氯霉素和诺氟沙星在牙鲆体内的药代动力学及残留消除规律研究
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摘要
近几年水产养殖病害发生呈现暴发性、大规模、高死亡率的趋势，药物防治以其效果直接、操作简单而成为水产动物疾病首选的防治措施，而且将会在很长的一段时间内占据主导地位。然而，日前进行的药物防治研究多偏重于针对病原的药物筛选、使用浓度、使用方法等药效学方面，缺乏对药物间的相互作用、药代动力学、毒理学及对养殖生态环境的影响等基础理论的探讨，造成近期及远期的严重负面影响；而且随着渔药使用的加强和增多，残留量的蓄积亦不可避免，给人类健康和环境带来很大危害。针对这一普遍现状，以国内的重要经济养殖鱼类牙鲆为试验对象，进行了本课题的研究，以期规范渔药临床使用，加强渔药的使用管理和残留监控，为食品卫生安全等提供可靠的理论依据。
本文采用HPLC法为定性定量手段，首次对氯霉素(chloramphenicol，CAP)在牙鲆(paralichthys olivaceus)体内的药动学及残留消除规律进行了研究。对氯霉素的临床应用效果从药动学角度进行了客观评价，对其残留危害进一步加深认识，适应了当前需要。
采用非房室模型统计矩原理分析CAP药动学数据。结果如下：(1)单次口服剂量为80mg·kg~(-1)的CAP，药物在牙鲆体内的药-时曲线呈明显双峰现象。主要药动学参数：T_(max(1))出现在2hr左右，鳃、肝、肾、血、肌C_(max(1))依次为15.01、11.80、10.35、8.56、5.21μg·ml~(-1)；C_(max(2))小于相应的C_(max(1))，T_(max(2))出现在8h；药-时曲线下面积(AUC)：肾、鳃、肝、血、肌分别为176.87、133.77、118.77、65.33、50.36mg·h·L~(-1)；消除半衰期(T_(1／2))为4.89～10.39h；平均驻留时间(MRT)为8.67～17.05h。结果表明：口服CAP在牙鲆体内吸收较迅速，但滞留时间较长，易造成残留；据MIC(0.2～6.25μg·ml~(-1))得CAP口服在牙鲆各组织中维持有效浓度的时间约8～16h，而肌肉中几乎所有时间只对部分病原菌有效，认为CAP在治疗牙鲆细菌感染上并不是很高效的药物。(2)连续5天口服剂量为40mg·kg~(-1)的CAP，5种组织中药物消除方程分别为：C_肾=5.4153e~(-0.006t)、C_鳃=1.2526e~(-0.0091t)、C_肝=2.8286e~(-0.0113t)、C_血=0.3341e~(-0.0114t)、C_肌~=0.8262e~(-0.0176t)；药物消除半衰期(T_(1／2))由小到大依次为T_肌39.38、T_血60.79、T_肝61.33、T_鳃77.01、T_肾115.50h。表明口服CAP在牙鲆体内消除缓慢，残留较严重，尤以肾脏、肝脏组织中最明显，易对人体产生危害。
针对当前喹诺酮类药物应用广泛，而对其残留研究缺乏应有的关注这一现状，本文首次进行了诺氟沙星(Norfloxacin，NFLX)在牙鲆体内的残留消除规律研究，确定临床休药期；并建立了药物分离提取及分析方法。
以30mg·kg~(-1)剂量连续5天口服灌胃给药，取样组织为血、液、肌肉、肝脏、肾脏、鳃。组织中药物先加入pH7.4磷酸盐缓冲液匀浆，再用乙腈提取，反相HPLC法测定药物浓度，此方法平均回收率7137％～82.13％，最低检测限达0.005μg·ml~(-1)。
氯霉素和诺氟沙星在牙鲜体内的药代动力学及残留消除规律研究
多次口服给药后各组织中NFLX的消除可用以下方程描述:C。=0 .2382e“耀川、C、
=0.1284e」，·‘“，52，、C血=0.2784e戒，·‘加，3月‘、C肝二0.1554e月，·‘，’‘，‘、C肌=0.5345e闷，‘，:，‘弓，:T一几由大
到小依次为T，247.sh、T 0 133.27h、T血128.33h、T肝47.14h、T，18.48h。研究
结果表明:NFLX在5种组织中消除速率快慢不一;肾脏及鳃等非食用组织为NFLX
残留的靶组织:若规定可食用组织中的NFLx最大残留限量(MRLs)为50林g·kg.!，
在本实验条件下，建议临床休药期10一15d。
The pharmacokinetics and tissue elimination of CAP in paralichthys olivaceus are the first studied in this thesis. The clinical effect of CAP is impersonality evaluated from the view of pharmacokinetics and the disserve is adequately recognized, which is adaptive to the nowaday demands.
