乳酸恩诺沙星可溶性粉在鸡的药动学及不同恩诺沙星盐制剂在鸡的残留消除规律研究
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摘要
恩诺沙星(enrofloxacin)为动物专用的第三代氟喹诺酮类抗菌药。具有抗菌谱广,杀菌活性强,且与其他抗菌药物无交叉耐药性以及生物利用度高,体内分布广泛等良好的药动学特征,已广泛用于国内外兽医临床。由于恩诺沙星在水中极微溶解,因此人们试图将恩诺沙星制成各种盐以改变其溶解性能,进而制成可溶性粉剂以方便临床用药。乳酸恩诺沙星、恩诺沙星钠和盐酸恩诺沙星正是这一努力的结果。本研究通过对乳酸恩诺沙星可溶性粉药动学的研究,了解乳酸恩诺沙星在鸡体内的过程和生物利用度,为制定临床合理给药方案提供依据；通过对恩诺沙星的不同盐制剂在鸡体内的残留消除规律研究,为制定其休药期提供依据,这对确保动物性食品安全和消费者的健康具有重要意义。
1乳酸恩诺沙星可溶性粉在鸡体内的药动学研究
对24只苏禽黄羽肉鸡分别静注和内服乳酸恩诺沙星10mg/1kgb.w.后进行药动学和生物利用度研究。血浆药物浓度采用高效液相色谱法测定(HPLC),所得恩诺沙星血药浓度数据用3p87计算机软件处理。静注乳酸恩诺沙星后的血药浓度-时间数据符合二室开放模型,主要动力学参数：t1/2α(0.45±0.16)h,t1/2β(7.02±1.42)h,CL(s)(0.38±0.10)L/kg/h,AUC(23.69±5.56)(mg/L)×h。内服乳酸恩诺沙星的血药浓度时间数据,符合有吸收因素二室模型,主要动力学参数：t1/2ka(0.60±0.01)h,tl/2ke(8.25±1.73)h,tpeak(2.44±0.17)h,Cmax(1.44±0.30)mg/L,AUC(20.74±3.80)(mg/L)×h,F87.54%。结果表明,乳酸恩诺沙星可溶性粉在鸡体内具有吸收快、分布广、消除较慢以及内服生物利用度高的药动学特征。
2鸡组织中恩诺沙星残留的HPLC检测方法的建立
取肌肉、肝脏和肾脏等样品绞碎后加入适量磷酸盐缓冲液匀浆,加入定量的标准工作液,混匀,离心,取上清液,C18固相萃取柱净化。收集的洗脱液经滤膜过滤后供高效液相色谱分析。色谱条件：色谱柱为Thermo ODS-2HYPERSIL C18(5.0μm,250×4.6mm),流动相为0.05mol/L磷酸溶液／三乙胺和乙腈,流速：1mL/min。高效液相色谱荧光检测器检测,发射波长和激发波长分别为450nm和280nm。结果显示,在本实验室条件下,恩诺沙星和环丙沙星在0.01～1.0μ g/mL,呈线性相关,相关系数大于0.999。检测限为0.01mg/kg。对空白试样进行3个水平(0.05、0.1、1mg/kg)加标回收率测定,回收率为74.1%-86.8%,批内和批间变异系数分别小于10%和7.5%。上述方法符合中华人民共和国农业部公布的《动物性食品中氟喹诺酮类药物残留检测——高效液相色谱法》国家标准,获得的技术参数能满足本次鸡组织中恩诺沙星残留试验的检测要求。
3三种恩诺沙星可溶性粉在鸡的残留消除规律研究
将乳酸恩诺沙星、恩诺沙星钠和盐酸恩诺沙星三种可溶性粉剂分别以临床推荐剂量,即100mg/L(以恩诺沙星计)给35只40日龄健康苏禽黄羽肉鸡混饮,连续给药7d。然后分别于停药后4h(即0休药期)、1d、3d、5d、7d、9d、11d共7个时间点进行采样,每个时间点宰杀5只鸡,及时取肌肉、肝脏和肾脏等组织样品。样品经绞碎后加入适量磷酸盐缓冲液匀浆,离心,取上清液,C18固相萃取柱净化。收集的洗脱液经滤膜过滤后供高效液相色谱分析。结果如下：
3.1乳酸恩诺沙星可溶性粉在鸡的残留消除规律：在0休药期时,测得的肌肉、肝脏和肾脏中的恩诺沙星标志残留物的残留量分别为(1.899±0.922)mg/kg、(2.574±1.171)mg/kg和(0.967±0.624)mg/kg；肌肉、肝脏、肾脏组织中的恩诺沙星标志残留物的残留量分别在停药5d、7d和3d时降至相应的最高残留限量(MRL)以下。恩诺沙星标志残留物平均残留量以实测数据用WT1.4计算软件拟合,肌肉、肝脏和肾脏的休药期结果分别为7.689d、7.339d和4.529d。鸡按推荐剂量饮水给药,建议休药期至少为8d。
