不同水温下强力霉素在斑点叉尾鮰体内药动学与残留规律研究
|
摘要
本文研究了不同水温(18±1℃和28±1℃)下,强力霉素(doxycycline, DOTC)在斑点叉尾鮰(Ictalurus punctatus)体内的药物动力学和残留消除规律。药动组以20mg/kg鱼体重单次口灌强力霉素后于0.083、0.167、0.25、0.5、1、2、4、8、12、16、24、48、72、96、120、144 h分别取血液,肌肉、肝脏、肾脏(每个时间点5尾鱼)。残留组以20 mg/kg鱼体重连续给斑点叉尾鮰口灌强力霉素5 d,于停药后第1、3、5、7、9、12、15、24、30、40 d分别取肌肉+皮、肝脏、肾脏三种组织(每个时间点5尾鱼)。采用高效液相色谱紫外检测法测定斑点叉尾鮰血浆和组织中强力霉素的浓度,用3p97药动学软件对药动组数据进行分析。
结果表明：不同水温下,强力霉素在斑点叉尾鮰体内的药时数据均符合二室开放式模型。18℃和28℃动力学方程分别为：C血浆=1.6928e-0.2018t和C血浆=1.3929e-0.1707t,药-时曲线呈明显双峰现象。在水温28℃和18℃时,DOTC在血液中第一次达峰时间Tmax(1)分别为30 min和1 h,浓度为0.58±0.094和1.2765±0.59μg/ml；第二次达峰时间Tmax(2)为8 h和12 h,浓度为4.26±0.714和2.2965±0.059μg/ml。在组织中,28℃和18℃条件下第一次达峰时间Tmax(1)肝脏均为1 h,肾为30 min和1 h,肌肉为30 min和1 h。第二次达峰的时间Tmax(2)肝脏为12 h和48 h,肾为8 h和16 h,肌肉出现在8 h和12 h。水温28℃下药-时曲线下面积(AUC)：肾、肝、血、肌肉分别为63.242、1282.076、142.379、62.348μg/ml·h。消除半衰期(T1/2(b))为31.091-48.767 h,吸收半衰期T1/2(ka)为0.207-5.34 h；水温18℃下药-时曲线下面积(AUC)：肾、肝、血、肌肉分别为117.084、3678.676、261.643、100.974μg/ml·h;(T1/2(b))为42.184-73.937 h,吸收半衰期T1/2(ka)为1.193-11.114 h。从以上结果看出,水温对斑点叉尾鮰体内的药物代谢有明显的影响,高水温时强力霉素在斑点叉尾鮰体内代谢和消除的较快,水温较低时强力霉素代谢和残留消除速度也随之减慢。从强力霉素在斑点叉尾鮰各组织中消除规律看,强力霉素在肝脏中的消除最慢。若将肝脏作为强力霉素在斑点叉尾鮰体内残留的靶组织,按欧盟和中国规定的动物组织中强力霉素在肝脏中最高残留限量(maximum residue limit, MRL) 300μg/kg计算休药期,建议18℃和28℃水温下,休药期分别为55 d和30d。若按强力霉素在可食组织肌肉+皮中最高残留限量300μg/kg计算休药期,建议休药期分别为22 d和19 d。
结论：在水温18℃条件下,DOTC在鱼体血浆和组织中的分布较慢,消除也慢；在水温28℃条件下,DOTC在鱼体血浆和肌肉中的分布较快,而消除也相对低温快。高温条件下组织中的浓度均比低温条件下的浓度高,且第二次达峰浓度Cmax(2)均大于第一次的浓度Cmax(1)。强力霉素在斑点叉尾鮰体内的消除速度与水温有密切关系,不同水温下相同组织,相同水温下不同组织中强力霉素的消除速率快慢不一(差异显著P<0.05)。本研究旨为不同水温条件下强力霉素在斑点叉尾鮰应用制定合理的给药方案及强力霉素在斑点叉尾鮰体内的残留限量和休药期提供理论依据。
The experiment was conducted to study the pharmacokinetics and residual elimination of doxycycline (DOTC) in the Channel Catfish (Ictalurus punctatus) in the different temperature (18±1℃and 28±1℃). At pharmacokinetic groups, after a single oral administration at a dose of 20 mg·kg-1 at0.083、0.167、0.25、0.5、1、2、4、8、12、16、24、48、72、96、120、144 h, channel catfish were killed and the plusma, muscle, liver, kindey tissues were collected (five fish was experimented at each time point). At residual groups, after repeated oral administration for 5 consecutive days, channel catfish were killed and the muscle and skin, liver, kindey tissues were collected after 1,3,5,7,9,12,15,24,30,40 d of oral administration (five fish was experimented at each time point). Doxycycline (DOTC) in plasma and tissues were determined by using high-performance liquid chromatography (HPLC) with UV detection.Pharmacokinetic parameters were calculated by using the 3p97 (Practical Pharmacokinetic Program) software (Mathematics Specisl Field Committee Chinese pharmacology institute,china).
