆鸿，等．斑节对虾血淋巴中诺氟沙星含量测定方法和药代动力学研究．鱼类病害研究，2001，23(3)：89-90．
54. Chair M, Nelis H J, Leger P, Sorgeloos P, De-leenheer A P. Accumulation oftrimethoprim, sulthmethoxazole, and N-acetyl sulfamethoxazole in fish and shrimp fed medicated Artemia franciscana. Antimicrob.-Agents-chemother. 1996,40(7):1649-1652.
55. Martinsen B, Horsberg T E. Comparative single-dose pharmacokinetics of four quinolones, oxolinic acid, flumequine, sarafloxacin, and enrofloxacin,in Atlantic sahnon(Salmo salar)held in seawater at 10℃. Antimicrob. Agents Chemother.1995,39:1059-1064.
56. Bretzlaff K N, Neff-Damis C A, Ott R S. FIorfenicol in non-lactating dairy cows:Pharmacokinetics binding to plasma proteins and effects on phagoxytosis by blood neutrophils. J Vet Pharmacol Therap, 1987,10:233-240.
57. Nouws J F M, Grondel J L, Schutte A R, Laurensen J. Pharmacokinetics of ciprofloxacin in carp, African catfish and rainbow trout.Vet Quart,1988,10:211-216.
58. A Roque a, A Molina-Aja b, C Bola'n-Mej(?)(?)a a, B Gomez-Gil. In vitro susceptibility to 15 antibiotics of vibrios isolated from penaeid shrimps in Northwestern Mexico. International Journal of Antimicrobial Agents,(2001)17:383-387.
59. A Roque, B Gomez-Gil. Therapeutic effects of enrofloxacin in anexperimental infection with a luminescent Vibrio harveyi in Artemia franciscana Kellog 1906. Aquaculture,2003,220:37-42.
60. L lntorre, S Cecchini, S Bertini, A M Cognetti Varriale, G Soldani, GMengozzi. Pharmacokinetics of enrofloxacin in the seabass(Dicentrarchus labrax). Aquaculture,2000,182:49-59.
61. J Manceau, M Gicquel, M Laurentie, P Sanders. Simultaneous determination ofenrofloxacin and ciprofloxacin in animal biological fluids by high-performance liquid chromatography Application ill pharmacokinetic studies in pig and rabbit.Journal of Chromatography B,1999,726:175-184.
62．胡功政，冯淇辉．恩诺沙星及其活性代谢物在传染性鼻炎鸡体的药动学．中国兽医学报，1999，(19)3：277-281．
63．应翔宁，杨永胜．兽用新型抗菌药物—恩诺沙星．中国兽药杂志，1999，(29)3：53-57．曾振灵，冯淇辉，恩诺沙星在猪体内的生物利用度及药物动力学研究．中国兽医学报，1996
(16) 6:605-612.
64. Bregante M A, Abadia A R, Aramayona J J, Garcia M A. Pharmacokinetics of enrofloxacin in rainbow trout after a single intravascular injection. ACTAS DEL IV CONGRESO NACIONAL DE ACUICULTURA, CENTRO DE INVESTIGACIONES MARINAS,PONTEVEDR(SPAIN),1993,709-712.
65. Bowser P R, Babish J G, Pharmacokinetics of fluoroquinolones in cultured salmonids. PROGRAM AND ABSTRACTS, SECOND INTERNATIONAL MARINE BIOTECHNOLOGY CONFERENCE,(IMBC'91),1991,55.
66. Martinsen B,Horsberg T E, Antimicrobial activities and pharmacokinetic properties of oxytetrac-ycline,sulfadiazine/trimethoprim, enrofioxacin, RO 09-1168, flumequine and oxolinic acid in Atlantic salmon(Salmo salar).INTERNATIONAL SYMPOSIUM ON AQUATIC ANIMALHEALTH:PROGRAM AND ABSTRACTS,1994,87.