3.2恩诺沙星钠可溶性粉在鸡的残留消除规律：在0休药期时,测得的肌肉、肝脏和肾脏中的恩诺沙星标志残留物的残留量分别为(1.253±0.319)mg/kg、(2.024±0.902)mg/kg和(0.576±0.099)mg/kg；肌肉、肝脏、肾脏组织中的恩诺沙星标志残留物的残留量分别在停药3d、5d和1d时降至相应的MRL以下。实测数据用WT1.4计算软件拟合,肌肉、肝脏和肾脏的休药期结果分别为4.919d、4.759d和3.369d。鸡按推荐剂量饮水给药,建议恩诺沙星钠可溶性粉的休药期至少为5d。
3.3盐酸恩诺沙星可溶性粉在鸡的残留消除规律：在0休药期时,测得的肌肉、肝脏和肾脏中的恩诺沙星标志残留物的残留量分别为(8.038±2.074)mg/kg、(12.678±3.667)mg/kg和(3.273±0.879)mg/kg；肌肉、肝脏、肾脏组织中的恩诺沙星标志残留物的残留量在停药第9d时降均至相应的MRL以下。实测数据用WT1.4计算软件拟合,肌肉、肝脏和肾脏的休药期结果分别为9.739d、9.549d和7.119d。鸡按推荐剂量饮水给药,建议盐酸恩诺沙星可溶性粉的休药期至少为10d。
结果表明,三种恩诺沙星可溶性粉剂按推荐剂量饮水给药,在0休药期时,均显示残留量肝脏最高,肌肉其次,肾脏最低,肝脏消除亦最慢。三种药物残留消除存在差异,乳酸恩诺沙星可溶性粉休药期至少为8d；恩诺沙星钠可溶性粉休药期至少为5d；盐酸恩诺沙星可溶性粉休药期至少为10d。乳酸恩诺沙星可溶性粉和恩诺沙星钠可溶性粉的休药期符合农业部第278号公告的在肉鸡饲养中使用恩诺沙星及可溶性粉的休药期为8d的规定,而盐酸恩诺沙星可溶性粉休药期则长于此规定。由此可见,恩诺沙星原制剂与恩诺沙星可溶性粉剂在鸡体内消除过程有一定差异,甚至不同的恩诺沙星可溶性粉制剂休药期也不同。
Enrofloxacin is the third generation fluoroquinolone with broad antimicrobial spectrum and high bactericidal activity which was developed exclusively for veterinary use.And it has no cross-resistance with other antimicrobial agents.Enrofloxacin showed favourable pharmacokinetic properties such as excellent bioavailability, large volume of distribution. However, enrofloxacin slightly soluble in water. Enrofloxacin lactate, enrofloxacin sodium and enrofloxacin hydrochloride as water-soluble powders provides a great convenience for clinical medication. The tests on the residues depletion of three kinds of enrofloxacin soluble powders in broiler tissues provided the theory basis for the withdrawal time to ensure the safety and security of human health and animal products in the international market competition.
