环丙沙星在鳗鲡体内的药代动力学及残留的消除规律研究
|
摘要
以鳗鲡(Anguilla japonica)为实验材料，对环丙沙星在其体内的药物代谢动力学行为及药物物中长期残留的消除过程作—研究。研究分两部分：
第一部分，研究环丙沙星在鳗鲡体内的药代动力学。将鳗鲡以50mg环丙沙星／Kg鳗鲡体重的剂量一次性口灌拌药饲料，分别于给药后的0.25hr、0.5hr、0.75hr、1hr、2hr、4hr、8hr、12hr、24hr、48hr、72hr及96hr时，各取5条鳗鲡，取其血液和肝脏组织，提取其中的环丙沙星，并采用高效液相色谱法对其进行药代动力学测定。药时曲线符合单室模型一级吸收，且环丙沙星在二组织中的药代动力学行为相象。曲线显示，0.25hr后的血药浓度已达到大多数敏感菌的MIC以上；4 hr后到达峰浓度；24hr时，血药浓度仍可使90％以上的受试菌受到抑制。肝脏组织中，灌药后0.25hr时，药物浓度已远远超过大多数敏感菌的MIC；4hr时，达到最高峰；直到24hr后，药物浓度仍在MIC值之上。因此，口灌环丙沙星既可在短时间内达到MIC以上的组织药物浓度，又表现出较好的长效作用。我们又将同一时间以上二组织中的环丙沙星浓度作一对比后发现，肝脏组织中的浓度几乎都高于血液组织中的。因为在鳗鲡体内，环丙沙星通过肾脏和肝脏两大器官排泄。环丙沙星在肝脏中需先经过浓缩作用，再以较高的浓度排出，从而出现了以上现象。环丙沙星在鳗鲡的血液及肝脏组织中的模型方程分别为：C=1.18384×(e~(-0.02000t)-e~(-1.99736t))，C=5.66049×(e~(-0.06999t)-e~(-0.69197t))。其主要药代动力学参数如下：血液组织中，t_((1／2)(ka))=0.34703hr，t_((1／2)(Ke))=34.65561hr，AUC=58.59613mg.L~(-1)hr，V_(a／f)=4.26628L；肝脏组织中，t~_((1／2)(Ka))=1.0017hr，t_((1／2)(Ke))=9.90325hr，AUC=72.69332mg.L~(-1). hr，V_(d／f)=0.98272L。由其药代学参数知，环丙沙星可较快地被机体完全吸收，在体内的消除速度却较慢，即药效持久；且环丙在鳗鲡体内的渗透性很强，能够较容易地穿透绝大部分组织，达到广泛的分布。。将二组织中环丙沙星的具体药代动力学参数作一比较，发现：(1)血液中的Ka大于肝脏中的，而t_((1／2)(Ka))和Tmax小于肝肌中的；血液中的Ke小于肝脏中的，t_((1／2)(Ke))却大于肝脏中的，这况明环丙沙星在血液中的吸收较肝脏中快，而消除则较肝脏中慢。(2)
肝脏对药物具有浓缩作用，致使环丙在肝脏中达到的峰浓度较血液中的高;且药
物在肝脏中的大量积累还造成环丙在肝脏中的吸收总量较血液中高。
第二部分，研究环丙沙星在鳗鲡组织中中长期残留的消除规律。同法给药后，
将鳗鲡分别置于26一28℃及18~22℃的水温条件下饲养。于第4d、5d、6d、7d、
gd、15d、21d和22d时，各取5条鳗鲡，取其血液和肝脏组织，提取其中的环
丙沙星药物残留。结果表明，26一28℃的水温条件下，血液组织中的环丙沙星在
中期消除速度相对较快;而在中后期，则肝脏中消除较快。二组织中的药物浓度
在第7d，均无法再测到。在18一咒℃的水温条件下，则是血液中环丙沙星的消
除速度一直快于肝脏中。至第Zld，血液中已检不到环丙沙星的含量;在肝脏中
则直到第22d刁‘不再检到环丙沙星。再比较两种水温条件下环丙沙星的消除情况
发现，药物的消除速度表现出随水温降低而减慢的现象。此外，在任一种水温条
件下，二组织中环丙沙星残留的消除曲线一直呈现简单的下降趋势，中途并不反
复，即无二次吸收作用。因此，依照本实验结果，在26一28℃水温下用药的鳗
鲡，其上市前环丙沙星的停药期应不少于7d;而在18一22℃水温下用药的鳗鲡，
其环丙沙星的停药期应大于21d。
In this experiment, pharmacokinetics and depletion role of Ciprofloxacin in eel (.Angttillaja, nica) were studied. The study contains two parts.