The results indicated that:1)The concentration-time course of DOTC in plasma and tissues can all be described by a two-compartment open model after a single oral administration at the different temperature. The kinetic equation were Cplasma=1.6928e-0.2018t和Cplasma=1.3929e-0.1707t respectively at 18℃and 28℃. It showed an obvious double-peak phenomenon. The main pharmacokinetic parameters were as follows:At 28℃and 18℃, the Tmax(1) of doxycycline was about 30 min and 1 h in plasma respectly. The Cmax(1)was 0.58±0.094和1.2765±0.59μg/ml inplasma. The Tmax (1) of doxycycline were both about 1 h in liver,30 min and 1 h in kidney,30 min and 1 h in muscle. The Tmax(2) of doxycycline was 12 h and 48 h in liver,8 h and 16 h in kidney, 8 h and 12 h in muscle. The area under concentration-time curve (AUC) was 63.242、1282.076、142.379、62.348μg·ml-1·h in kidney, liver, plasma, muscle respectively at 28℃. At 28℃,the elimination half-life (T1/2b)was 31.091～48.767 h and the absorption half-life (T1/2(ka)) was 0.207～5.34 h. The AUC was 117.084、3678.676、261.643、100.974μg·ml-1·h in kidney, liver, plasma, muscle respectively at 18℃. At 18℃,the T1/2b was 42.184～73.937 h and the T1/2(ka) was 1.193～11.114 h. The results show that the pharmacokinetics and depletion speed of doxycycline in channel catfish closely relates with the water temperature. The depletion of DOTC residue in channel catfish is faster at higher water temperature. The speed from fast to slow is muscle and skin、kidney、liver. To compare with other tissues, the elimination of DOTC residue in muscle and skin was slowest, liver was the main reservoir of DOTC residue in channel catfish. If take liver as target tissue in this experiment. According to the maximum residue limit (MRL) of 300μg/kg in liver, The withdrawl period should not be less than 55 d and 30 d at 18℃and 28℃under this experiment condition. And if take an edible tissue of muscle and skin as target tissue in this experiment. According to the maximum residue limit (MRL)of 300μg·kg-1 in muscle and skin. The withdrawl period should not be less than 22 d和19 d at 18℃and 28℃respectively.
The conclusion was that the pharmacokinetics and depletion speed of doxycycline in channel catfish closely relates with the water temperature. The elimination rate was markedly different in different water temperature at the same tissues or different water temperature at the same tissues(P<0.05). At 18℃, the distribution and eliminate of DOTC was slower than at 28℃in plasma and tissues. The concentration of DOTC in tissues at 28℃were all higher than the lower temperature groups. The CmaX(2) was exceeded than the corresponding Cmax(1) The reliable theory basis to make dosage regimen and withdrawl time at different water temperature based on the study.
结果表明：不同水温下,强力霉素在斑点叉尾鮰体内的药时数据均符合二室开放式模型。18℃和28℃动力学方程分别为：C血浆=1.6928e-0.2018t和C血浆=1.3929e-0.1707t,药-时曲线呈明显双峰现象。在水温28℃和18℃时,DOTC在血液中第一次达峰时间Tmax(1)分别为30 min和1 h,浓度为0.58±0.094和1.2765±0.59μg/ml；第二次达峰时间Tmax(2)为8 h和12 h,浓度为4.26±0.714和2.2965±0.059μg/ml。在组织中,28℃和18℃条件下第一次达峰时间Tmax(1)肝脏均为1 h,肾为30 min和1 h,肌肉为30 min和1 h。第二次达峰的时间Tmax(2)肝脏为12 h和48 h,肾为8 h和16 h,肌肉出现在8 h和12 h。水温28℃下药-时曲线下面积(AUC)：肾、肝、血、肌肉分别为63.242、1282.076、142.379、62.348μg/ml·h。消除半衰期(T1/2(b))为31.091-48.767 h,吸收半衰期T1/2(ka)为0.207-5.34 h；水温18℃下药-时曲线下面积(AUC)：肾、肝、血、肌肉分别为117.084、3678.676、261.643、100.974μg/ml·h;(T1/2(b))为42.184-73.937 h,吸收半衰期T1/2(ka)为1.193-11.114 h。从以上结果看出,水温对斑点叉尾鮰体内的药物代谢有明显的影响,高水温时强力霉素在斑点叉尾鮰体内代谢和消除的较快,水温较低时强力霉素代谢和残留消除速度也随之减慢。从强力霉素在斑点叉尾鮰各组织中消除规律看,强力霉素在肝脏中的消除最慢。若将肝脏作为强力霉素在斑点叉尾鮰体内残留的靶组织,按欧盟和中国规定的动物组织中强力霉素在肝脏中最高残留限量(maximum residue limit, MRL) 300μg/kg计算休药期,建议18℃和28℃水温下,休药期分别为55 d和30d。若按强力霉素在可食组织肌肉+皮中最高残留限量300μg/kg计算休药期,建议休药期分别为22 d和19 d。
结论：在水温18℃条件下,DOTC在鱼体血浆和组织中的分布较慢,消除也慢；在水温28℃条件下,DOTC在鱼体血浆和肌肉中的分布较快,而消除也相对低温快。高温条件下组织中的浓度均比低温条件下的浓度高,且第二次达峰浓度Cmax(2)均大于第一次的浓度Cmax(1)。强力霉素在斑点叉尾鮰体内的消除速度与水温有密切关系,不同水温下相同组织,相同水温下不同组织中强力霉素的消除速率快慢不一(差异显著P<0.05)。本研究旨为不同水温条件下强力霉素在斑点叉尾鮰应用制定合理的给药方案及强力霉素在斑点叉尾鮰体内的残留限量和休药期提供理论依据。