67．刘涤洁，陈杖榴，冯淇辉．恩诺沙星和环丙沙星对金葡菌的抗菌后效应及抗菌后亚抑菌浓度效应．中国兽医学报，2002，(22)3：278-275．
68. Hsu H M, Bowser P R, Schachte J H Jr, Scarlett JM, Babish J G. Winter field trials of enrofloxacin for the control of Aeromonas salmonicida infection in salmonids. Journal of the World Aquaculture Society,1995,(26)3:307-314.
69. Hsu Hui-Min, Wooster G A, Bowser P R. Efficacy of enrofloxacin for the treatment of salmonids with bacterial kidney disease, caused by Renibacterium salmoninarum. Journal of Aquatic Animal Health, 1994,(6)3:220-223.
70. Bowser P R, Wooster G A, Hsu H-M. Laboratory efficacy of enrofloxacin for the control of Aeromonas salmonicida infection in rainbow trout. J AQUAT ANIMAL HEALTH,1994,(6)4:288-291.
7l．黄德林，严成，马勋，侯玉成．恩诺沙星药物对儿株禽源致病性大肠杆菌的药敏试验．绵阳经济技术高等专科学校学报，1999，(16)1：57-60．
72．熊礼宽，杨应周，王仕洪，林振南．氧氟沙星和环丙沙星对快速生长分支杆菌最低抑菌浓度测定，中国防痨杂志，1999，(17)1：24-25．
73．毛芝娟，卓华龙．锯缘青蟹细菌性传染病的病原菌研究．水产科学，2000，(20)1：8-11蒋志伟，王宝安，王永坤，庄国洪．环丙沙星对水产动物气单胞菌的药效学研究．兽药与饲料添加剂，1999，(4)3：3-5．
74．王丽平，江善祥，张建芹，史晓丽．盐酸沙拉沙星的体外抗菌作用．2001，(33)4：24-26．叶启薇，陈杖榴．环丙沙星与甲氧苄氨嘧啶(TMP)的体外联合抑菌研究．中国兽药杂志，1999，
(33) 4：14-18．
75． 周亮．喹诺酮类抗菌后效应．中国医院药学杂志，1998，(18) 2：76-77． 王浴生．抗生素后效应及其临床意义．中国抗生素杂志，1996(21) 4：306-316．
76． Bowser P R, Wooster G A, Hsu H-M. Laboratory efficacy of enrofloxacin for the control of Aeromonas salmonicida infection in rainbow trout. J AQUAT ANIMAL HEALTH, 1994 (6) 4: 288-291．
77． Hsu Hui-Min, Wooster G A, Bowser P R. Tissue distribution of enrofloxacin in fingerling rainbow trout One orhynchus mykiss following different doses of oral administration. Journal of the World Aquaculture Society, 1994, (25) 4: 535-540．
78． Swastika IBM, JayaIBMS, Kokarkin C, TaslihanA. The use of enrofloxacin to prevent mor-tality of tiger shrimp(Penaeus monodon Fab. )larvae due to Vibrio sp. Bulletin of the Brackishwater Aquaculture Development Centre, Jepara. 1992, (9) 1-2: 56-67．
79． Dalsgaard I, Bjerregaard J. Enrofloxacin as an antibiotic in fish. PROCEEDINGS OF THE 5th CONGRESS OF THE EUROPEAN ASSOCIATION FOR VETERINARY PHARMACOLOGY AND TOXICOLOGY, 1991, 300-301．
80． Bowser P R, Schachte J H Jr, Wooster G A, Babish J G. Experimental treatment of Aeromonas salmonicida infections with enrofloxacin and oxolinic acid: Field trails. Journal of Aquatic Animal Health, 1990, (2) 198-203．
2．李涛．兽医药物动力学．哈尔滨：东北农学院出版社，1985．
3．高清芳，冯克玉，张晓友．现代临床药学．北京：人民军医出版社，1997．34-37．
4．姜立英．动物药理学．中国人民解放军军牧大学，1996．
5. Chang Y L, Chou M H, Lin M F, et al. Determination and pharmacokinetic study of unbound cefepime inrat bile by iquidchromatography with on-line microdialysis. J Chromatogr A, 2001,914:77-82.