In part one, pharmacokinetics of Ciprofloxacin in eel was studied.Eels were fed with the dosage of Ciprofloxacin of 50mg/Kg once.After 0. 25hr, 0. 5hr,
0.75hr, 1hr, 2hr, 4hr, 8hr, 12h, 24hr, 48hr, 72hr and 96hr, 5 eels were caught each time. The levels of Ciprofloxacin in their plasma and livers were determined by HPLC. The results show "that the profile in those two tissues conform to one-compartment model with first order absorption and lag time. Pharmacokinetics of Ciprofloxacin in eels' plasma are similar to those in liver.In the study,after 0.25hr,the level of drug was higher than MIC;after 4hr,it reached Grafter 24hr, it was still higher than MIC90. Situation in liver was the same. Even after 24hr, the level of Ciprofloxacin in liver was higher than MIC. So, the lever of Ciprofloxacin in tissues rises up rapidly and could keep higher than MIC in a long time. The level of drug in liver is higher than it is in plasma at the same time. Because Ciprofloxacin is excreted through kidney and liver in eel.Before this,drug should be concentrated.The equations of Ciprofloxacin in plasma and liver are : C=l. 18384× (e-0.02000t-e-1.99736t) , C=5. 66049 × (e-0.06999t-e-0.069197t). The main pharmacokinetic parameters were:in plasma, t1/2(Ka)=0. 34703hr, t1/2(Ke)=34. 65561hr , AUC =58. 59613 rag. L ~ '. hr , Vd/f=4. 26628L;in liver, t1/2(Ka)=l. 0017hr, t1/2(Ke) = 9. 90325hr, AUC= 72. 69332mg. L -1. hr, Vd/r=0. 98272L. These parameters show that, in eel, Ciprofloxacin could be
absorbed quickly and completely, however be excreted slowly. Ciprofloxacin could also penetrate tissues well and has a wide distribution in eel.The parameters: Ka and
t1/2(Ke) in plasma are higher than those in liver;to t1/2(Ka),Tmax and Ke, it is the op, site.lt reveals that in plasma , drug is absorbed more quickly than
in liver;but is excreted more slowly than in liver.The Cmax, and the quantity of drug absorbed into liver are both higher than those in plasma.This result is caused by the concentration of drug in liver.
In part two, depletion role of Ciprofloxacin in eel was studied.Eels were kept at temperatures of 26-28℃ and 18~22℃ after had been fed with Ciprofloxacin. After 4d, 5d, 6d, 7d, 9d, 15d, 21d and 22d, 5 eels were caught each time. We determined the levels of drug in their plasma and livers, then find: at the temperature of 26-28 ℃, Ciprofloxacin in plasma disappeared more quickly when it was early;at the later stage,
Ciprofloxacin in liver disappeared more quickly. We could not determine Ciprofloxacin in these two tissues after Vd.But at the temperature of 18~22℃, the depletion speed of Ciprofloxacin in plasma was always quicker than in liver.After 21d,we could not find Ciprofloxacin in plasma.In liver.it needs 22d. The depletion
speed of Ciprofloxacin residues decelerates with the drop of water temperature. And at the two kinds of water temperature, the levels of drug in two tissues always declined. As a result, at the temperature of 26-2 8℃, eels should be kept from Ciprofloxacin at least 7ds before sale; at the temperature of 18-22℃, it needs more than 22ds .
