氯霉素在鲈鱼体内的药代动力学及残留规律的研究
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摘要
氯霉素是水产养殖中广泛应用的一类抗菌药物。本研究采用高效液相色谱法为定性、定量手段，研究了氯霉素在健康鲈鱼体内的药代动力学及在组织中的残留消除规律。由单剂量给药参数推算出多剂量给药方案，为临床用药提供理论依据；根据单剂量和多剂量给药后，药物在组织中的消除规律制定合理的休药期，为临床及公共卫生检测提供理论依据。
采用MCP-KP自动化药动学分析程序对数据进行分析。分析结果表明：鲈鱼单剂量口服氯霉素后(80mg/kg)，血药经时过程符合一级吸收一室模型，其理论方程为：C_(血液)=30.815(e~(-0.0614t)-e~(-0.662t))；主要动力学参数如下：K_a为0.662h~(-1)，T_(1/2Ka)，为1.047h；C_(max)为21.093μg/ml、T_(max)为3.961h、AUC为438.31mg.l~(-1).h~(-1)；Kel为0.0614h~(-1)、T_(1/2k)为11.293h。
组织中氯霉素的经时过程均符合一级吸收二项指数方程，理论方程及主要动力学参数如下：C_(肌肉)=33.515(e~(-0.085t)-e~(-0.219t)，C_(max)为30.815μg/ml、T_(max)为7.079h、AUC为662.370mg.l~(-1).h~(-1)、Kel为0.085h~(-1)、T_(1/2)K为8.174h。
C_(肝脏)=18.597(e~(-0.062t)-e~(-1.854t))，C_(max)为14.231μg/ml、T_(max)为1.894h、AUC为226.910mg.l~(-1).h~(-1)；Kel为0.062h~(-1)、T_(1/2)K为11.118h。
C_(肾脏)=26.024(e~(-0.052t)-e~(-0.399t))，C_(max)为36.037μg/ml、T_(max)为5.889h、AUC为946.07mg.l~(-1).h~(-1)；Kel为0.052h~(-1)、T_(1/2)K为13.424h。
多剂量(40mg/kg)给药后药物在组织中的消除可以用以下方程描述：C_(血液)=3.40e~(-0.403t)、C_(肌肉)=4.342e~(-0.458t)、C_(肝脏)=2.152e~(-0.239t)、C_(肾脏)=64.155e~(-1.443t)。按照消除方程，计算氯霉素在组织中达到0.01μg/ml所需要的时间，血液、肌肉、肝脏、肾脏分别为：14.164、13.261、22.476、6.075d。
药动学与组织动力学结果表明：氯霉素口服给药后，在鲈鱼体内吸收迅速，分布广泛，体内消除半衰期较长。组织中药物浓度较高，高于氯霉素对大多数细菌的最小抑菌浓度(0.01～5μg/ml)。根据血液与组织动力学参数，结合临床应用，提出合理给药方案为：按照40mg/kg.b.w的剂量，每日一次。
根据单剂量和多剂量给药后药物在组织中的消除规律，制定合理的休药期为大于23天。
Chloramphenico1 is one of the antibiotics widely used in aquacuIture. In this study, the
pharmacokinetic and residuaI characteristics of Chloraznphnicol in hea1thy Perch are studied
by using the High Performance Liquid Chromatography. In order to provide the theoretical
bases fOr the clinical use of Chloramphnicol, the multiple-dose pharmacokinetic parameters
were assessed according to the single-dose pharmacokinetic parameters. The withdrawal time
was deduced by the elimination of ChloramphnicoI, which must be usefu1 to the residue
monitoring fOr public heaIth.
Data were analyzed with the pharrnacokinetic coniputer program MCP-KP. The results
showed that the plasma concentration-time course of ChloramphnicoI can be described by a
one-compartment open model with the first order absorPtion after oraI administration
(80mg/kg). Its theoretical equation was as foIlows: C bItal = 30.8l5 (e -- o.oo14 t - e -- o.bo2 l ), and
the main pharmacokinetic parameters were those: K. 0'662h-l, T l/2K. I '047h, C max 2l '093 ll
g/mI, T max 3 '96l h, AUC 438.3 l mg.l-'.h-', Kel 0.06l4h-', T,l2k l l .293h.