The experiment was conducted to study the pharmacokinetics and residual elimination of doxycycline (DOTC) in the Channel Catfish (Ictalurus punctatus) in the different temperature (18±1℃and 28±1℃). At pharmacokinetic groups, after a single oral administration at a dose of 20 mg·kg-1 at0.083、0.167、0.25、0.5、1、2、4、8、12、16、24、48、72、96、120、144 h, channel catfish were killed and the plusma, muscle, liver, kindey tissues were collected (five fish was experimented at each time point). At residual groups, after repeated oral administration for 5 consecutive days, channel catfish were killed and the muscle and skin, liver, kindey tissues were collected after 1,3,5,7,9,12,15,24,30,40 d of oral administration (five fish was experimented at each time point). Doxycycline (DOTC) in plasma and tissues were determined by using high-performance liquid chromatography (HPLC) with UV detection.Pharmacokinetic parameters were calculated by using the 3p97 (Practical Pharmacokinetic Program) software (Mathematics Specisl Field Committee Chinese pharmacology institute,china).
The results indicated that:1)The concentration-time course of DOTC in plasma and tissues can all be described by a two-compartment open model after a single oral administration at the different temperature. The kinetic equation were Cplasma=1.6928e-0.2018t和Cplasma=1.3929e-0.1707t respectively at 18℃and 28℃. It showed an obvious double-peak phenomenon. The main pharmacokinetic parameters were as follows:At 28℃and 18℃, the Tmax(1) of doxycycline was about 30 min and 1 h in plasma respectly. The Cmax(1)was 0.58±0.094和1.2765±0.59μg/ml inplasma. The Tmax (1) of doxycycline were both about 1 h in liver,30 min and 1 h in kidney,30 min and 1 h in muscle. The Tmax(2) of doxycycline was 12 h and 48 h in liver,8 h and 16 h in kidney, 8 h and 12 h in muscle. The area under concentration-time curve (AUC) was 63.242、1282.076、142.379、62.348μg·ml-1·h in kidney, liver, plasma, muscle respectively at 28℃. At 28℃,the elimination half-life (T1/2b)was 31.091～48.767 h and the absorption half-life (T1/2(ka)) was 0.207～5.34 h. The AUC was 117.084、3678.676、261.643、100.974μg·ml-1·h in kidney, liver, plasma, muscle respectively at 18℃. At 18℃,the T1/2b was 42.184～73.937 h and the T1/2(ka) was 1.193～11.114 h. The results show that the pharmacokinetics and depletion speed of doxycycline in channel catfish closely relates with the water temperature. The depletion of DOTC residue in channel catfish is faster at higher water temperature. The speed from fast to slow is muscle and skin、kidney、liver. To compare with other tissues, the elimination of DOTC residue in muscle and skin was slowest, liver was the main reservoir of DOTC residue in channel catfish. If take liver as target tissue in this experiment. According to the maximum residue limit (MRL) of 300μg/kg in liver, The withdrawl period should not be less than 55 d and 30 d at 18℃and 28℃under this experiment condition. And if take an edible tissue of muscle and skin as target tissue in this experiment. According to the maximum residue limit (MRL)of 300μg·kg-1 in muscle and skin. The withdrawl period should not be less than 22 d和19 d at 18℃and 28℃respectively.
The conclusion was that the pharmacokinetics and depletion speed of doxycycline in channel catfish closely relates with the water temperature. The elimination rate was markedly different in different water temperature at the same tissues or different water temperature at the same tissues(P<0.05). At 18℃, the distribution and eliminate of DOTC was slower than at 28℃in plasma and tissues. The concentration of DOTC in tissues at 28℃were all higher than the lower temperature groups. The CmaX(2) was exceeded than the corresponding Cmax(1) The reliable theory basis to make dosage regimen and withdrawl time at different water temperature based on the study.