1. Pharmacokinetic study of enrofloxacin lactate soluble powder in broilers
The pharmacokinetics and bioavailability of enrofloxacin lactate were investigated in24healthy Shuqinhuang Chicken. Enrofloxacin lactate was administered intravenously (i.v.) and orally (p.o.) at a dose10mg/kg body weight(clinically recommend dose). The concentrations of enrofloxacin lactate in plasma were determined by high-performance liquid chromatography (HPLC).Pharmacokinetic analysis of plasma concentration-time data after single i.v. and p.o. administration were performed with the pharmacokinetic computer program3p87. Following intravenous administration, the drug concentration-time graph was characteristic of a two-compartment open model, The main pharmacokinetic parameters of enrofloxacin lactate:t1/2a (0.45±0.16) h, t1/2β (7.02±1.42) h, CL(s)(0.38±0.10) mg/kg/h, AUC (23.69±5.56)(mg/L)×h.The results showed that the concentration-time data of enrofloxacin in plasma after oral administration are fitted to a two-compartment open model. The main pharmacokinetic parameters:t1/2ka (0.60±0.01)h, t1/2kc (8.25±1.73)h, tpeak (2.44±0.17) h, Cmax (1.44±0.30) mg/L, AUC (20.74±3.80)(mg/L)×h, F87.54%. Enrofloxacin concentrations in plasma after the drug administration showed that a rapid distribution phase was followed by the slower elimination phase in broilers. The bioavailability was high by the oral routes.
2. Determination of enrofloxacin residues in broiler tissues by high performance liquid chromatography
Samples of muscle, liver and kidney were thawed and homogenated.The phosphate-buffered saline were added to the samples and vortexed and centrifuged. The supernatant was concentrated and purificated by C18column solid phase extraction. The liquid was filtered through0.45μm disposable syringe filters prior to analysis by HPLC system. Chromatographic analyses were carried out on a reversed-phase liquid chromatography systerm with fluorescence detector with excitation wave length of280nm and emission wave length of450nm.The straight line established by standard addition was used as the quantitative standard curve for determination of enrofloxacin and ciprofloxacin by HPLC. The results showed that the linear range was0.01-1.0μg/mL and correlation coefficients were more than0.999. The detection limit for broilers tissues was0.01mg/kg. The enrofloxacin and ciprofloxacin were analyzed in spiked samples of three kinds of chicken tissues with mean recoveries in the range of74-1%-86-8%at spiked levels of0.05、0.1、1mg/kg. The relative standard deviations of CV of within group, the CV between groups were no more than10%and7%,respectively. The method is sufficient for routine residue analysis.
3. Comparison of residues depletion of different enrofloxacin salt preparation in broiler tissues
The study was performed in35,40-day-old, healthy Shuqinhuang Chicken, weighing1.5±0.2kg body weight. They were administered three kinds of enrofloxacin soluble powders p.o. once per day at a dose of100mg/L for seven successive days,respectively. Five broilers per day were slaughtered at0,1,3,5,7,9,11days after the last administration. The residues of enrofloxacin and its active metabolite ciprofloxacin were extracted from the homogenized tissue with phosphate-buffered saline and they were determined by high performance liquid chromatography.
3.1The residue elimination of enrofloxacin lactate soluble powder:
Enrofloxacin concentrations in muscle,liver and kidney were(1.899±0.922) mg/kg,(2.574±1.171) mg/kg and (0.967±0.624) mg/kg respectively at zero withdrawal time. The muscle, liver and kidney tissue residues of enrofloxacin decreased to less than MRL after5d,7d and3d of withdrawal time, respectively.The raw data were analysed with WT1.4program. Results showed that the withdrawal time of enrofloxacin lactate in broilers was at least8d.
3.2The residue elimination of enrofloxacin sodium soluble powder:
Enrofloxacin concentrations in muscle,liver and kidney were (1.253±0.319) mg/kg,(2.024±0.902) mg/kg and (0.576±0.099) mg/kg respectively at zero withdrawal time. The muscle, liver and kidney tissue residues of enrofloxacin decreased to less than MRL after3d,5d and Id of withdrawal time,respectively.The raw data were analysed with WT1.4program. Results showed that the withdrawal time of enrofloxacin sodium in broilers was at least5d.
3.3The residue elimination of enrofloxacin hydrochloride soluble powder:
Enrofloxacin concentrations in muscle, liver and kidney were (8.038±2.074) mg/kg,(12.678±3.667)mg/kg and (3.273±0.879)mg/kg respectively at zero withdrawal time. The residues of enrofloxacin have not been detected in the tissues of broiler after9d of withdrawal time.The raw data were analysed with WT1.4program. Results showed that the withdrawal time of enrofloxacin hydrochloride in broilers was at least10d.