6．邱银生．兽用喹诺酮类抗菌剂Enrofioxacin的研究概况，中国兽药杂志，1993，27(3)：52-55．
7．钟大放．药物代谢与药物动力学基础研究展望．辽宁药物与临床，2000，3(4)：145-149．
8．宋振玉．药物代谢研究—意义、方法、应用．北京：人民卫生出版社，1990．
9．钟大放．药物代谢．北京：中国医药科技出版社，1996
10．刘昌孝．药物动力学数据库．北京：中国医药科技出版社，1994．
11. Gumbleton M, Sneader W, pharmacokinetic considerrations in rational drug design. Clin Pharmacokinet, 1994, 26:161-1687.
12．李燕，朱秀媛．细胞色素P450酶系的研究．见：现代药理实验方法．张均田主编，北京医科大学中国协和医科大学联合出版社，1998，1643-1650．
13. Humphrey M J, Smith D A. Roleof metabolismand pharmacokinetics studies in the discovery of new drugs-present and future perspectives. Xenobiotica. 1992, 22:743-755.
14．李健，王群，孙修涛．噁喹酸对水生生物细菌病的防治效果及残留研究．中国水产科学，2001，8(3)：45-49
15．艾晓辉、左文功、贺路．淡水养殖鱼类细菌出血性败血病药物防治研究．中国水产科学，1997，4(3)：54-61．
16．潘连德，陈辉．药物防治的临床药理学与水产药物学问题．水产科技情报，1998，25(4)：169-174．
17．李兆新，冷凯良，李健，李晓川，王维芬．我国渔药质量状况及水产品中渔药残留监控．海洋水产研究，1994，28(3)：10-12．
18．李思发．水产苗种工程和水产种质资源研究．中国水产，1999，(3)：12-15．
19．李兆新．水生生物药物残留监控刻不容缓．中国水产，2000，(8)：8-9．
20．艾晓辉，陈正望，等．磺胺二甲嘧啶在银鲫体内的药动血及组织残留研究．淡水渔业，2001，31(6)：52-54．
21. Kleinow K M, Beilfuss W L, Jarboe H H. Pharmacokinetics, bioavailability, distribution, and
metabolism of Sulfadimethoxine in Rainbow Trout(Oncorhynchus mykiss). J Fish Aquat ANAL Sci,1992, 49:1070-1077.
22. Ryuji U. Pharmacokinetics and bioavailability of Sulfamonomethoxine in cultured Eel. Fish Pathology,1988,33(4):297-301.
23 Calvin C W, Steven A B. Extraction and enzyme immunoassay of Sulfadimethoxine residues in Channel Catfish(Ictalurus punctatus). J AOAC Int,1994,77:1460-1466.
24. Samuelsen O B, Lunestad B T, Jelmert A. Pharmacokinetics and efficacy studies on bath-administering potentiated Sulphonamides in Atlantic halibut, Hippoglossus hippogloss us. Fish Dis, 1997, 20:287-29.
25. Gupld B C, Holmes E. Quantitative structure-metabolism relationships using computational chemistry:pattern recognition analysis and Statistical prediction of phass Ⅱ conjugation reacuions of substituted benzoic acids in the rat. Xenobiotica, 1999,29:27-42.
26. Kazuaki U, Takaiko A, Ryuji U. Pharmacokinetics and metabolism of Sulfamonomethoxine in Rainbow Trout(Oncorhynchus mykiss)and yellowtail(Sariola quinqueradiata)following bolus intravascular administration Aquaculture,1997,153:1-8.
27. Joel E H, Richard D L, Rose M N, et al. Liquid Chromatographic dtermination of Sulfamethazine in Feed. J ASSOC OFF ANAL CHEM,1988,71(5):1054-1056.
