【作者】 丁俊仁；

【导师】 汪开毓； 艾晓辉；

【作者基本信息】 四川农业大学 ， 基础兽医学， 2010， 硕士

【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。更多还原

【Abstract】 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.更多还原