【作者】 郭海燕；

【导师】 张其中；

【作者基本信息】 西南大学 ， 水生生物学， 2007， 硕士

【摘要】 本文主要研究不同水温条件、不同给药途径、不同剂量情况下诺氟沙星在鲫鱼和草鱼中的药动学、残留和生物利用度情况，其血清、肌肉、肝脏和肾脏中的药物用反相高效液相色谱法（Re-HPCL）测定。实验结果如下：在（25.4±0.3）℃水温条件下，以10mg/kg剂量单次给鲫鱼肌肉注射诺氟沙星后，血药浓度在第一个采样点2min时即达到最大值（6.6708±0.9242）μg/ml，随后浓度逐渐下降，其血药浓度-时间数据用一级吸收二室模型描述较为合适，分布半衰期t_1/2α和消除半衰期分别t_1/2β为（0.4231±0.0880）h和（9.1613±3.6362）h。在（26±1）℃水温条件下，以10mg/kg剂量单次给草鱼幼鱼口灌诺氟沙星后，其血药浓度-时间数据用一级吸收二室模型描述较为合适，吸收半衰期t_1/2Ka、分布半衰期t_1/2α和消除半衰期t_1/2β分别为：（0.1468±0.0046）h、（0.5224±0.0812）h和（82.8811±0.7391）h。在（25.0±0.4）℃水温条件下，以10mg/kg剂量单次给草鱼成鱼静脉注射诺氟沙星后，其血药浓度-时间数据用三室开放模型描述较为合适，深室分布半衰期t_1/2pi、浅室分布半衰期t_1/2α和消除半衰期t_1/2β分别为：（0.0252±0.0150）h、（0.7716±0.3687）h和（151.42±21.093）h。在（25.0±0.4）℃水温条件下，以10mg/kg剂量单次给草鱼成鱼口灌诺氟沙星后，其血药浓度-时间数据用一级吸收二室开放模型描述较为合适，吸收半衰期t_1/2Kα分布半衰期t_1/2α和消除半衰期t_1/2β分别为：（0.1157±0.0279）h、（1.1299±0.3276）h和（175.21±43.166）h。在（25.0±0.4）℃水温条件下，以10mg/kg剂量单次给草鱼成鱼混饲口灌诺氟沙星后，其血药浓度-时间数据用一级吸收二室开放模型较为合适，吸收半衰期t_1/2Kα、分布半衰期t_1/2α和消除半衰期t_1/2β分别为：（0.1949±0.0798）h、（0.8836±0.1476）h和（66.428±7.1048）h。药物静脉注射实际上在注射结束的同时，血药浓度已达到高峰，其生物利用度可以认为是100％，因此以静脉注射为对照，草鱼成鱼口灌给药的生物利用度为50.75％，混饲口灌给药的生物利用度为33.74％。多剂量连续5d混饲给药后，鲫鱼停药后第8d肌肉、血清和肝脏中未检测到药物，此时肾脏中药物浓度已降到（0.0463±0.0134）μg/g，低于0.05μg/g；草鱼肌肉中停药后第12d未检测到药物，此时血清、肝脏和肾脏中的药物浓度分别降为（0.0287±0.0015）μg/ml、（0.0181±0.0042）μg/g和（0.0369±0.0037）μg/g，均低于0.05μg/ml或μg/g。综上所述，根据给药方式的不同，对诺氟沙星的吸收从快到慢依次为：静脉注射、肌肉注射、口灌、混饲口灌，由于静脉注射和肌肉注射时水产动物对诺氟沙星的吸收十分迅速，在体内分布广泛而且组织浓度较高，并且消除比较缓慢，所以当鱼病严重或者希望较快地发挥药效时，可以选择这两种给药方式进行治疗。水产养殖实践中最常用的口灌给药和混饲给药，具有口服吸收快，分布广泛，在体内滞留的时间比较长，且有效药物浓度能达到一般细菌的最小抑菌浓度至少是24小时以上。为了充分保障消费者的安全，选择肌肉中未检测出药物且其他组织内药物浓度均低于0.05μg/ml或μg/g的时间为可以起捕食用的时间。初步建议在（23±1）℃水温条件下，以10mg/kg连续5d混饲给鲫鱼诺氟沙星，休药期至少为最后一次给药后的8d；在（19±1）℃水温条件下，以10mg/kg连续5d混饲给草鱼诺氟沙星，休药期至少为最后一次给药后的12d。更多还原