The results showed that residue concentrations in the tissues found in all examined tissues were liver> muscle> kidney for kidney at zero withdrawal time. The liver had the slowest elimination. The withdrawal time of enrofloxacin lactate,enrofloxacin sodium and enrofloxacin hydrochloride in broilers was8d,5d and10d respectively.The withdrawal time of enrofloxacin in broilers was8d in the bulletin NO.278issued by the Ministry of Agriculture.Thus, different enrofloxacin soluble powder and enrofloxacin in broilers have some differences in the process of elimination and the withdrawal time is also slightly different.
1乳酸恩诺沙星可溶性粉在鸡体内的药动学研究
对24只苏禽黄羽肉鸡分别静注和内服乳酸恩诺沙星10mg/1kgb.w.后进行药动学和生物利用度研究。血浆药物浓度采用高效液相色谱法测定(HPLC),所得恩诺沙星血药浓度数据用3p87计算机软件处理。静注乳酸恩诺沙星后的血药浓度-时间数据符合二室开放模型,主要动力学参数：t1/2α(0.45±0.16)h,t1/2β(7.02±1.42)h,CL(s)(0.38±0.10)L/kg/h,AUC(23.69±5.56)(mg/L)×h。内服乳酸恩诺沙星的血药浓度时间数据,符合有吸收因素二室模型,主要动力学参数：t1/2ka(0.60±0.01)h,tl/2ke(8.25±1.73)h,tpeak(2.44±0.17)h,Cmax(1.44±0.30)mg/L,AUC(20.74±3.80)(mg/L)×h,F87.54%。结果表明,乳酸恩诺沙星可溶性粉在鸡体内具有吸收快、分布广、消除较慢以及内服生物利用度高的药动学特征。
2鸡组织中恩诺沙星残留的HPLC检测方法的建立
取肌肉、肝脏和肾脏等样品绞碎后加入适量磷酸盐缓冲液匀浆,加入定量的标准工作液,混匀,离心,取上清液,C18固相萃取柱净化。收集的洗脱液经滤膜过滤后供高效液相色谱分析。色谱条件：色谱柱为Thermo ODS-2HYPERSIL C18(5.0μm,250×4.6mm),流动相为0.05mol/L磷酸溶液／三乙胺和乙腈,流速：1mL/min。高效液相色谱荧光检测器检测,发射波长和激发波长分别为450nm和280nm。结果显示,在本实验室条件下,恩诺沙星和环丙沙星在0.01～1.0μ g/mL,呈线性相关,相关系数大于0.999。检测限为0.01mg/kg。对空白试样进行3个水平(0.05、0.1、1mg/kg)加标回收率测定,回收率为74.1%-86.8%,批内和批间变异系数分别小于10%和7.5%。上述方法符合中华人民共和国农业部公布的《动物性食品中氟喹诺酮类药物残留检测——高效液相色谱法》国家标准,获得的技术参数能满足本次鸡组织中恩诺沙星残留试验的检测要求。
3三种恩诺沙星可溶性粉在鸡的残留消除规律研究
将乳酸恩诺沙星、恩诺沙星钠和盐酸恩诺沙星三种可溶性粉剂分别以临床推荐剂量,即100mg/L(以恩诺沙星计)给35只40日龄健康苏禽黄羽肉鸡混饮,连续给药7d。然后分别于停药后4h(即0休药期)、1d、3d、5d、7d、9d、11d共7个时间点进行采样,每个时间点宰杀5只鸡,及时取肌肉、肝脏和肾脏等组织样品。样品经绞碎后加入适量磷酸盐缓冲液匀浆,离心,取上清液,C18固相萃取柱净化。收集的洗脱液经滤膜过滤后供高效液相色谱分析。结果如下：
3.1乳酸恩诺沙星可溶性粉在鸡的残留消除规律：在0休药期时,测得的肌肉、肝脏和肾脏中的恩诺沙星标志残留物的残留量分别为(1.899±0.922)mg/kg、(2.574±1.171)mg/kg和(0.967±0.624)mg/kg；肌肉、肝脏、肾脏组织中的恩诺沙星标志残留物的残留量分别在停药5d、7d和3d时降至相应的最高残留限量(MRL)以下。恩诺沙星标志残留物平均残留量以实测数据用WT1.4计算软件拟合,肌肉、肝脏和肾脏的休药期结果分别为7.689d、7.339d和4.529d。鸡按推荐剂量饮水给药,建议休药期至少为8d。
3.2恩诺沙星钠可溶性粉在鸡的残留消除规律：在0休药期时,测得的肌肉、肝脏和肾脏中的恩诺沙星标志残留物的残留量分别为(1.253±0.319)mg/kg、(2.024±0.902)mg/kg和(0.576±0.099)mg/kg；肌肉、肝脏、肾脏组织中的恩诺沙星标志残留物的残留量分别在停药3d、5d和1d时降至相应的MRL以下。实测数据用WT1.4计算软件拟合,肌肉、肝脏和肾脏的休药期结果分别为4.919d、4.759d和3.369d。鸡按推荐剂量饮水给药,建议恩诺沙星钠可溶性粉的休药期至少为5d。
3.3盐酸恩诺沙星可溶性粉在鸡的残留消除规律：在0休药期时,测得的肌肉、肝脏和肾脏中的恩诺沙星标志残留物的残留量分别为(8.038±2.074)mg/kg、(12.678±3.667)mg/kg和(3.273±0.879)mg/kg；肌肉、肝脏、肾脏组织中的恩诺沙星标志残留物的残留量在停药第9d时降均至相应的MRL以下。实测数据用WT1.4计算软件拟合,肌肉、肝脏和肾脏的休药期结果分别为9.739d、9.549d和7.119d。鸡按推荐剂量饮水给药,建议盐酸恩诺沙星可溶性粉的休药期至少为10d。