The kinetics process of Chloramphnicol in tissues can all be described by the
biexponential equation with the first order absorption, and the theoreticaI equations and the
main pharmacokinetic parameters were as follows f
C muscIe = 33'515 (e -- o.os5 t - e - 9'2l9 t ), C max 30'8l5 P g/ml, T m.x 7'079h, AUC
662.370mg. l-I .h-',KeI 0.085h-I, T,,,k 8. 1 74h.
C li..,= l 8'597 (e -- o.o62 t - e -- l'854t ), C max I 4.23 l u g/ml, T mtx l '894h, AUC 226.9l0mg.I-
'.h", Kel0.062h- ', T,,2k I l. l l8h.
C kidney = 26'024 (e -- o.o52 l- e -- o.399 l ), C mas 36.037 u g/ml, T m.x 5'889h, AUC 946.07mg.l'
'.h-', Kel 0.052h", T,,,k l3.424h.
The elimination characteristics of muItipIe-dose administrition (40mg/kg) can be
described by the equations aS fOllows f C bl- = 3.40 e -- o.4o3 1' C mutcIe = 4'342 e -o.45a l' C liv,l
= 2.l52 e -o.239 t' C kideey = 64.l55 e - I'M3 t. According to the equations, the time taken by the
concentrations of Chloramphnicol dropping to 0.0l ll glml in blood. muscle. Iiver and kidney
was l4.l64. l3.26l' 22.476. 6.075 days respectively.
The resuItS of phdriacokinetic and residual studies show that after oraI administration,
Chloramphnicol can be absorbed quickly. distributed widely and eliminated slowly. The
2
concentrations in tissues were so high that they are almost higher than the MIC of
ChloramphnicoI fOr most bacteriec Acc6rding to the pharmacokinetic parameters, binding
with the use in the clinic, we suggest the reasonab1e administration project as that the Perch
can be given Chloramphenicol once a day by the oral administration dose of 40mg/kg body
weight.
According to the regular of ChIoraznphenicol elimination, we suggest the withdrawal
time should be about twenty-three days.
采用MCP-KP自动化药动学分析程序对数据进行分析。分析结果表明：鲈鱼单剂量口服氯霉素后(80mg/kg)，血药经时过程符合一级吸收一室模型，其理论方程为：C_(血液)=30.815(e~(-0.0614t)-e~(-0.662t))；主要动力学参数如下：K_a为0.662h~(-1)，T_(1/2Ka)，为1.047h；C_(max)为21.093μg/ml、T_(max)为3.961h、AUC为438.31mg.l~(-1).h~(-1)；Kel为0.0614h~(-1)、T_(1/2k)为11.293h。
组织中氯霉素的经时过程均符合一级吸收二项指数方程，理论方程及主要动力学参数如下：C_(肌肉)=33.515(e~(-0.085t)-e~(-0.219t)，C_(max)为30.815μg/ml、T_(max)为7.079h、AUC为662.370mg.l~(-1).h~(-1)、Kel为0.085h~(-1)、T_(1/2)K为8.174h。
C_(肝脏)=18.597(e~(-0.062t)-e~(-1.854t))，C_(max)为14.231μg/ml、T_(max)为1.894h、AUC为226.910mg.l~(-1).h~(-1)；Kel为0.062h~(-1)、T_(1/2)K为11.118h。
C_(肾脏)=26.024(e~(-0.052t)-e~(-0.399t))，C_(max)为36.037μg/ml、T_(max)为5.889h、AUC为946.07mg.l~(-1).h~(-1)；Kel为0.052h~(-1)、T_(1/2)K为13.424h。
多剂量(40mg/kg)给药后药物在组织中的消除可以用以下方程描述：C_(血液)=3.40e~(-0.403t)、C_(肌肉)=4.342e~(-0.458t)、C_(肝脏)=2.152e~(-0.239t)、C_(肾脏)=64.155e~(-1.443t)。按照消除方程，计算氯霉素在组织中达到0.01μg/ml所需要的时间，血液、肌肉、肝脏、肾脏分别为：14.164、13.261、22.476、6.075d。
药动学与组织动力学结果表明：氯霉素口服给药后，在鲈鱼体内吸收迅速，分布广泛，体内消除半衰期较长。组织中药物浓度较高，高于氯霉素对大多数细菌的最小抑菌浓度(0.01～5μg/ml)。根据血液与组织动力学参数，结合临床应用，提出合理给药方案为：按照40mg/kg.b.w的剂量，每日一次。
根据单剂量和多剂量给药后药物在组织中的消除规律，制定合理的休药期为大于23天。
Chloramphenico1 is one of the antibiotics widely used in aquacuIture. In this study, the
pharmacokinetic and residuaI characteristics of Chloraznphnicol in hea1thy Perch are studied
by using the High Performance Liquid Chromatography. In order to provide the theoretical
bases fOr the clinical use of Chloramphnicol, the multiple-dose pharmacokinetic parameters
were assessed according to the single-dose pharmacokinetic parameters. The withdrawal time
was deduced by the elimination of ChloramphnicoI, which must be usefu1 to the residue
monitoring fOr public heaIth.
