不同温度下麻保沙星在鲫体内的药物动力学及残留研究
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摘要
本课题研究了在15℃和25℃两种水温条件下,麻保沙星在鲫体内的药物动力学特征和残留消除规律。样品用内标法定量,通过液-液萃取、氮气吹干、浓缩等步骤进行前处理,麻保沙星含量用反相高效液相色谱法(RP-HPLC)测定。本研究建立的标准曲线相关性好,相关系数(r)均在0.9990以上。平均萃取回收率:血浆中在90%以上;肌肉、肝胰脏和肾脏中均超过80%;皮肤中在73%以上。各组织中相对回收率的值在85%-115%之间,准确度高。日内变异系数均小于10%,日间变异系数均小于15%,方法具有较好的精密度。麻保沙星在鲫血浆、肌肉、皮肤、肝胰脏和肾脏中的检测限分别为0.02μg/mL、0.02μg/g、0.025μg/g、0.02μg/g、0.025μg/g;定量限分别为0.05μg/mL、0.05μg/g、0.0625μg/g、0.05μg/g、0.0625μg/g。
对鲫以10mg/kg·bw的剂量单次口灌麻保沙星进行药动学研究,结果显示,麻保沙星在鲫体内吸收迅速,分布广泛,消除半衰期长,水温对药物在鲫体内的药动学过程影响显著。房室模型分析表明,在两个水温条件下的药时数据均符合有吸收二室开放模型,15℃条件下的主要药物动力学参数为:吸收半衰期(t_(1/2ka))0.36h;分布半衰期(t_(1/2α))4.48h;达峰时间(T_(max))1.74h;峰浓度(C_(max))6.43μg/mL;消除半衰期(t_(1/2β))50.75h;表观分布容积(V_d/F)1.36L/kg;清除率(CL_b)0.03 L/(h·kg);药时曲线下面积(AUC)301.80μg·h/mL。25℃条件下的主要药物动力学参数为:吸收半衰期(t_(1/2ka))0.23h;分布半衰期(t_(1/2α))0.87h;达峰时间(T_(max))0.78h;峰浓度(C_(max))8.36μg/mL;消除半衰期(t_(1/2β))25.05h;表观分布容积(V_d/F)0.87L/kg;清除率(CL_b)0.05 L/(h·kg);药时曲线下面积(AUC)182.80μg·h/mL。
在药物残留研究中,以10mg/kg·bw·d的剂量连续3d口灌给药后,于最后一次给药后的3、10、24、48、72、96、144、192、240、312h采集肌肉、皮肤、肝胰脏和肾脏样品进行分析测定。结果显示,在低温条件下麻保沙星的消除较高温条件慢,在最后一次给药后的13d仍能在各组织中检测到药物,皮肤中的药物浓度最高。与其他三种组织相比,皮肤中药物消除最慢,建议将其作为麻保沙星在鲫体内的残留靶组织。
药动学试验结果表明,在15℃以5.46mg/kg·bw的剂量每2d经口给药一次、25℃以4.41mg/kg·bw的剂量1d经口给药一次可达到理想的抑菌和杀菌效果;残留试验结果表明,为确保食品安全,建议休药期在15℃不低于68d,在25℃不低于30d。
Pharmacokinetics and residue elimination of marbofloxacin(MBF) were studied in crucian carp(Carassius auratus) kept at two water temperatures of 15 and 25℃.MBF concentrations in plasma and tissues were analyzed by means of reversed-phase high-performance liquid chromatography(RP-HPLC) after liquid-liquid extraction.The correlation of calibration curves were all good,which correlation coeffcients(r) were more than 0.9990.The average extraction recoveries were more than 90%from plasma, more than 80%from muscle,liver and kidney,and more than 73%from skin.The method was accurate and the relative recoveries were in the range of 85%-115%in all tissues.The intra-day and inter-day coefficients of variation were less than 10%and 15%, respectively.This indicated that the method had a good precision.The limits of detection (LOD) were 0.02μg/mL,0.02μg/g,0.025μg/g,0.02μg/g and 0.025μg/g in plasma,muscle, skin,liver and kidney,respectively.The limits of quantitation(LOQ) were 0.05μg/mL, 0.05μg/g,0.0625μg/g,0.05μg/g and 0.0625μg/g in the corresponding tissues, respectively.