结果表明,三种恩诺沙星可溶性粉剂按推荐剂量饮水给药,在0休药期时,均显示残留量肝脏最高,肌肉其次,肾脏最低,肝脏消除亦最慢。三种药物残留消除存在差异,乳酸恩诺沙星可溶性粉休药期至少为8d；恩诺沙星钠可溶性粉休药期至少为5d；盐酸恩诺沙星可溶性粉休药期至少为10d。乳酸恩诺沙星可溶性粉和恩诺沙星钠可溶性粉的休药期符合农业部第278号公告的在肉鸡饲养中使用恩诺沙星及可溶性粉的休药期为8d的规定,而盐酸恩诺沙星可溶性粉休药期则长于此规定。由此可见,恩诺沙星原制剂与恩诺沙星可溶性粉剂在鸡体内消除过程有一定差异,甚至不同的恩诺沙星可溶性粉制剂休药期也不同。
Enrofloxacin is the third generation fluoroquinolone with broad antimicrobial spectrum and high bactericidal activity which was developed exclusively for veterinary use.And it has no cross-resistance with other antimicrobial agents.Enrofloxacin showed favourable pharmacokinetic properties such as excellent bioavailability, large volume of distribution. However, enrofloxacin slightly soluble in water. Enrofloxacin lactate, enrofloxacin sodium and enrofloxacin hydrochloride as water-soluble powders provides a great convenience for clinical medication. The tests on the residues depletion of three kinds of enrofloxacin soluble powders in broiler tissues provided the theory basis for the withdrawal time to ensure the safety and security of human health and animal products in the international market competition.
1. Pharmacokinetic study of enrofloxacin lactate soluble powder in broilers
The pharmacokinetics and bioavailability of enrofloxacin lactate were investigated in24healthy Shuqinhuang Chicken. Enrofloxacin lactate was administered intravenously (i.v.) and orally (p.o.) at a dose10mg/kg body weight(clinically recommend dose). The concentrations of enrofloxacin lactate in plasma were determined by high-performance liquid chromatography (HPLC).Pharmacokinetic analysis of plasma concentration-time data after single i.v. and p.o. administration were performed with the pharmacokinetic computer program3p87. Following intravenous administration, the drug concentration-time graph was characteristic of a two-compartment open model, The main pharmacokinetic parameters of enrofloxacin lactate:t1/2a (0.45±0.16) h, t1/2β (7.02±1.42) h, CL(s)(0.38±0.10) mg/kg/h, AUC (23.69±5.56)(mg/L)×h.The results showed that the concentration-time data of enrofloxacin in plasma after oral administration are fitted to a two-compartment open model. The main pharmacokinetic parameters:t1/2ka (0.60±0.01)h, t1/2kc (8.25±1.73)h, tpeak (2.44±0.17) h, Cmax (1.44±0.30) mg/L, AUC (20.74±3.80)(mg/L)×h, F87.54%. Enrofloxacin concentrations in plasma after the drug administration showed that a rapid distribution phase was followed by the slower elimination phase in broilers. The bioavailability was high by the oral routes.
