【作者】 谭超；

【导师】 孙志良；

【作者基本信息】 湖南农业大学 ， 基础兽医， 2007， 硕士

【摘要】 本研究建立了单诺沙星（Danofloxacin,DAN,）在鲫鱼（Crucian Carps,CarassiusAuratus）血浆和组织中反相高效液相色谱法检测方法,并对单诺沙星在鲫鱼体内的药物动力学与残留消除规律进行了研究。在水温21±2℃下,单剂量肌注(15mg·kg^-1)给药。取给药后不同时间的鲫鱼血浆和肌肉、肾脏、肝脏等组织,用乙腈沉淀组织中的蛋白质,正己烷和乙醚去脂。采用反相高效液相色谱法测定血浆和各组织中单诺沙星的质量浓度。用MCPKP软件处理血浆药物浓度与时间数据。结果表明:鲫鱼肌注给药的药时数据适合二室开放模型,主要药物动力学参数为:表观分布容积（V）为5.0990±0.0615mg·h^-1;分布相半衰期(T_1/2a)为0.5275±0.0081h;消除相半衰期(T_1/2β)为286.9439±18.5950h;周边室向中央室转运一级速率常数(K₂₁)为0.4184±0.0056h^-1;消除速度一级速度常数(K₁₀)为0.0076±0.0005h^-1;中央室向周边室转运一级速率常数(K₁₂)为0.8904±0.0154h^-1;药时曲线下面积（AUC）为387.7677±23.7793mg·L^-1·h^-1;总消除率（Cl）为0.0387±0.0025L·h^-1;单诺沙星在健康鲫鱼体内的主要药物动力学特征为:吸收快且完全,消除缓慢,作用时间长,血药浓度高,组织穿透力强。单诺沙星在肾脏、肝脏和肌肉组织中的代谢动力学特征不一。单剂量肌注后在肾脏的代谢动力学模式都为一级吸收二室开放模型,而肌肉和肝脏中的药代动力学模式都为一级吸收一室开放模型,在肌肉中的代谢动力学参数为:t_1/2Ka为0.8241±0.0021h;t_1/2Ke为15.2287±0.1858h;Cmax为2.6536±0.0063μg·ml^-1;Tmax为3.6659±0.0071h;在肝脏中的代谢动力学参数为:t_1/2Ka为2.9919±0.6623h;t_1/2Ke为4.3335±2.1599h;Cmax为14.3835±1.0043μg·ml^-1;Tmax为5.1652±0.0393h;在肾脏中的代谢动力学参数为:t_1/2Ka为0.4763±0.0004h,t_1/2β为20.3188+0.1173h;t_1/2Ka为1.8762±0.0129h;Cmax为13.8920±0.0509μg·ml^-1;Tmax为1.4488±0.0058h。单诺沙星在肾脏、肝脏和肌肉组织中的消除规律不一。3种组织的消除半衰期T_1/2肌肉为21.656h;T_1/2肝脏为19.250h;T_1/2肾脏为25.667h。肝脏消除最快,其次为肌肉,肾脏最慢;但肾脏一般不会食用,故建议肌肉作为单诺沙星在鲫鱼体内的残留靶组织。肌肉以100μg·kg^-1为最高残留限量,建议休药期不低于7d。采用改良寇氏法研究了单诺沙星对鲫鱼的急性毒性作用,结果表明:单诺沙星肌注给药对鲫鱼的半数致死量(LD₅₀)为125.89mg·kg^-1·bw^-1;半数致死量的标准误(SlogLD₅₀)为0.0231,LD₅₀95%可信限范围为:125.89±3.04mg·kg^-1·bw^-1,以上数据说明单诺沙星对鲫鱼毒性很低,在治疗范围内(5mg·kg^-1·bw^-1)是安全无毒的。更多还原

【Abstract】 The plasma pharmacokinetics and tissue residuesl of danofloxacin were investigated in Crucian Carps under experimental field at 21±2℃water temperature,after single intramuscular administration of the injection 15mg·kg^-1.The blood and tissues samples were collected at different time and danofloxacin concentrations were determined by using reversed-phase high performance liquid chromatography（RP-HPLC）.The tissues samples were collected,the protein was deposited by methyl cyanide from tissues.All of those dates were treated by MCPKP pharmacokinetic software.The results indicated that plasma concentration-time data of danofloxacin mesylate were fitted to a two-compartment open model,with absorption and elimination half-life(T_1/2Ka,T_1/2Ke)is 0.5275±0.0081h and 286.944±1.8595h.Area under the plasma druge concentration-time curve（AUC）was 387.7677±23.7793mg·L^-1-h^-1.Cl was 0.0387±0.0025L·h^-1.The main pharmacokinetic parameters were as follows:absorbed rapidly and completely,eliminated slowly,long effect time,high plasma concentration and strong penetrability of tissue.The tissue pharmacokinetics and residuesl of danofloxacin were investigated in Crucian Carps.The pharmacokinetic characteristics in muscle and Liver following muslar injection both described by one-compartment open model with one-compart-ment absorption.which is in Kidney can be described by a two-compar-ment open model with one-compart-ment absorption..The main pharmacokinetic paramerers of muslar injection in muscle as follows:t_1/2Kais 0.8241±0.0021h;t_1/2Keis 15.2287±0.1858h;Cmax is 2.6536±0.0063μg·ml^-1;Tmax is 3.6659±0.0071h;In Liver were shown below:t_1/2Kais 2.9919±0.6623h,t_1/2Keis 4.3335±2.1599h;Cmax is 14.3835±1.0043μg·ml^-1,Tmax is 5.1652±0.0393h;In Kidney the main pharmacokinetic paramerers as follows:t_1/2Kais 0.4763±0.0004h,Cmax is 13.8920±0.0509μg·ml^-1;Tmax is 1.4488±0.0058h。The elimination half-life are respectively:T_1/2肌肉21.656h;T_1/2肝脏19.250h;T_1/2肾脏25.667 h.The muscle was as main reservoirs of danofloxacin mesylate in Crucian Carps.It is proposed that withdrawal period should be not less that 7 day acconding to the mamimum residues limit（MRL）of 100μg·kg^-1in muscle.In order to direct using danafloxacin-being used specially for animals in aquaciculture and ensure the security ofish and fish products,the means of improved Karber was used to determine the toxicity of danafloxacin to crucian.The hardness and content of dissolved ooxygen in waiter were measured to insure the accuracy of the result.更多还原