引文
1 刘同忠,张泽波,等.盐酸多西环素防治疑似鸡传染性喉气管炎[J].畜禽业,1999,7(7)：43-44
2 陈志华.防治禽大肠杆菌病常用药物[J].中国家禽,2004,12(26)：27-29
3 操继跃.猪呼吸系统感染性疾病药物治疗[J].养殖与饲料动物疾病防治,2005,4：39-43
4 刘辉旺,刘义明,刘祥国.动物性食品中多西环素残留的检测方法[J].河南畜牧兽医,2008,29(1)：27-28
5 廖昌容,陈毕生.抗生素在水产动物体内的药代动力学研究进展[J].中国兽药杂志,2004,38(3)：30-34
6 陈育枝,张元元,袁希平,等.动物四环素类抗生素现状及前景[J].兽药与饲料添加剂,2006,11(3)：16-17
7 EU. Commission Regulation (EC) No.508/1999 of 4 March 1999.amending Annex-es I to IV to Council Regulation (EEC) No.2377/90 laying down a Community pro-cedure for the establishment of maximum residue imits of veterinary medicinal products in foodstuffs of animal origin. Official Journal of the European Commun-ities,1999.
8 卢运战,祁克宗,朱良强.四环素类药物残留检测方法研究进展[J].家禽科学,2006,10(6)：36-39
9 张建成.四环素类抗生素研究进展[J].河北医药,2005,7(27)：545-546
10 段丽丽,沈建忠.四环素类药物作用研究进展[J].兽医兽药,2005,1：41-44
11 王金花,操继跃,翟克影.盐酸多西环素在猪体内的药物动力学及其残留[J].中国兽医学报,2008,28(11)：1313-1316
12 谭峰.四环素和喹诺酮类药物分析方法研究[D].西北大学硕士学位论文,2001.(5)
13 Axisa B, Naylor A R, Bell P R F, T hompsonM M. Simple and reliable method of Doxycycline determination in human plasma and biological tissues. Journal of Chromatography B,2000,744:359-365
14 庞国芳,曹彦忠,张进杰,等.高效液相色谱法同时测定禽肉中土霉素、四环素、金霉素、强力霉素残留的研究[J].分析测试学报,2005,24(4)：61-63
15 张素霞,李俊锁,钱传范.牛奶中四环素类药物多残留分析方法研究一MSPD—HPLC—UV[J].畜牧兽医学报,2002,33(1)：51-54
16 黄志勇,蔡洪基,黄高凌,等.水产品中四环素类抗生素残留量的高效液相 色谱测定方法[J].福建分析测试,2005,14(1)：2093-2095
17 王淑芬.鸡组织中脱氧土霉素测定方法研究[J].辽宁畜牧兽医,2004,3：30-31
18 Ibrahim A.Aisarra I A, Niazy E M,AI-Sayed Y M, A I-Khamis K I, Ibrahim M E-A.High performance liquid chromatographic method for the determination of doxycycline in human plasma and its application in pharmacokinetic studys. Saudi Pharmaceutical Journal,2005,13(1):42-47
19 Cinquina A L,Longo F, Anastasi G, Giannetti L.Validation of a high-performan-ce liquid chromatography method for the determination of oxytetracycline, tetracyc-line, chlortetracycline and doxycycline in bovine milk and muscle. Journal of Chromatography A,2003,987:227-233
20 Ruth R, Dina F, Arie L. Bioequivalence study of two formulations of doxycycline. Current therapeutic research,1998,59 (5):315-324.
21 杨菱,宋金春.四环素类抗生素不良反应[J].医药导报,1994,13(1)：39-40
22 陈高英,杨青林,司荣君,等.四环素的不良反应及过敏反应[J].畜牧兽医科技信息,2005,4：50
23 陈育枝,张元元,袁希平,等.动物四环素类抗生素现状及前景[J].兽药与饲料添加剂,2006,1(3)：16-17
24 曲甍甍,孙立伟,陈錾,等.兽药添加剂阿散酸和土霉素的毒理学研究[J].农业环境科学学报,2004,23(2)：240-244
25 Samuelsen O B, Torsvik A. Long-range changes in oxytetracyline concentration and bacterial resistance toward oxytetracyline in a fish farm sediment after medication [J].Sci Total Environ,1992,114:25-36.