【Abstract】 The present study investigated the pharmacokinetics, residues and bioavailabilities of norfloxacin （NFX） in Carassius auratus and Ctenopharyngodon idellus L. at different water temperature, administration routes and doses. The drug concentrations in serum, muscle, liver and kidney were determined by Re-high performance liquid chromatography （Re-HPLC）. The research is the first one that ever has been done in China.Following a single-dosing intramuscular injection of 10 mg NFX/kg body weight in C. auratus at the water temperature （25.4±0.3）℃, the drug concentration in the serum amounted to the largest （6.6708±0.9242）μg/ml immediately at the first sampling point in 2 min, then declined. The results show that the serum concentration-time data were best described as a two-compartment open model with first order absorption, the half-life of distribution t_1/2α was （0.4231±0.0880）h, the half-life of elimination t_1/2β was （9.1613±3.6362）h.Following a single-dosing oral administration of 10 mg NFX/kg body weight in C. idellus at the water temperature （26±1）℃, the serum concentration-time data were best described as a two-compartment open model with first order absorption, the half-life of absorption t_1/2Ka was （0.1468±0.0046）h, the half-life of distribution t_1/2α was （0.5224±0.0812）h, the half-life of elimination t_1/2β was （82.8811±0.7391）h.Following a single-dosing intravenous injection of 10 mg NFX/kg weight in C. idellus at the water temperature （25.0±0.4）℃, the serum concentration-time data were best described as a three-compartment open model, the half-life of distribution in deep compartment t_1/2pi was （0.0252±0.0150）h, the half-life of distribution in shallow compartment t_1/2α was （0.7716±0.3687）h, the half-life of elimination t_1/2β was （151.42±21.093）h.Following a single-dosing oral administration of 10 mg NFX/kg weight in C. idellus at the water temperature （25.0±0.4）℃, the serum concentration-time data were best described as a two-compartment open model with first order absorption, the half-life of absorption t_1/2α Was （0.1157±0.0279）h, the half-life of distribution t_1/2α was （1.1299±0.3276）h, the half-life of elimination t_1/2β was （175.21±43.166）h.Following a single-dosing oral administration of 10 mg NFX/kg weight mixed feed in C. idellus at the water temperature （25.0±0.4）℃, the serum concentration-time data were best described as a two-compartment open model with first order absorption, the half-life of absorption t_1/2ka was （0.1949±0.0798）h, the half-life of distribution t_1/2α was （0.8836±0.1476）h, the half-life of elimination t_1/2β was （66.428±7.1048）h.In fact the drug concentration reached the peak concentration at the end of intravenous injection, the drug bioavailability could be considered as 100％. So the bioavailability of p.o. was 50.75％and the bioavailability of p.o. with feed was 33.74％by the contrast of i.v. in C. idellus.Two kinds of fish were treated with feed at the dosage of 10 mg/kg NFX per day for 5 days. No drugs were detected in muscle, serum and liver in C. auratus, the concentration in kidney is （0.0463±0.0134）μg/g and lower than 0.05μg/g on Day 8. As for C. idellus, no drugs were detected in muscle and the drug concentrations declined to （0.0287±0.0015）μg/ml, （0.0181±0.0042）μg/g and （0.0369±0.0037）μg/g in the serum, liver and kidney on Day 12 respectively, all below 0.05μg/ml orμg/g.Taking together, the following routes of administration could be sequenced in descending order according to their NFX absorption speeds: intravenous injection, intramuscular injection, oral administration, oral administration with feed. Following intravenous and intramuscular injection, the absorption of norfloxacin in aquatic animals was very rapid, and absorbed NFX was widely distributed with a rather high concentration in the tissues, and the elimination took time. So in cases of serious diseases in which fast pharmaceutical effect was required, the two routes would be preferred. In aquaculture practices, the most common routes are oral and oral administration with feed which boasted of fast absorption, wide distribution, long-time stay in the body and a concentration equal to the minimal inhibitory concentration for common bacteria.For the sake of consumers’ wellbeing, we recommend the fish can be consumed only when no drug is detected in muscle and the drug concentrations are lower than 0.05μg/ml orμg/g in other tissues, the day we define as a withdrawal period. Therefore, we suggest a withdrawal period should last at least for 8 days in C. auratus at the water temperature （23±1）℃and 12 days in C. idellus at the water temperature （19±1）℃after they have been administered with feed at a dosage of 10mg/kg.更多还原