Data were analyzed with the pharrnacokinetic coniputer program MCP-KP. The results
showed that the plasma concentration-time course of ChloramphnicoI can be described by a
one-compartment open model with the first order absorPtion after oraI administration
(80mg/kg). Its theoretical equation was as foIlows: C bItal = 30.8l5 (e -- o.oo14 t - e -- o.bo2 l ), and
the main pharmacokinetic parameters were those: K. 0'662h-l, T l/2K. I '047h, C max 2l '093 ll
g/mI, T max 3 '96l h, AUC 438.3 l mg.l-'.h-', Kel 0.06l4h-', T,l2k l l .293h.
The kinetics process of Chloramphnicol in tissues can all be described by the
biexponential equation with the first order absorption, and the theoreticaI equations and the
main pharmacokinetic parameters were as follows f
C muscIe = 33'515 (e -- o.os5 t - e - 9'2l9 t ), C max 30'8l5 P g/ml, T m.x 7'079h, AUC
662.370mg. l-I .h-',KeI 0.085h-I, T,,,k 8. 1 74h.
C li..,= l 8'597 (e -- o.o62 t - e -- l'854t ), C max I 4.23 l u g/ml, T mtx l '894h, AUC 226.9l0mg.I-
'.h", Kel0.062h- ', T,,2k I l. l l8h.
C kidney = 26'024 (e -- o.o52 l- e -- o.399 l ), C mas 36.037 u g/ml, T m.x 5'889h, AUC 946.07mg.l'
'.h-', Kel 0.052h", T,,,k l3.424h.
The elimination characteristics of muItipIe-dose administrition (40mg/kg) can be
described by the equations aS fOllows f C bl- = 3.40 e -- o.4o3 1' C mutcIe = 4'342 e -o.45a l' C liv,l
= 2.l52 e -o.239 t' C kideey = 64.l55 e - I'M3 t. According to the equations, the time taken by the
concentrations of Chloramphnicol dropping to 0.0l ll glml in blood. muscle. Iiver and kidney
was l4.l64. l3.26l' 22.476. 6.075 days respectively.
The resuItS of phdriacokinetic and residual studies show that after oraI administration,
Chloramphnicol can be absorbed quickly. distributed widely and eliminated slowly. The
2
concentrations in tissues were so high that they are almost higher than the MIC of
ChloramphnicoI fOr most bacteriec Acc6rding to the pharmacokinetic parameters, binding
with the use in the clinic, we suggest the reasonab1e administration project as that the Perch
can be given Chloramphenicol once a day by the oral administration dose of 40mg/kg body
weight.
According to the regular of ChIoraznphenicol elimination, we suggest the withdrawal
time should be about twenty-three days.