第一部分，研究环丙沙星在鳗鲡体内的药代动力学。将鳗鲡以50mg环丙沙星／Kg鳗鲡体重的剂量一次性口灌拌药饲料，分别于给药后的0.25hr、0.5hr、0.75hr、1hr、2hr、4hr、8hr、12hr、24hr、48hr、72hr及96hr时，各取5条鳗鲡，取其血液和肝脏组织，提取其中的环丙沙星，并采用高效液相色谱法对其进行药代动力学测定。药时曲线符合单室模型一级吸收，且环丙沙星在二组织中的药代动力学行为相象。曲线显示，0.25hr后的血药浓度已达到大多数敏感菌的MIC以上；4 hr后到达峰浓度；24hr时，血药浓度仍可使90％以上的受试菌受到抑制。肝脏组织中，灌药后0.25hr时，药物浓度已远远超过大多数敏感菌的MIC；4hr时，达到最高峰；直到24hr后，药物浓度仍在MIC值之上。因此，口灌环丙沙星既可在短时间内达到MIC以上的组织药物浓度，又表现出较好的长效作用。我们又将同一时间以上二组织中的环丙沙星浓度作一对比后发现，肝脏组织中的浓度几乎都高于血液组织中的。因为在鳗鲡体内，环丙沙星通过肾脏和肝脏两大器官排泄。环丙沙星在肝脏中需先经过浓缩作用，再以较高的浓度排出，从而出现了以上现象。环丙沙星在鳗鲡的血液及肝脏组织中的模型方程分别为：C=1.18384×(e~(-0.02000t)-e~(-1.99736t))，C=5.66049×(e~(-0.06999t)-e~(-0.69197t))。其主要药代动力学参数如下：血液组织中，t_((1／2)(ka))=0.34703hr，t_((1／2)(Ke))=34.65561hr，AUC=58.59613mg.L~(-1)hr，V_(a／f)=4.26628L；肝脏组织中，t~_((1／2)(Ka))=1.0017hr，t_((1／2)(Ke))=9.90325hr，AUC=72.69332mg.L~(-1). hr，V_(d／f)=0.98272L。由其药代学参数知，环丙沙星可较快地被机体完全吸收，在体内的消除速度却较慢，即药效持久；且环丙在鳗鲡体内的渗透性很强，能够较容易地穿透绝大部分组织，达到广泛的分布。。将二组织中环丙沙星的具体药代动力学参数作一比较，发现：(1)血液中的Ka大于肝脏中的，而t_((1／2)(Ka))和Tmax小于肝肌中的；血液中的Ke小于肝脏中的，t_((1／2)(Ke))却大于肝脏中的，这况明环丙沙星在血液中的吸收较肝脏中快，而消除则较肝脏中慢。(2)
肝脏对药物具有浓缩作用，致使环丙在肝脏中达到的峰浓度较血液中的高;且药
物在肝脏中的大量积累还造成环丙在肝脏中的吸收总量较血液中高。
第二部分，研究环丙沙星在鳗鲡组织中中长期残留的消除规律。同法给药后，
将鳗鲡分别置于26一28℃及18~22℃的水温条件下饲养。于第4d、5d、6d、7d、
gd、15d、21d和22d时，各取5条鳗鲡，取其血液和肝脏组织，提取其中的环
丙沙星药物残留。结果表明，26一28℃的水温条件下，血液组织中的环丙沙星在
中期消除速度相对较快;而在中后期，则肝脏中消除较快。二组织中的药物浓度
在第7d，均无法再测到。在18一咒℃的水温条件下，则是血液中环丙沙星的消
除速度一直快于肝脏中。至第Zld，血液中已检不到环丙沙星的含量;在肝脏中
则直到第22d刁‘不再检到环丙沙星。再比较两种水温条件下环丙沙星的消除情况
发现，药物的消除速度表现出随水温降低而减慢的现象。此外，在任一种水温条
件下，二组织中环丙沙星残留的消除曲线一直呈现简单的下降趋势，中途并不反
复，即无二次吸收作用。因此，依照本实验结果，在26一28℃水温下用药的鳗
鲡，其上市前环丙沙星的停药期应不少于7d;而在18一22℃水温下用药的鳗鲡，
其环丙沙星的停药期应大于21d。
In this experiment, pharmacokinetics and depletion role of Ciprofloxacin in eel (.Angttillaja, nica) were studied. The study contains two parts.