28．王群，孙修涛，刘德月，等．复方新诺明在鲈鱼体内的药物代谢动力学研究．海洋科学，2001，25：35-38．
29. Samuelsen O B, Pursell L, Smith P, et al. Multiple-dose Pharmacokinetics study of Romet~(30) in Atlantic salmon(Sahno salar)and in vitro antibacterial activity against Aeromonas. Aquaculture,1997,152:287-296.
30. Harry B, Goran B. Temperature-Related absorption and excretion of Oxytetracycline in Rainbow Trout(Salmo gairdner R.). J Aquaculture.1990,84:363-372.
31. Joseph U, Daniel P, Robert A B, et al. Quantitation of Sulfamethazine in pork tissue by-Layer Chromato-graphy. JAOAC Int, 1993,77(2):335-341.
32．邱银生，兽川喹诺酮类抗菌剂 Enrofloxacin的研究概况[J]中国兽药杂忐，1993，2，7(3)：52-55
33．曾振灵，冯淇辉．氟喹诺酮类抗菌剂在畜禽体内的药物动力学研究进展[J]．中国兽药杂志，1994，28(4)：52-55．
34．王建元，刘玉年．氟喹诺酮类抗菌药在动物上的应用[J]．中国兽医学报，1996，16(3)：305-306．
35. B L broome, D L brooks, J G babish. Pharmacokinetic properties ofenrofloxacin in rabbits[J]. AM J Vet Res, 1991, 52(11):1835-1841.
36. A Anadon, M R Martinez-Larranaga, C Yelez, Pharmacokinetics of enrofloxacin and its N desethyl-and oxo-rnetabolites in broiler chickesn[J].AM J Vet Res,1998,28(3).2084-2089
37. A Anadon, M R Martinez-Larranaga, M J Diaz. Pharmacokinetics and residues of enrofloxacin in chickens[J]. AM J Vet Res,1995,56(4):501-506.
38．邱银生，朱式欧，郝玉萍．烟酸诺氟沙星在猪、鸡体内的组织残留研究[J]．中国兽药杂志 ，1994，28(3)：10-12．
39．丁焕中，冯洪辉，曾振灵，陈杖榴．沙拉沙星(sarafioxacin)在鸡体内的药动学．中国兽医学报，2000，5(20)：493-496．
40. Ueno R, Okada Y, Tatsuno T. Pharmacokinetics and metabolism of miloxacin in culturedeel. Aquaculture, 2001,193:1124.
41．胡功政，冯淇辉．恩诺沙星及其活性代谢物在鸡体内的药物动力学．中国兽医学报，1999，19(2)：171-174．
42. Mahmood I. Pharmacokinetic analysis of the absorption characteristics of diclofenac sodium in man by use of a multi-segment absorption model. J Pharm Pharmacol,1996,48(12):1260.
43. Elema M O, HoffK A, Kristensen H G. Bioavailability offlumequine after oral admihistration to Atlantic saimon(salmo salarL.).Aquaculture, 1995, 136:209-219.
44. Samuelsen O B, Ervik A.Single dose pharmacokinetics study of flumequine after intravenous,intraperitoneal and oral administration to Atlantic halibut(Hippoglossus hippoglossus)held in seawater at 9℃.Aquaculture, 1997,158:215-227.
45. Piakas S M, EI Said K R, Musser S M. Pharmacokinetics tissues distribution and metabolism of flumequine in channel catfish(Ictalurus punctatus).Aquaculture, 2000,187:1-14.
46．丁勇，血流限速生理药动学模型的平均稳态浓度．中国医学物理学杂志，1996，13(3)：146-148．
47. Chang Y L, Chou M H, Lin M F. Determination and pharmacokinetic study of unbound cefepime inrat bile by iquidchromatography with on-line microdialysis. J Chromatogr A, 2001,914:77-82.
48．黄丽．浅谈影响药效的因素．黑龙江医药，1999，12(4)：229-230．
49. Barnes A C, Hastings T S, Amyes S G B. Aquaculture antibacterials are antagonised by seawater cations, J Fish Dis, 1995,18:463-465.