2. Determination of enrofloxacin residues in broiler tissues by high performance liquid chromatography
Samples of muscle, liver and kidney were thawed and homogenated.The phosphate-buffered saline were added to the samples and vortexed and centrifuged. The supernatant was concentrated and purificated by C18column solid phase extraction. The liquid was filtered through0.45μm disposable syringe filters prior to analysis by HPLC system. Chromatographic analyses were carried out on a reversed-phase liquid chromatography systerm with fluorescence detector with excitation wave length of280nm and emission wave length of450nm.The straight line established by standard addition was used as the quantitative standard curve for determination of enrofloxacin and ciprofloxacin by HPLC. The results showed that the linear range was0.01-1.0μg/mL and correlation coefficients were more than0.999. The detection limit for broilers tissues was0.01mg/kg. The enrofloxacin and ciprofloxacin were analyzed in spiked samples of three kinds of chicken tissues with mean recoveries in the range of74-1%-86-8%at spiked levels of0.05、0.1、1mg/kg. The relative standard deviations of CV of within group, the CV between groups were no more than10%and7%,respectively. The method is sufficient for routine residue analysis.
3. Comparison of residues depletion of different enrofloxacin salt preparation in broiler tissues
The study was performed in35,40-day-old, healthy Shuqinhuang Chicken, weighing1.5±0.2kg body weight. They were administered three kinds of enrofloxacin soluble powders p.o. once per day at a dose of100mg/L for seven successive days,respectively. Five broilers per day were slaughtered at0,1,3,5,7,9,11days after the last administration. The residues of enrofloxacin and its active metabolite ciprofloxacin were extracted from the homogenized tissue with phosphate-buffered saline and they were determined by high performance liquid chromatography.
3.1The residue elimination of enrofloxacin lactate soluble powder:
Enrofloxacin concentrations in muscle,liver and kidney were(1.899±0.922) mg/kg,(2.574±1.171) mg/kg and (0.967±0.624) mg/kg respectively at zero withdrawal time. The muscle, liver and kidney tissue residues of enrofloxacin decreased to less than MRL after5d,7d and3d of withdrawal time, respectively.The raw data were analysed with WT1.4program. Results showed that the withdrawal time of enrofloxacin lactate in broilers was at least8d.
3.2The residue elimination of enrofloxacin sodium soluble powder:
Enrofloxacin concentrations in muscle,liver and kidney were (1.253±0.319) mg/kg,(2.024±0.902) mg/kg and (0.576±0.099) mg/kg respectively at zero withdrawal time. The muscle, liver and kidney tissue residues of enrofloxacin decreased to less than MRL after3d,5d and Id of withdrawal time,respectively.The raw data were analysed with WT1.4program. Results showed that the withdrawal time of enrofloxacin sodium in broilers was at least5d.
3.3The residue elimination of enrofloxacin hydrochloride soluble powder:
Enrofloxacin concentrations in muscle, liver and kidney were (8.038±2.074) mg/kg,(12.678±3.667)mg/kg and (3.273±0.879)mg/kg respectively at zero withdrawal time. The residues of enrofloxacin have not been detected in the tissues of broiler after9d of withdrawal time.The raw data were analysed with WT1.4program. Results showed that the withdrawal time of enrofloxacin hydrochloride in broilers was at least10d.
The results showed that residue concentrations in the tissues found in all examined tissues were liver> muscle> kidney for kidney at zero withdrawal time. The liver had the slowest elimination. The withdrawal time of enrofloxacin lactate,enrofloxacin sodium and enrofloxacin hydrochloride in broilers was8d,5d and10d respectively.The withdrawal time of enrofloxacin in broilers was8d in the bulletin NO.278issued by the Ministry of Agriculture.Thus, different enrofloxacin soluble powder and enrofloxacin in broilers have some differences in the process of elimination and the withdrawal time is also slightly different.
引文
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