26 方宝霞,陈富超,李开俊.多西环素的不良反应与临床合理应用[J].中国误诊学杂志,2006,20(6)：4084-4085
27 张仲秋.畜禽药物使用手册[M].北京：中国农业大学出版社,2000,55-56
28 Pijper A,Van K B,Schoevers E J, Verheijden J H M,Van M.In vitro activity of fi -ve tetracyclines and some other antimicrobial agents against four porcine respirat-ory tract pathogens. Journal of veterinary pharmacology and therapeutics,1989, 12:267-276
29曾振灵,刘付启荣.脱氧土霉素对人工诱发鸡大肠杆菌病的疗效[J].中国畜禽传染病,1997,4：37-39
30 Terlaak E A, Pijper A, Noordergraaf H, Schoevers E J, Verheijden J H M. A Compa-rison of methods for in vitro susceptibility testing of porcine mycoplasma species. Thesis(A.Pijper) PhD University of Utrecht,1991,35(2):228-233
31李仲兴,王秀华,孟晓洁,等.多西环素对224株肠球菌的体外抗菌活性研究[J].河北医科大学学报,2004,25(6)：348-351
32 Sanders P,Cicquel.M, Hurtaud.D, Chapel A M, Gaudiche. C&B ousquet.E. Absolu-te bioavailabilitu of doxycycline after oral a ministration in medicated feed to pigs. Proceedings of the 14th IPVS Congress.1996,663
33司红彬,梁松林,许桂芹,等.4味中药及其与抗菌药的复方制剂的MIC测定[J].中国兽药杂志,2006,40(2)：31-34
34张蜀,谭载友,陈济民.家兔中盐酸多西环素缓释凝胶牙龈给药与口服给药的比较[J].广东药学院学报,2005,21(1)：21-23
35袁延文,殷生章,赵恒寿.盐酸多西环素对鸡白痢和禽霍乱的疗效试验[J].中国兽药杂志,2006,40(9)：48-50
36张军凤,杨晓东.应用盐酸多西环素冻干粉针治疗猪附红细胞体病及其混合感染[J].兽药疫苗,2006,3：48-49
37曹洪敬,徐培莲,任素芳,等.强力霉素对鸡毒支原体病的临床治疗试验.山东农业科学,1996,3：50
38陈锡美,王毅军,朱风尚.强力霉素对溃疡性结肠炎大鼠治疗作用的实验研究[J].同济大学学报,2005,3(26)：4-7
39蒋涛,常巍巍.猪圆环病毒和猪链球病混合感染的诊断体会[J].河南畜牧兽医,2005,26(5)：48
40董国良,王秀清,李桂军.兔病毒性出血症和附红细胞混合感染的诊治[J].疾病防治-特种经济动植物,2005,6：44
41孟小亮,陈昌福,吴志新,等.嗜水气单胞菌对盐酸多西环素的耐药性获得与 消失速率研究[J].长江大学学报,3009,6(1)：42-44
42魏树礼,张强.生物药剂学与药物动力学[M].北京：北京医科大学出版社,1997.208-217
43刘雅红,冯淇辉.兽药药物动力学研究新进展一兽医群体药物动力学[J].中国兽医学报,2000,20(5)：18-52
44 Sun Y, Peng Y, Aksornkoae N, Johnson J R,Boring J G, Scruggs D, Cooper R C, Laizure S C,Shukla A J. Controlled release of oxytetracycline in sheep. Journal of Controlled Release,2002,85(1):125-134
45夏文江,尼.吉尔德-汉森,波.尼尔森.土霉素的药物动力学研究[J].中国兽医科技,1984,3：19-24
46 Ei-Aty A M, Goudah A, Zhou H H. Pharmacokinetics of doxycycline after administration as a single intravenous bolus and intramuscular doses to non-lact-ating Egyptian goats.Pharmacol Res,2004,49:487-491
47 Ole-Mapenay I M,Mitema E S,Maitho T E. Aspects of the pharmacokinetics of Doxycycline given to healthy and pneumonic East African dwarf goats by intram-uscular injection. Veterinary Research Communications,1997,21(6):453-462
48杨海峰,覃少华,王加才,等.2种多西环素注射液在健康猪体内的药动学比较[J].畜牧与兽医学,2007,1.
49 Riond.J.L& Riviere, J.E.Pharmacokintics and metabolic inertness of doxycycline in young pigs. American Journal of Veterinary Research,1998,51:1271-1275
50 Uno K. Pharmacokinetic study of oxytetracycline in healthy and vibriosisinfected ayu (Plecoglossus altivelis) [J]. Aquaculture,1996,143:33-42.
51 Abedini S, Namdari R, Law FCP. Comparative pharmacokinetics and bioava-ilability of oxytetracycline in rainbow trout and Chinook salmon[J]. Aquaculture, 1998,162:23-32.
52 Croubels S. Liquid chromatographic separation of doxycycline and 4-epidoxycycl-ine in a tissue depletion study of doxycycline in turkeys. Journal of Chromatography B,1998,708:145-152
53 Yoshimura H,Osawa N,Rasa F S.Hermawati D,Werdiningsih S. Isriyanthi N M, Sugimori T. Food Addit. Animal Contain,1991,8:65
54 Wang W F, Lin H, Xue C H. Elimination of chloramphenicol, sulphamethoxazole and oxytetracycline in shrimp, Penaeus chinensis following medicated-feed treatm-ent. Environment International.2004,30:367-373
55李美同,郭文林,仲锋,等.土霉素在鳗鲡组织中残留的消除规律[J].水产学报,1997,21(1)：39-43
56徐维海,林黎明,朱校斌,等.四环素类抗菌药物在吉富罗非鱼体内的代谢动力学研究[J].水产科学,2004,23(3)：1-3
57杨先乐,湛嘉.氯霉素在罗非鱼体内的代谢和消除规律.水生生物学报,2005,29(3)：266-271.