In part one, pharmacokinetics of Ciprofloxacin in eel was studied.Eels were fed with the dosage of Ciprofloxacin of 50mg/Kg once.After 0. 25hr, 0. 5hr,
0.75hr, 1hr, 2hr, 4hr, 8hr, 12h, 24hr, 48hr, 72hr and 96hr, 5 eels were caught each time. The levels of Ciprofloxacin in their plasma and livers were determined by HPLC. The results show "that the profile in those two tissues conform to one-compartment model with first order absorption and lag time. Pharmacokinetics of Ciprofloxacin in eels' plasma are similar to those in liver.In the study,after 0.25hr,the level of drug was higher than MIC;after 4hr,it reached Grafter 24hr, it was still higher than MIC90. Situation in liver was the same. Even after 24hr, the level of Ciprofloxacin in liver was higher than MIC. So, the lever of Ciprofloxacin in tissues rises up rapidly and could keep higher than MIC in a long time. The level of drug in liver is higher than it is in plasma at the same time. Because Ciprofloxacin is excreted through kidney and liver in eel.Before this,drug should be concentrated.The equations of Ciprofloxacin in plasma and liver are : C=l. 18384× (e-0.02000t-e-1.99736t) , C=5. 66049 × (e-0.06999t-e-0.069197t). The main pharmacokinetic parameters were:in plasma, t1/2(Ka)=0. 34703hr, t1/2(Ke)=34. 65561hr , AUC =58. 59613 rag. L ~ '. hr , Vd/f=4. 26628L;in liver, t1/2(Ka)=l. 0017hr, t1/2(Ke) = 9. 90325hr, AUC= 72. 69332mg. L -1. hr, Vd/r=0. 98272L. These parameters show that, in eel, Ciprofloxacin could be
absorbed quickly and completely, however be excreted slowly. Ciprofloxacin could also penetrate tissues well and has a wide distribution in eel.The parameters: Ka and
t1/2(Ke) in plasma are higher than those in liver;to t1/2(Ka),Tmax and Ke, it is the op, site.lt reveals that in plasma , drug is absorbed more quickly than
in liver;but is excreted more slowly than in liver.The Cmax, and the quantity of drug absorbed into liver are both higher than those in plasma.This result is caused by the concentration of drug in liver.
In part two, depletion role of Ciprofloxacin in eel was studied.Eels were kept at temperatures of 26-28℃ and 18~22℃ after had been fed with Ciprofloxacin. After 4d, 5d, 6d, 7d, 9d, 15d, 21d and 22d, 5 eels were caught each time. We determined the levels of drug in their plasma and livers, then find: at the temperature of 26-28 ℃, Ciprofloxacin in plasma disappeared more quickly when it was early;at the later stage,
Ciprofloxacin in liver disappeared more quickly. We could not determine Ciprofloxacin in these two tissues after Vd.But at the temperature of 18~22℃, the depletion speed of Ciprofloxacin in plasma was always quicker than in liver.After 21d,we could not find Ciprofloxacin in plasma.In liver.it needs 22d. The depletion
speed of Ciprofloxacin residues decelerates with the drop of water temperature. And at the two kinds of water temperature, the levels of drug in two tissues always declined. As a result, at the temperature of 26-2 8℃, eels should be kept from Ciprofloxacin at least 7ds before sale; at the temperature of 18-22℃, it needs more than 22ds .