Fish were administered orally with a single dosage of 10mg/kg body weight in the pharmacokinetics group.The results revealed that the pharmacokinetic characteristics of MBF in crucian carp manifested rapid absorption,wide distribution and slow elimination. Water temperature played an important role in the kinesics process.The plasma concentration-time data conformed to two-compartment open models at both temperatures.The absorption half-lives(t_(1/2ka)) of MBF were found to be 0.36 and 0.23h at 15 and 25℃,respectively,and the distribution half-lives(t_(1/2α)) were 4.48h at 15℃and 0.87h at 25℃.The maximum plasma concentration(C_(max)) and the time-point of maximum plasma concentration(T_(max)) were calculated as 6.43μg/mL and 1.74h at 15℃and 8.36μg/mL and 0.78h at 25℃.The elimination half-lives(t_(1/2β)) were 50.75 and 25.05h at 15 and 25℃,respectively.The distribution volumes(V_d/F) of MBF were estimated to be 1.36L/kg at 15℃and 0.87L/kg at 25℃.The total clearances of MBF (CL_b) were computed as 0.03 and 0.05L/(h·kg) at 15 and 25℃,respectively.The areas under the concentration-time curve(AUC) were 301.80μg·h/mL at 15℃and 182.80μg·h/mL at 25℃.
After repeated oral administration with a dosage of 10mg/kg body weight per day for 3 days,fish were sacrificed at 3,10,24,48,72,96,144,192,240 and 312h after the last administration and samples of muscle,skin,liver and kidney were collected to determine MBF concentrations.The results showed that the elimination half-lives(t_(1/2ke)) of MBF from all tissues at 15℃were longer than those at 25℃.The drug could still be detected at 13d time-point after the last administration at both temperatures,and the concentrations of MBF were highest in skin at this time-point.Comparing with the other tissues,the elimination of MBF in skin was slowest,which behaved as a reservoir in crucian carp.
The pharmacokinetics study revealed that a repeated oral dosage of 5.46mg/kg body weight every two days at 15℃and a repeated oral dosage of 4.41mg/kg body weight every day at 25℃might be efficacious against bacteria in crucian carp.Based on the results of the residue study,the withdrawal periods should not be less than 68d at 15℃and 30d at 25℃in order to make the tissues safe for consumption.
对鲫以10mg/kg·bw的剂量单次口灌麻保沙星进行药动学研究,结果显示,麻保沙星在鲫体内吸收迅速,分布广泛,消除半衰期长,水温对药物在鲫体内的药动学过程影响显著。房室模型分析表明,在两个水温条件下的药时数据均符合有吸收二室开放模型,15℃条件下的主要药物动力学参数为:吸收半衰期(t_(1/2ka))0.36h;分布半衰期(t_(1/2α))4.48h;达峰时间(T_(max))1.74h;峰浓度(C_(max))6.43μg/mL;消除半衰期(t_(1/2β))50.75h;表观分布容积(V_d/F)1.36L/kg;清除率(CL_b)0.03 L/(h·kg);药时曲线下面积(AUC)301.80μg·h/mL。25℃条件下的主要药物动力学参数为:吸收半衰期(t_(1/2ka))0.23h;分布半衰期(t_(1/2α))0.87h;达峰时间(T_(max))0.78h;峰浓度(C_(max))8.36μg/mL;消除半衰期(t_(1/2β))25.05h;表观分布容积(V_d/F)0.87L/kg;清除率(CL_b)0.05 L/(h·kg);药时曲线下面积(AUC)182.80μg·h/mL。
在药物残留研究中,以10mg/kg·bw·d的剂量连续3d口灌给药后,于最后一次给药后的3、10、24、48、72、96、144、192、240、312h采集肌肉、皮肤、肝胰脏和肾脏样品进行分析测定。结果显示,在低温条件下麻保沙星的消除较高温条件慢,在最后一次给药后的13d仍能在各组织中检测到药物,皮肤中的药物浓度最高。与其他三种组织相比,皮肤中药物消除最慢,建议将其作为麻保沙星在鲫体内的残留靶组织。
药动学试验结果表明,在15℃以5.46mg/kg·bw的剂量每2d经口给药一次、25℃以4.41mg/kg·bw的剂量1d经口给药一次可达到理想的抑菌和杀菌效果;残留试验结果表明,为确保食品安全,建议休药期在15℃不低于68d,在25℃不低于30d。