50．朱秋华，钱国英．3种药物在甲鱼体内的残留研究．中国水产科学，2001，8(3)：50-53．
51．陈文银，印春华．诺氟沙早在中华鳖体内的药代动力学研究．水产学报，1997，21(4)：434-436．
52．杨先乐、刘至治、横山雅仁盐酸环丙沙星在中华绒鳌蟹体内约物代谢动力学研究．鱼类病害研究，2001，23(3)：89．
53．房文红、邵锦华、施兆鸿，等．斑节对虾血淋巴中诺氟沙星含量测定方法和药代动力学研究．鱼类病害研究，2001，23(3)：89-90．
54. Chair M, Nelis H J, Leger P, Sorgeloos P, De-leenheer A P. Accumulation oftrimethoprim, sulthmethoxazole, and N-acetyl sulfamethoxazole in fish and shrimp fed medicated Artemia franciscana. Antimicrob.-Agents-chemother. 1996,40(7):1649-1652.
55. Martinsen B, Horsberg T E. Comparative single-dose pharmacokinetics of four quinolones, oxolinic acid, flumequine, sarafloxacin, and enrofloxacin,in Atlantic sahnon(Salmo salar)held in seawater at 10℃. Antimicrob. Agents Chemother.1995,39:1059-1064.
56. Bretzlaff K N, Neff-Damis C A, Ott R S. FIorfenicol in non-lactating dairy cows:Pharmacokinetics binding to plasma proteins and effects on phagoxytosis by blood neutrophils. J Vet Pharmacol Therap, 1987,10:233-240.
57. Nouws J F M, Grondel J L, Schutte A R, Laurensen J. Pharmacokinetics of ciprofloxacin in carp, African catfish and rainbow trout.Vet Quart,1988,10:211-216.
58. A Roque a, A Molina-Aja b, C Bola'n-Mej(?)(?)a a, B Gomez-Gil. In vitro susceptibility to 15 antibiotics of vibrios isolated from penaeid shrimps in Northwestern Mexico. International Journal of Antimicrobial Agents,(2001)17:383-387.
59. A Roque, B Gomez-Gil. Therapeutic effects of enrofloxacin in anexperimental infection with a luminescent Vibrio harveyi in Artemia franciscana Kellog 1906. Aquaculture,2003,220:37-42.
60. L lntorre, S Cecchini, S Bertini, A M Cognetti Varriale, G Soldani, GMengozzi. Pharmacokinetics of enrofloxacin in the seabass(Dicentrarchus labrax). Aquaculture,2000,182:49-59.
61. J Manceau, M Gicquel, M Laurentie, P Sanders. Simultaneous determination ofenrofloxacin and ciprofloxacin in animal biological fluids by high-performance liquid chromatography Application ill pharmacokinetic studies in pig and rabbit.Journal of Chromatography B,1999,726:175-184.
62．胡功政，冯淇辉．恩诺沙星及其活性代谢物在传染性鼻炎鸡体的药动学．中国兽医学报，1999，(19)3：277-281．
63．应翔宁，杨永胜．兽用新型抗菌药物—恩诺沙星．中国兽药杂志，1999，(29)3：53-57．曾振灵，冯淇辉，恩诺沙星在猪体内的生物利用度及药物动力学研究．中国兽医学报，1996
(16) 6:605-612.
64. Bregante M A, Abadia A R, Aramayona J J, Garcia M A. Pharmacokinetics of enrofloxacin in rainbow trout after a single intravascular injection. ACTAS DEL IV CONGRESO NACIONAL DE ACUICULTURA, CENTRO DE INVESTIGACIONES MARINAS,PONTEVEDR(SPAIN),1993,709-712.
65. Bowser P R, Babish J G, Pharmacokinetics of fluoroquinolones in cultured salmonids. PROGRAM AND ABSTRACTS, SECOND INTERNATIONAL MARINE BIOTECHNOLOGY CONFERENCE,(IMBC'91),1991,55.