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87．李爱华、朱模忠、解庆宾等，氯霉素在健康、沙门氏菌和肝损伤小型猪体内的药代动力研究，江苏农学院学报，1990，11(1)：55-59
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68. Nouws et al, Pharmacokinetics of antimicrobials in some fresh water fish speices.Chemotherapy in aquaculture 1992, 437-447
69．林丽芳、刘妙颖，氯霉素的临床合理应用，河北医学，1999，91-92
70．张双贵、王振敏，氯霉素的副作用，1997，03
71．秦建华、赵月兰、张明勇，氯霉素引起雏鸡骨髓造血机能抑制的观察，中国家禽，1995，(3)：19
72. Holt D,Harvey D, Hurley R et al. Chloramphenicol toxicity Adverse Drug React Toxicol Rev 1993,12(2):83-95
73. Commission of the European communities(1992) Veterinary Drugs Residue,Residues in food-preducing Animals and Their Products:reference Materails and Methods,Report EUR 14126,RJ.Heitzman(Ed.),Commission of the European Communities, Rrussels,Belgium
74．庄无忌主编，《各国食品和饲料中农药兽药残留限量大全》，中国对外经济贸易出版社，第一版，1995，990-999
75．动物性食品中兽药残留标准，中华人民共和国1997年9月发布，农牧发[1997]7号
76. Wal JM, Peleran JC, Bortes GF et al. High performance liquid chromatographic determination of Chloramphenicol in milk J Assoc Off Anal Chem 1980 Sep;63(5):1044-1048
77. Hollstein E, Laue W, Zapff G et al. Gas-chromatographic determination of chloramphenicol residues in animal material Nahrung 1981;25(2):143-149
78. Abjean JP et al Screening of chloramphenicol residues in pork muscle by planar chromatography J AOAC Int 1994 Sep:77(5):1101-1104
79. Carol J, Singer and Stanley E. Katz et al. Microbiological assay for chloramphenicol residues J Assoc Off Anal Chem 1985;68(5): 1037-1041
80. Van de Water C, Haagsma N,Van Kooten PJ et al. An enzyme-linked immunosorbent assay for the determination of chloramphenicol using a monoclonal antibody, Application to residues in swine muscle tissue Z Lebensm Unters Forsch 1987 Sep;185:(3)202-207
81．叶永茂，现代兽药残留的控制与测定，食品理化检验，1992，(1)：1-11
82．李万章，色谱分析中生物样品的前处理方法，药物分析杂志，1996，16(1)：55-59
83．王世平、王静等主编，《现代仪器分析原理与技术》，哈尔滨工业大学出版社，1999
84．安登魁主编，《药物分析》，人民卫生出版社，第三版，1996年
85．南京药学院药物分析教研室，《体内药物分析》，人民出版社，1982年
86．李健，噁喹酸对水生生物细菌病的防治效果及残留研究，中国水产科学，2001，8(3)
87．李爱华、朱模忠、解庆宾等，氯霉素在健康、沙门氏菌和肝损伤小型猪体内的药代动力研究，江苏农学院学报，1990，11(1)：55-59
88．陈昌福、毛芝娟、王敏，福建爱德华氏菌对土霉素、氯霉素和链霉素的感受性、耐药性研究，淡水渔业，1996(3)：3-6
89．喻运珍、艾桃山、张萍香，嗜水气单胞菌对4种中草药和4种抗生素耐药性的比较研究，内陆水产，1999(5)：5-6
90. OrrW W, Evaluation of lintravenous chloramphenicol. A preliminary report.Antibiotica Chemotherapy, 1951(1):63-67
91．黄文芳、段圣和、温桂芳，鲇鱼苗烂尾病病原体的初步研究，华南师范大学学报(自然科学版)，1994(4)：18-24
92．高汉娇、林永泰、陈昌福，水库爆发性鱼病及其防治技术研究Ⅲ某些药物对鲢爆发病病原菌的试管内抗菌作用 水利渔业，1995(3)：16-18
93．刘金屏、聂丽苹、李太武，皱纹盘鲍脓包病的研究，中国水产科学，1995(2)：78-84
94. Malikova M, Habrda J et al. Residues of chloramphenicol in the calf organism following parenteral administration of the Czechoslovavaj preparation Chronicin inj Vet Med (Praha) 1976 Mar;21(3): 175-185
95. Gassner B, Wuethrich A et al. Pharmacokinetic and toxcological aspects of the medication of beef-type calaves with an oral formulation of chloramphenicol pakmitate J Vet Pharacol Ther 1994 Aug;17(4):279-283
96．陈锦富、胡政主编，淡水养殖病害诊断与防治手册，上海科学技术出版社，2000，182-187
97．王振龙、宋憬愚主编，鱼病诊断与防治(淡水鱼)，中国农业大学出版社，1999，48
98．王宏田、徐永立、张培军主编，海水鱼类疾病的防治，海洋出版社，2000，90