Pharmacokinetics and residue elimination of marbofloxacin(MBF) were studied in crucian carp(Carassius auratus) kept at two water temperatures of 15 and 25℃.MBF concentrations in plasma and tissues were analyzed by means of reversed-phase high-performance liquid chromatography(RP-HPLC) after liquid-liquid extraction.The correlation of calibration curves were all good,which correlation coeffcients(r) were more than 0.9990.The average extraction recoveries were more than 90%from plasma, more than 80%from muscle,liver and kidney,and more than 73%from skin.The method was accurate and the relative recoveries were in the range of 85%-115%in all tissues.The intra-day and inter-day coefficients of variation were less than 10%and 15%, respectively.This indicated that the method had a good precision.The limits of detection (LOD) were 0.02μg/mL,0.02μg/g,0.025μg/g,0.02μg/g and 0.025μg/g in plasma,muscle, skin,liver and kidney,respectively.The limits of quantitation(LOQ) were 0.05μg/mL, 0.05μg/g,0.0625μg/g,0.05μg/g and 0.0625μg/g in the corresponding tissues, respectively.
Fish were administered orally with a single dosage of 10mg/kg body weight in the pharmacokinetics group.The results revealed that the pharmacokinetic characteristics of MBF in crucian carp manifested rapid absorption,wide distribution and slow elimination. Water temperature played an important role in the kinesics process.The plasma concentration-time data conformed to two-compartment open models at both temperatures.The absorption half-lives(t_(1/2ka)) of MBF were found to be 0.36 and 0.23h at 15 and 25℃,respectively,and the distribution half-lives(t_(1/2α)) were 4.48h at 15℃and 0.87h at 25℃.The maximum plasma concentration(C_(max)) and the time-point of maximum plasma concentration(T_(max)) were calculated as 6.43μg/mL and 1.74h at 15℃and 8.36μg/mL and 0.78h at 25℃.The elimination half-lives(t_(1/2β)) were 50.75 and 25.05h at 15 and 25℃,respectively.The distribution volumes(V_d/F) of MBF were estimated to be 1.36L/kg at 15℃and 0.87L/kg at 25℃.The total clearances of MBF (CL_b) were computed as 0.03 and 0.05L/(h·kg) at 15 and 25℃,respectively.The areas under the concentration-time curve(AUC) were 301.80μg·h/mL at 15℃and 182.80μg·h/mL at 25℃.
After repeated oral administration with a dosage of 10mg/kg body weight per day for 3 days,fish were sacrificed at 3,10,24,48,72,96,144,192,240 and 312h after the last administration and samples of muscle,skin,liver and kidney were collected to determine MBF concentrations.The results showed that the elimination half-lives(t_(1/2ke)) of MBF from all tissues at 15℃were longer than those at 25℃.The drug could still be detected at 13d time-point after the last administration at both temperatures,and the concentrations of MBF were highest in skin at this time-point.Comparing with the other tissues,the elimination of MBF in skin was slowest,which behaved as a reservoir in crucian carp.
The pharmacokinetics study revealed that a repeated oral dosage of 5.46mg/kg body weight every two days at 15℃and a repeated oral dosage of 4.41mg/kg body weight every day at 25℃might be efficacious against bacteria in crucian carp.Based on the results of the residue study,the withdrawal periods should not be less than 68d at 15℃and 30d at 25℃in order to make the tissues safe for consumption.
引文
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