66. Martinsen B,Horsberg T E, Antimicrobial activities and pharmacokinetic properties of oxytetrac-ycline,sulfadiazine/trimethoprim, enrofioxacin, RO 09-1168, flumequine and oxolinic acid in Atlantic salmon(Salmo salar).INTERNATIONAL SYMPOSIUM ON AQUATIC ANIMALHEALTH:PROGRAM AND ABSTRACTS,1994,87.
67．刘涤洁，陈杖榴，冯淇辉．恩诺沙星和环丙沙星对金葡菌的抗菌后效应及抗菌后亚抑菌浓度效应．中国兽医学报，2002，(22)3：278-275．
68. Hsu H M, Bowser P R, Schachte J H Jr, Scarlett JM, Babish J G. Winter field trials of enrofloxacin for the control of Aeromonas salmonicida infection in salmonids. Journal of the World Aquaculture Society,1995,(26)3:307-314.
69. Hsu Hui-Min, Wooster G A, Bowser P R. Efficacy of enrofloxacin for the treatment of salmonids with bacterial kidney disease, caused by Renibacterium salmoninarum. Journal of Aquatic Animal Health, 1994,(6)3:220-223.
70. Bowser P R, Wooster G A, Hsu H-M. Laboratory efficacy of enrofloxacin for the control of Aeromonas salmonicida infection in rainbow trout. J AQUAT ANIMAL HEALTH,1994,(6)4:288-291.
7l．黄德林，严成，马勋，侯玉成．恩诺沙星药物对儿株禽源致病性大肠杆菌的药敏试验．绵阳经济技术高等专科学校学报，1999，(16)1：57-60．
72．熊礼宽，杨应周，王仕洪，林振南．氧氟沙星和环丙沙星对快速生长分支杆菌最低抑菌浓度测定，中国防痨杂志，1999，(17)1：24-25．
73．毛芝娟，卓华龙．锯缘青蟹细菌性传染病的病原菌研究．水产科学，2000，(20)1：8-11蒋志伟，王宝安，王永坤，庄国洪．环丙沙星对水产动物气单胞菌的药效学研究．兽药与饲料添加剂，1999，(4)3：3-5．
74．王丽平，江善祥，张建芹，史晓丽．盐酸沙拉沙星的体外抗菌作用．2001，(33)4：24-26．叶启薇，陈杖榴．环丙沙星与甲氧苄氨嘧啶(TMP)的体外联合抑菌研究．中国兽药杂志，1999，
(33) 4：14-18．
75． 周亮．喹诺酮类抗菌后效应．中国医院药学杂志，1998，(18) 2：76-77． 王浴生．抗生素后效应及其临床意义．中国抗生素杂志，1996(21) 4：306-316．
76． Bowser P R, Wooster G A, Hsu H-M. Laboratory efficacy of enrofloxacin for the control of Aeromonas salmonicida infection in rainbow trout. J AQUAT ANIMAL HEALTH, 1994 (6) 4: 288-291．
77． Hsu Hui-Min, Wooster G A, Bowser P R. Tissue distribution of enrofloxacin in fingerling rainbow trout One orhynchus mykiss following different doses of oral administration. Journal of the World Aquaculture Society, 1994, (25) 4: 535-540．
78． Swastika IBM, JayaIBMS, Kokarkin C, TaslihanA. The use of enrofloxacin to prevent mor-tality of tiger shrimp(Penaeus monodon Fab. )larvae due to Vibrio sp. Bulletin of the Brackishwater Aquaculture Development Centre, Jepara. 1992, (9) 1-2: 56-67．
79． Dalsgaard I, Bjerregaard J. Enrofloxacin as an antibiotic in fish. PROCEEDINGS OF THE 5th CONGRESS OF THE EUROPEAN ASSOCIATION FOR VETERINARY PHARMACOLOGY AND TOXICOLOGY, 1991, 300-301．
80． Bowser P R, Schachte J H Jr, Wooster G A, Babish J G. Experimental treatment of Aeromonas salmonicida infections with enrofloxacin and oxolinic acid: Field trails. Journal of Aquatic Animal Health, 1990, (2) 198-203．