58艾晓辉,刘长征,周运涛.不同水温和给药方式下磺胺甲嗯唑在草鱼体内的药动学研究[J].水生生物学报,2005,29(2)：210—214
59 Curtis L R, Kemp C J, Svec A V. Biliary excretion of [super(14)C] taurocholate by rainbow trout(Salmo gairdneri) is stimulated at warmer acclimation temperature [J]. Comp Blochem Physiol,1986.84(1):87—90.
60 Kleinow K M, Jarboe H H, Shoemaker K E. Comparative pharmacokinetics and bioavailability of oxolinic acid in channel catfish (lctalurus punctatus) and rainbow trout (Oncorhynchus myliss)[J]. Can J Fish Aquac Sci,1994,51:1205-1211.
61 Adel H. Karara, William L. Hayton. A pharmacokinetic analysis of the effect of temperature on the accumulation of di-2-ethylhexyl phthalate (DEHP) in sheeps head min now. Aquatic Toxicology,1989,15(1):27-36
62 R. Namdari, S. Abedini, F. C. P. Law.Tissue distribution and elimination of oxytetracycline in seawater chinook and coho salmon following medicated-feed treatment.Aquaculture,1996,144(1):27-38
63.刘永涛,艾晓辉,杨红.不同水温下氟甲砜霉素在斑点叉尾鲴体内的药代动力学研究[J].水生生物学报,2009,33(1)：1-6
64 Abd Ei-Aty A M, Goudah A, Zhou H H. Pharmacokinetics of doxycycline after administration as a single intravenous bolus and intramuscular doses to non-lactating Egyptian goats[J]. Pharmacol Res,2004,49:487-491.
65 Jha V K, Jayachandran C, Singh M K, Singh S D. Pharmacokinetic data on do-xycycline and its distribution in different biological fluids in female goats. Vete -rinary Research Commumications,1989,13:11-16
66朱模忠.兽药手册[M].北京：化学工业出版社,2002：70-73.
67周怀梧.药物吸收多峰现象的动力学研究[J].现代应用药学,1989,6(2)：37-40.
68肖亮,王婧,王承明,等.土霉素在草鱼体内的组织残留研究[J].湖北农业科学,2007,5：466-468.
69姜素椿,宋克(译).最新广谱喹诺酮类抗微生物药[M].北京：人民军医出版社,1991.
2 陈志华.防治禽大肠杆菌病常用药物[J].中国家禽,2004,12(26)：27-29
3 操继跃.猪呼吸系统感染性疾病药物治疗[J].养殖与饲料动物疾病防治,2005,4：39-43
4 刘辉旺,刘义明,刘祥国.动物性食品中多西环素残留的检测方法[J].河南畜牧兽医,2008,29(1)：27-28
5 廖昌容,陈毕生.抗生素在水产动物体内的药代动力学研究进展[J].中国兽药杂志,2004,38(3)：30-34
6 陈育枝,张元元,袁希平,等.动物四环素类抗生素现状及前景[J].兽药与饲料添加剂,2006,11(3)：16-17
7 EU. Commission Regulation (EC) No.508/1999 of 4 March 1999.amending Annex-es I to IV to Council Regulation (EEC) No.2377/90 laying down a Community pro-cedure for the establishment of maximum residue imits of veterinary medicinal products in foodstuffs of animal origin. Official Journal of the European Commun-ities,1999.
8 卢运战,祁克宗,朱良强.四环素类药物残留检测方法研究进展[J].家禽科学,2006,10(6)：36-39
9 张建成.四环素类抗生素研究进展[J].河北医药,2005,7(27)：545-546
10 段丽丽,沈建忠.四环素类药物作用研究进展[J].兽医兽药,2005,1：41-44
11 王金花,操继跃,翟克影.盐酸多西环素在猪体内的药物动力学及其残留[J].中国兽医学报,2008,28(11)：1313-1316
12 谭峰.四环素和喹诺酮类药物分析方法研究[D].西北大学硕士学位论文,2001.(5)
13 Axisa B, Naylor A R, Bell P R F, T hompsonM M. Simple and reliable method of Doxycycline determination in human plasma and biological tissues. Journal of Chromatography B,2000,744:359-365
14 庞国芳,曹彦忠,张进杰,等.高效液相色谱法同时测定禽肉中土霉素、四环素、金霉素、强力霉素残留的研究[J].分析测试学报,2005,24(4)：61-63
15 张素霞,李俊锁,钱传范.牛奶中四环素类药物多残留分析方法研究一MSPD—HPLC—UV[J].畜牧兽医学报,2002,33(1)：51-54
16 黄志勇,蔡洪基,黄高凌,等.水产品中四环素类抗生素残留量的高效液相 色谱测定方法[J].福建分析测试,2005,14(1)：2093-2095
17 王淑芬.鸡组织中脱氧土霉素测定方法研究[J].辽宁畜牧兽医,2004,3：30-31
18 Ibrahim A.Aisarra I A, Niazy E M,AI-Sayed Y M, A I-Khamis K I, Ibrahim M E-A.High performance liquid chromatographic method for the determination of doxycycline in human plasma and its application in pharmacokinetic studys. Saudi Pharmaceutical Journal,2005,13(1):42-47
19 Cinquina A L,Longo F, Anastasi G, Giannetti L.Validation of a high-performan-ce liquid chromatography method for the determination of oxytetracycline, tetracyc-line, chlortetracycline and doxycycline in bovine milk and muscle. Journal of Chromatography A,2003,987:227-233
20 Ruth R, Dina F, Arie L. Bioequivalence study of two formulations of doxycycline. Current therapeutic research,1998,59 (5):315-324.