引文
1 戚好文．喹诺酮类抗菌药的研究进展．中国抗生素杂志，1999，24(12)增刊：41-44
2 Ksuajima H,Ishida R,Uchida H.Phototoxicity of gatifloxacin,a new quinolone,and its related drags in Guinea pigs. Jpn Phannacol Ther, 1998,26(10): 1655-1660
3 Ferguson J,Mcewen J,Gohler K,et al Phototoxic pitential of gatifloxacin,a new
fluoroquinolone antimicrobial.Drugs, 1999,58(Suppl 2):S397-S399
4 Domagala JM.Structure-activity and structure-side-effect relationship for the quinolone antibacterials.J Antimicrob Chemother, 1994,33:685-706
5 屈凌波，刘艳，郭宗儒．氟喹诺酮类药物构效关系的研究进展．中国药物化学杂志，2001，11(4)：241-244
6 徐锐，周晴中．氟喹诺酮药物的作用机制与构效关系．淮海工学院学报，1998，1：55-59
7 张致平．喹诺酮类抗菌药研究的新进展．中国抗生素杂志，1999，24(1)：61-68
8 俞庆森，蔡国强，朱龙观．喹诺酮类C-2位构效关系的分子力学和量子化学研究．药学学报，1994，(29)：595-602
9 朱龙观，俞庆森，陈凯先，等．1-环丙基-5-取代-7-(4-甲基哌嗪基)-6，8-二氟-1，4-二氢-4-氧-3喹啉羧酸定量构效关系的比较分子力场分析(CoMFA)研究．中国药物化学杂志，1995，5(3)：187-192
10 张仕善，叶云，肖顺林．氟喹诺酮类药物的构效关系．泸州医学院学报，1997，20(2)：114-116
11 周伟澄，张秀平，氟喹诺酮药物研究新进展．中国新药杂志，2000，9(10)：667-669
12 陈瑞红，梁建华，张石革．第四代氟喹诺酮类药物的研究与应用进展．中国药房，2001，12(2)：114-115
13 吴问根，王尔华．氟喹诺酮类抗菌剂的构效关系．药学进展，1999，23(3)：147-153
14 周伟澄，张秀平．氟喹诺酮类药物研究的新进展．中国医药工业杂志，1997，28(2)：75-81
15 吴斌，王尔华．新一类氟喹诺酮药物—苯磺酰胺氟喹诺酮．药学进展，2000，24(3)：148-154
16 姜素椿，宋克主译．最新广谱喹诺酮类抗微生物药．人民军医出版社，1991
17 王海生．抗感染药物合理应用．人民卫生出版社，2002
18 戴自英．实用抗菌药物学．上海科学技术出版社，1996
19 Childs SJ.Safety of the fluoroquinolone antibiotics:Focus on molecular structure. Infect Urol,2000,13(1):3-10
20 蒋元敏．氟喹诺酮类药的不良反应．广西医学，2001，23(4)：856～859
21 金有豫．药理学．人民卫生出版社，2001
22 Albini A.Photoinduced drugreactivity and its relation to the photostability of pharmaceutical preparatious with photosensitivity effects. ISTISAN(Ital), 1998,(98/13):23-29
23 Mall I,Traynor, NJ,Ferguson J.Recent developments in fluroquinolone phototoxicity. Photoder-Photoimmunol Photomed, 1999,15(1):32-37
24 Ferguson J,Dawe R.Phototoxicity in quinolones:comparison ofciprofloxacin and grepafloxacin. J Antimicrob Chemother, 1997,40(Suppl. A):93-98
25 孙定人，王士凡，王功立，张小明．药物不良反应．人民卫生出版社，1996
26 汪安稳．环丙沙星不良反应国内文献的系统性综述．药物流行病学杂志，2000，9(1)：18-19
27 魏尔清，耿宝琴，临床药理学教程．科学出版社，2001
28 牟振国．环丙沙星的药动学、药物相互作用及不良反应．中国药业，1998，7(6)：33-34
29 马广慈．药物分析方法与应用．科学出版社，2000
30 谢恺舟，陈国宏，戴国俊，祁永红．高效液相色谱法测定鸡组织中环丙沙星残留．肉类工业，2001，1：165-168
31 陈杖榴，丁焕中．动物性食品中的兽药残留及兽药和添加剂的应用．中国家禽，2002，24(17)：5-7
32 李爱师．动物性食品中兽药残留问题．解放军预防医学杂志，1997，15(3)：232-234
33 Hunter J E B,Bennett M,Hart C A,et al.Apromycin-resistant Escheriehia coli isolated from pigs and a stockman. Epidemiol Infect, 1994,112:473-480
34 Hunter J E B,Shelleg J C,Wahon J R,et al. Apromycin-resistant plasmids in Escheriehia coli:Possible transfer to Salmonella typhimurim in calves. Epidemiol Infect, 1992,108:271-278
35 Wollenberger L,Halling-Serensen B,Kusk K O.Acute and chronic toxicity of veterioary antibiotics to daphnia magna. Chemosphere,2000,40(7):723-730
36 Stumpf M,Temes TA,Wilken RD,Rodrigues SV,Baumann W.Polar drag residues