The concentrations of CAP are determined by High Performance Liquid Chromatography, and the pharmacokinetic data derived from the experiment are analyzed by non-compartmental methods based on statistical moment theory. The results indicate that: (1)The concentration-time curves of CAP shows an obvious double-peak phenomenon after oral administration at a dose of 80mg.kg-1. The main pharmacokinetic parameters are as follows: Tmax(1) is about 2h, Cmax(1) is 15.01,11.80,10.35,8.56,5.21 g'ml-1 in gill, liver, kidney, blood, muscle respectively; Cmax(2) is smaller than the corresponding Cmax(1), Tmax(2) is 8h; AUC is 176.87, 133.77, 118.77, 65.33, 50.36mg'h'L"1 in kidney, gill, liver, blood, muscle respectively; t1/2 4.89~10.39h; MRT 8.67~17.05h. The results show that the CAP can be absorbed quickly after oral administration in paralichthys olivaceus, but the residence time is long; According to MRLs, the time of maitaining effective drug levels in tissues is about 8~16h, However, drug concentration in muscle is
only effective to partial pathogens during almost all the time. It is considered that CAP is not the most effective drug in preventing and curing the bacterial infection of paralichthys olivaceus. (2) After oral administration at dose of 40mg kg-1 for five consecutive days,The elimination characteristics of CAP in five tissues can be described by the equations as follows: Ckidney=5.4153e-0.006t, Cgill=1.2526e-0.0091t, Cliver=2.8286e-0.0113t, Cblood=0.3341e-0.0114t, Cmuscle=0.8262e-0.0176t; T1/2 are 39.38h(Tmuscle), 60.79h(Tblood), 61.33h(Tliver), 77.01(Tgill)h, 115.50h(Tkidney) respectively. It shows that the elimination of CAP from the body is retarded and the residual amount in the body is great; especially, residual levels in the kidney and liver are highest, which are severe harmful to human body.
Quinolones are widely used in aquaculture and the studies lay particular stress on pharmacokinetics about clinical application currently, and that the study of regularity of depletion is neglected. Owing to above causes, the residues and depletion of norfloxacin are the first studied in paralichthys olivaceus in this thesis. Blood, muscle, liver, kidney and gill are sampled after oral administration at dose of 30mg kg-1 for five consecutive days. The samples are homogenated with pH7.4 sodium phosphate buffer and extracted with acetonitrile after shaking, and the tissue concentrations of Norfloxacin are
determinated using reversed-phase HPLC(RP-HPLC). The elimination equations of NFLX in five tissues are as follows: Ckidney=0.2382e-0.)028t, Cgil,=0.1284e-0.0052t, Cblood=0.2784e-0.0054t, CMver=0.1554e-0.0147t, Cmuslee=0.5345e-0.0375t; The overall recovery is 71.37%~82.13%; The limit of detection is 0.005ug . ml-1; T1/2 are Tkidney247.5h, Tgill133.27h, Tblood128.33h, Tlver47.14h, Tmusciel8.48h respectively. The results show that the elimination speed is deeply defferent in five tissues; Kidney and gill are main reservoirs of norfloxain in paralichthys olivaceus; It is suggested that the drug withdrawl period is10~15d in the light of the maximum residue limits of 50 g . kg-1.
本文采用HPLC法为定性定量手段，首次对氯霉素(chloramphenicol，CAP)在牙鲆(paralichthys olivaceus)体内的药动学及残留消除规律进行了研究。对氯霉素的临床应用效果从药动学角度进行了客观评价，对其残留危害进一步加深认识，适应了当前需要。
采用非房室模型统计矩原理分析CAP药动学数据。结果如下：(1)单次口服剂量为80mg·kg~(-1)的CAP，药物在牙鲆体内的药-时曲线呈明显双峰现象。主要药动学参数：T_(max(1))出现在2hr左右，鳃、肝、肾、血、肌C_(max(1))依次为15.01、11.80、10.35、8.56、5.21μg·ml~(-1)；C_(max(2))小于相应的C_(max(1))，T_(max(2))出现在8h；药-时曲线下面积(AUC)：肾、鳃、肝、血、肌分别为176.87、133.77、118.77、65.33、50.36mg·h·L~(-1)；消除半衰期(T_(1／2))为4.89～10.39h；平均驻留时间(MRT)为8.67～17.05h。结果表明：口服CAP在牙鲆体内吸收较迅速，但滞留时间较长，易造成残留；据MIC(0.2～6.25μg·ml~(-1))得CAP口服在牙鲆各组织中维持有效浓度的时间约8～16h，而肌肉中几乎所有时间只对部分病原菌有效，认为CAP在治疗牙鲆细菌感染上并不是很高效的药物。(2)连续5天口服剂量为40mg·kg~(-1)的CAP，5种组织中药物消除方程分别为：C_肾=5.4153e~(-0.006t)、C_鳃=1.2526e~(-0.0091t)、C_肝=2.8286e~(-0.0113t)、C_血=0.3341e~(-0.0114t)、C_肌~=0.8262e~(-0.0176t)；药物消除半衰期(T_(1／2))由小到大依次为T_肌39.38、T_血60.79、T_肝61.33、T_鳃77.01、T_肾115.50h。表明口服CAP在牙鲆体内消除缓慢，残留较严重，尤以肾脏、肝脏组织中最明显，易对人体产生危害。