21 杨菱,宋金春.四环素类抗生素不良反应[J].医药导报,1994,13(1)：39-40
22 陈高英,杨青林,司荣君,等.四环素的不良反应及过敏反应[J].畜牧兽医科技信息,2005,4：50
23 陈育枝,张元元,袁希平,等.动物四环素类抗生素现状及前景[J].兽药与饲料添加剂,2006,1(3)：16-17
24 曲甍甍,孙立伟,陈錾,等.兽药添加剂阿散酸和土霉素的毒理学研究[J].农业环境科学学报,2004,23(2)：240-244
25 Samuelsen O B, Torsvik A. Long-range changes in oxytetracyline concentration and bacterial resistance toward oxytetracyline in a fish farm sediment after medication [J].Sci Total Environ,1992,114:25-36.
26 方宝霞,陈富超,李开俊.多西环素的不良反应与临床合理应用[J].中国误诊学杂志,2006,20(6)：4084-4085
27 张仲秋.畜禽药物使用手册[M].北京：中国农业大学出版社,2000,55-56
28 Pijper A,Van K B,Schoevers E J, Verheijden J H M,Van M.In vitro activity of fi -ve tetracyclines and some other antimicrobial agents against four porcine respirat-ory tract pathogens. Journal of veterinary pharmacology and therapeutics,1989, 12:267-276
29曾振灵,刘付启荣.脱氧土霉素对人工诱发鸡大肠杆菌病的疗效[J].中国畜禽传染病,1997,4：37-39
30 Terlaak E A, Pijper A, Noordergraaf H, Schoevers E J, Verheijden J H M. A Compa-rison of methods for in vitro susceptibility testing of porcine mycoplasma species. Thesis(A.Pijper) PhD University of Utrecht,1991,35(2):228-233
31李仲兴,王秀华,孟晓洁,等.多西环素对224株肠球菌的体外抗菌活性研究[J].河北医科大学学报,2004,25(6)：348-351
32 Sanders P,Cicquel.M, Hurtaud.D, Chapel A M, Gaudiche. C&B ousquet.E. Absolu-te bioavailabilitu of doxycycline after oral a ministration in medicated feed to pigs. Proceedings of the 14th IPVS Congress.1996,663
33司红彬,梁松林,许桂芹,等.4味中药及其与抗菌药的复方制剂的MIC测定[J].中国兽药杂志,2006,40(2)：31-34
34张蜀,谭载友,陈济民.家兔中盐酸多西环素缓释凝胶牙龈给药与口服给药的比较[J].广东药学院学报,2005,21(1)：21-23
35袁延文,殷生章,赵恒寿.盐酸多西环素对鸡白痢和禽霍乱的疗效试验[J].中国兽药杂志,2006,40(9)：48-50
36张军凤,杨晓东.应用盐酸多西环素冻干粉针治疗猪附红细胞体病及其混合感染[J].兽药疫苗,2006,3：48-49
37曹洪敬,徐培莲,任素芳,等.强力霉素对鸡毒支原体病的临床治疗试验.山东农业科学,1996,3：50
38陈锡美,王毅军,朱风尚.强力霉素对溃疡性结肠炎大鼠治疗作用的实验研究[J].同济大学学报,2005,3(26)：4-7
39蒋涛,常巍巍.猪圆环病毒和猪链球病混合感染的诊断体会[J].河南畜牧兽医,2005,26(5)：48
40董国良,王秀清,李桂军.兔病毒性出血症和附红细胞混合感染的诊治[J].疾病防治-特种经济动植物,2005,6：44
41孟小亮,陈昌福,吴志新,等.嗜水气单胞菌对盐酸多西环素的耐药性获得与 消失速率研究[J].长江大学学报,3009,6(1)：42-44
42魏树礼,张强.生物药剂学与药物动力学[M].北京：北京医科大学出版社,1997.208-217
43刘雅红,冯淇辉.兽药药物动力学研究新进展一兽医群体药物动力学[J].中国兽医学报,2000,20(5)：18-52
44 Sun Y, Peng Y, Aksornkoae N, Johnson J R,Boring J G, Scruggs D, Cooper R C, Laizure S C,Shukla A J. Controlled release of oxytetracycline in sheep. Journal of Controlled Release,2002,85(1):125-134
45夏文江,尼.吉尔德-汉森,波.尼尔森.土霉素的药物动力学研究[J].中国兽医科技,1984,3：19-24
46 Ei-Aty A M, Goudah A, Zhou H H. Pharmacokinetics of doxycycline after administration as a single intravenous bolus and intramuscular doses to non-lact-ating Egyptian goats.Pharmacol Res,2004,49:487-491
47 Ole-Mapenay I M,Mitema E S,Maitho T E. Aspects of the pharmacokinetics of Doxycycline given to healthy and pneumonic East African dwarf goats by intram-uscular injection. Veterinary Research Communications,1997,21(6):453-462
48杨海峰,覃少华,王加才,等.2种多西环素注射液在健康猪体内的药动学比较[J].畜牧与兽医学,2007,1.