in sewage and natural waters in the state of Rio de Janeiro,Brazil.Sci Total Environ, 1999 12,225(12):135-141
37 苏定冯，缪朝玉，王永铭．药理学进展．人民卫生出版社，2002
2 Ksuajima H,Ishida R,Uchida H.Phototoxicity of gatifloxacin,a new quinolone,and its related drags in Guinea pigs. Jpn Phannacol Ther, 1998,26(10): 1655-1660
3 Ferguson J,Mcewen J,Gohler K,et al Phototoxic pitential of gatifloxacin,a new
fluoroquinolone antimicrobial.Drugs, 1999,58(Suppl 2):S397-S399
4 Domagala JM.Structure-activity and structure-side-effect relationship for the quinolone antibacterials.J Antimicrob Chemother, 1994,33:685-706
5 屈凌波，刘艳，郭宗儒．氟喹诺酮类药物构效关系的研究进展．中国药物化学杂志，2001，11(4)：241-244
6 徐锐，周晴中．氟喹诺酮药物的作用机制与构效关系．淮海工学院学报，1998，1：55-59
7 张致平．喹诺酮类抗菌药研究的新进展．中国抗生素杂志，1999，24(1)：61-68
8 俞庆森，蔡国强，朱龙观．喹诺酮类C-2位构效关系的分子力学和量子化学研究．药学学报，1994，(29)：595-602
9 朱龙观，俞庆森，陈凯先，等．1-环丙基-5-取代-7-(4-甲基哌嗪基)-6，8-二氟-1，4-二氢-4-氧-3喹啉羧酸定量构效关系的比较分子力场分析(CoMFA)研究．中国药物化学杂志，1995，5(3)：187-192
10 张仕善，叶云，肖顺林．氟喹诺酮类药物的构效关系．泸州医学院学报，1997，20(2)：114-116
11 周伟澄，张秀平，氟喹诺酮药物研究新进展．中国新药杂志，2000，9(10)：667-669
12 陈瑞红，梁建华，张石革．第四代氟喹诺酮类药物的研究与应用进展．中国药房，2001，12(2)：114-115
13 吴问根，王尔华．氟喹诺酮类抗菌剂的构效关系．药学进展，1999，23(3)：147-153
14 周伟澄，张秀平．氟喹诺酮类药物研究的新进展．中国医药工业杂志，1997，28(2)：75-81
15 吴斌，王尔华．新一类氟喹诺酮药物—苯磺酰胺氟喹诺酮．药学进展，2000，24(3)：148-154
16 姜素椿，宋克主译．最新广谱喹诺酮类抗微生物药．人民军医出版社，1991
17 王海生．抗感染药物合理应用．人民卫生出版社，2002
18 戴自英．实用抗菌药物学．上海科学技术出版社，1996
19 Childs SJ.Safety of the fluoroquinolone antibiotics:Focus on molecular structure. Infect Urol,2000,13(1):3-10
20 蒋元敏．氟喹诺酮类药的不良反应．广西医学，2001，23(4)：856～859
21 金有豫．药理学．人民卫生出版社，2001
22 Albini A.Photoinduced drugreactivity and its relation to the photostability of pharmaceutical preparatious with photosensitivity effects. ISTISAN(Ital), 1998,(98/13):23-29
23 Mall I,Traynor, NJ,Ferguson J.Recent developments in fluroquinolone phototoxicity. Photoder-Photoimmunol Photomed, 1999,15(1):32-37
24 Ferguson J,Dawe R.Phototoxicity in quinolones:comparison ofciprofloxacin and grepafloxacin. J Antimicrob Chemother, 1997,40(Suppl. A):93-98
25 孙定人，王士凡，王功立，张小明．药物不良反应．人民卫生出版社，1996
26 汪安稳．环丙沙星不良反应国内文献的系统性综述．药物流行病学杂志，2000，9(1)：18-19
27 魏尔清，耿宝琴，临床药理学教程．科学出版社，2001
28 牟振国．环丙沙星的药动学、药物相互作用及不良反应．中国药业，1998，7(6)：33-34
29 马广慈．药物分析方法与应用．科学出版社，2000
30 谢恺舟，陈国宏，戴国俊，祁永红．高效液相色谱法测定鸡组织中环丙沙星残留．肉类工业，2001，1：165-168
31 陈杖榴，丁焕中．动物性食品中的兽药残留及兽药和添加剂的应用．中国家禽，2002，24(17)：5-7
32 李爱师．动物性食品中兽药残留问题．解放军预防医学杂志，1997，15(3)：232-234
33 Hunter J E B,Bennett M,Hart C A,et al.Apromycin-resistant Escheriehia coli isolated from pigs and a stockman. Epidemiol Infect, 1994,112:473-480
34 Hunter J E B,Shelleg J C,Wahon J R,et al. Apromycin-resistant plasmids in Escheriehia coli:Possible transfer to Salmonella typhimurim in calves. Epidemiol Infect, 1992,108:271-278
35 Wollenberger L,Halling-Serensen B,Kusk K O.Acute and chronic toxicity of veterioary antibiotics to daphnia magna. Chemosphere,2000,40(7):723-730
36 Stumpf M,Temes TA,Wilken RD,Rodrigues SV,Baumann W.Polar drag residues
in sewage and natural waters in the state of Rio de Janeiro,Brazil.Sci Total Environ, 1999 12,225(12):135-141
37 苏定冯，缪朝玉，王永铭．药理学进展．人民卫生出版社，2002