针对当前喹诺酮类药物应用广泛，而对其残留研究缺乏应有的关注这一现状，本文首次进行了诺氟沙星(Norfloxacin，NFLX)在牙鲆体内的残留消除规律研究，确定临床休药期；并建立了药物分离提取及分析方法。
以30mg·kg~(-1)剂量连续5天口服灌胃给药，取样组织为血、液、肌肉、肝脏、肾脏、鳃。组织中药物先加入pH7.4磷酸盐缓冲液匀浆，再用乙腈提取，反相HPLC法测定药物浓度，此方法平均回收率7137％～82.13％，最低检测限达0.005μg·ml~(-1)。
氯霉素和诺氟沙星在牙鲜体内的药代动力学及残留消除规律研究
多次口服给药后各组织中NFLX的消除可用以下方程描述:C。=0 .2382e“耀川、C、
=0.1284e」，·‘“，52，、C血=0.2784e戒，·‘加，3月‘、C肝二0.1554e月，·‘，’‘，‘、C肌=0.5345e闷，‘，:，‘弓，:T一几由大
到小依次为T，247.sh、T 0 133.27h、T血128.33h、T肝47.14h、T，18.48h。研究
结果表明:NFLX在5种组织中消除速率快慢不一;肾脏及鳃等非食用组织为NFLX
残留的靶组织:若规定可食用组织中的NFLx最大残留限量(MRLs)为50林g·kg.!，
在本实验条件下，建议临床休药期10一15d。
The pharmacokinetics and tissue elimination of CAP in paralichthys olivaceus are the first studied in this thesis. The clinical effect of CAP is impersonality evaluated from the view of pharmacokinetics and the disserve is adequately recognized, which is adaptive to the nowaday demands.
The concentrations of CAP are determined by High Performance Liquid Chromatography, and the pharmacokinetic data derived from the experiment are analyzed by non-compartmental methods based on statistical moment theory. The results indicate that: (1)The concentration-time curves of CAP shows an obvious double-peak phenomenon after oral administration at a dose of 80mg.kg-1. The main pharmacokinetic parameters are as follows: Tmax(1) is about 2h, Cmax(1) is 15.01,11.80,10.35,8.56,5.21 g'ml-1 in gill, liver, kidney, blood, muscle respectively; Cmax(2) is smaller than the corresponding Cmax(1), Tmax(2) is 8h; AUC is 176.87, 133.77, 118.77, 65.33, 50.36mg'h'L"1 in kidney, gill, liver, blood, muscle respectively; t1/2 4.89~10.39h; MRT 8.67~17.05h. The results show that the CAP can be absorbed quickly after oral administration in paralichthys olivaceus, but the residence time is long; According to MRLs, the time of maitaining effective drug levels in tissues is about 8~16h, However, drug concentration in muscle is
only effective to partial pathogens during almost all the time. It is considered that CAP is not the most effective drug in preventing and curing the bacterial infection of paralichthys olivaceus. (2) After oral administration at dose of 40mg kg-1 for five consecutive days,The elimination characteristics of CAP in five tissues can be described by the equations as follows: Ckidney=5.4153e-0.006t, Cgill=1.2526e-0.0091t, Cliver=2.8286e-0.0113t, Cblood=0.3341e-0.0114t, Cmuscle=0.8262e-0.0176t; T1/2 are 39.38h(Tmuscle), 60.79h(Tblood), 61.33h(Tliver), 77.01(Tgill)h, 115.50h(Tkidney) respectively. It shows that the elimination of CAP from the body is retarded and the residual amount in the body is great; especially, residual levels in the kidney and liver are highest, which are severe harmful to human body.
Quinolones are widely used in aquaculture and the studies lay particular stress on pharmacokinetics about clinical application currently, and that the study of regularity of depletion is neglected. Owing to above causes, the residues and depletion of norfloxacin are the first studied in paralichthys olivaceus in this thesis. Blood, muscle, liver, kidney and gill are sampled after oral administration at dose of 30mg kg-1 for five consecutive days. The samples are homogenated with pH7.4 sodium phosphate buffer and extracted with acetonitrile after shaking, and the tissue concentrations of Norfloxacin are
determinated using reversed-phase HPLC(RP-HPLC). The elimination equations of NFLX in five tissues are as follows: Ckidney=0.2382e-0.)028t, Cgil,=0.1284e-0.0052t, Cblood=0.2784e-0.0054t, CMver=0.1554e-0.0147t, Cmuslee=0.5345e-0.0375t; The overall recovery is 71.37%~82.13%; The limit of detection is 0.005ug . ml-1; T1/2 are Tkidney247.5h, Tgill133.27h, Tblood128.33h, Tlver47.14h, Tmusciel8.48h respectively. The results show that the elimination speed is deeply defferent in five tissues; Kidney and gill are main reservoirs of norfloxain in paralichthys olivaceus; It is suggested that the drug withdrawl period is10~15d in the light of the maximum residue limits of 50 g . kg-1.
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