49 Riond.J.L& Riviere, J.E.Pharmacokintics and metabolic inertness of doxycycline in young pigs. American Journal of Veterinary Research,1998,51:1271-1275
50 Uno K. Pharmacokinetic study of oxytetracycline in healthy and vibriosisinfected ayu (Plecoglossus altivelis) [J]. Aquaculture,1996,143:33-42.
51 Abedini S, Namdari R, Law FCP. Comparative pharmacokinetics and bioava-ilability of oxytetracycline in rainbow trout and Chinook salmon[J]. Aquaculture, 1998,162:23-32.
52 Croubels S. Liquid chromatographic separation of doxycycline and 4-epidoxycycl-ine in a tissue depletion study of doxycycline in turkeys. Journal of Chromatography B,1998,708:145-152
53 Yoshimura H,Osawa N,Rasa F S.Hermawati D,Werdiningsih S. Isriyanthi N M, Sugimori T. Food Addit. Animal Contain,1991,8:65
54 Wang W F, Lin H, Xue C H. Elimination of chloramphenicol, sulphamethoxazole and oxytetracycline in shrimp, Penaeus chinensis following medicated-feed treatm-ent. Environment International.2004,30:367-373
55李美同,郭文林,仲锋,等.土霉素在鳗鲡组织中残留的消除规律[J].水产学报,1997,21(1)：39-43
56徐维海,林黎明,朱校斌,等.四环素类抗菌药物在吉富罗非鱼体内的代谢动力学研究[J].水产科学,2004,23(3)：1-3
57杨先乐,湛嘉.氯霉素在罗非鱼体内的代谢和消除规律.水生生物学报,2005,29(3)：266-271.
58艾晓辉,刘长征,周运涛.不同水温和给药方式下磺胺甲嗯唑在草鱼体内的药动学研究[J].水生生物学报,2005,29(2)：210—214
59 Curtis L R, Kemp C J, Svec A V. Biliary excretion of [super(14)C] taurocholate by rainbow trout(Salmo gairdneri) is stimulated at warmer acclimation temperature [J]. Comp Blochem Physiol,1986.84(1):87—90.
60 Kleinow K M, Jarboe H H, Shoemaker K E. Comparative pharmacokinetics and bioavailability of oxolinic acid in channel catfish (lctalurus punctatus) and rainbow trout (Oncorhynchus myliss)[J]. Can J Fish Aquac Sci,1994,51:1205-1211.
61 Adel H. Karara, William L. Hayton. A pharmacokinetic analysis of the effect of temperature on the accumulation of di-2-ethylhexyl phthalate (DEHP) in sheeps head min now. Aquatic Toxicology,1989,15(1):27-36
62 R. Namdari, S. Abedini, F. C. P. Law.Tissue distribution and elimination of oxytetracycline in seawater chinook and coho salmon following medicated-feed treatment.Aquaculture,1996,144(1):27-38
63.刘永涛,艾晓辉,杨红.不同水温下氟甲砜霉素在斑点叉尾鲴体内的药代动力学研究[J].水生生物学报,2009,33(1)：1-6
64 Abd Ei-Aty A M, Goudah A, Zhou H H. Pharmacokinetics of doxycycline after administration as a single intravenous bolus and intramuscular doses to non-lactating Egyptian goats[J]. Pharmacol Res,2004,49:487-491.
65 Jha V K, Jayachandran C, Singh M K, Singh S D. Pharmacokinetic data on do-xycycline and its distribution in different biological fluids in female goats. Vete -rinary Research Commumications,1989,13:11-16
66朱模忠.兽药手册[M].北京：化学工业出版社,2002：70-73.
67周怀梧.药物吸收多峰现象的动力学研究[J].现代应用药学,1989,6(2)：37-40.
68肖亮,王婧,王承明,等.土霉素在草鱼体内的组织残留研究[J].湖北农业科学,2007,5：466-468.
69姜素椿,宋克(译).最新广谱喹诺酮类抗微生物药[M].北京：人民军医出版社,1991.