恩诺沙星及其代谢物在方正银鲫组织中的代谢及消除规律
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摘要
近年来水产养殖中的常用药物恩诺沙星在鲫中的残留问题比较突出,但目前国家未对其在鲫中的休药期作出明确规定。为做到鲫养殖中科学合理使用恩诺沙星,在12～15℃水温条件下,以60 mg/kg.b.w.剂量,对体质量为(250±10)g的健康方正银鲫(Carassius auratus gibelio)灌服恩诺沙星;在灌服后0～120 d内不间断采样,用高效液相色谱-串联质谱仪检测,研究恩诺沙星及其代谢产物环丙沙星在方正银鲫鳃、血浆、肌肉、皮肤、肝脏和肾脏中的代谢及消除规律,从而为恩诺沙星在方正银鲫中的休药期制定提供参考。结果显示:灌药后,恩诺沙星在方正银鲫血浆、肌肉、肝脏、鳃、肾脏和皮肤中的达峰时间t_(max)分别为9、18、24、24、48和48 h,肾脏、肝脏、肌肉、血浆、鳃和皮肤中的达峰浓度c_(max)分别为30.490、21.372、18.715、16.636、15.157和11.663 mg/kg;皮肤中的消除半衰期t_(1/2β)最大,为338.2 h,血浆中最小,为93.303 h;代谢产物环丙沙星的代谢及消除趋势与恩诺沙星大致相同,血浆中达峰值产生最早,t_(max)为18 h,肾脏中的峰浓度最大,c_(max)为547.26μg/kg。结果表明,方正银鲫以单次口灌60 mg/kg.b.w.剂量恩诺沙星,皮肤和肌肉中的恩诺沙星和环丙沙星总量需要1 200度日才能满足限量要求。本研究为恩诺沙星在鲫鱼养殖中的科学使用提供了数据支撑。
In recent years,the residues of Enrofloxacin that has been commonly used in aquaculture have become more serious in Carassius auratus gibelio,however,no any clear regulation on its withdrawal period has been developed by the state.In order to scientifically use the Enrofloxacin in carp breeding,the following experiment was carried out.Healthy Carassius auratus gibelio with body mass of(250±10)g was fed with Enrofloxacin at a dose of 60 mg/kg.b.w.under the water temperature of 12 to 15℃,and then incessantly sampled within 0 to 120 d to test by high performance liquid chromatography-tandem mass spectrometry(HPLC-MS),hence the metabolism mechanism was studied,as well as the elimination rule of Enrofloxacin and its metabolite(Ciprofloxacin)in gill,plasma,muscle,skin,liver and kidney,which could provide some references for defining its withdrawal period.The results showed that,after administration,the peak time(t_(max))of Enrofloxacin in plasma,muscle,liver,gill,kidney and skin was 9,18,24,24,48 and 48 h,respectively and the peak concentration(c_(max))was 16.636,18.715,21.372,15.157,30.490 and 11.663 mg/kg,respectively.The elimination half-life(t_(1/2β))in skin was the maximum,which was 338.2 h,and in plasma it was the minimum(93.303 h).The metabolism and elimination trend of Ciprofloxacin was similar to that of Enrofloxacin,specially,the peak value first appeared in plasma with t_(max) of 18 h,and the peak concentration reached the maximum in kidney with c_(max) of 547.26μg/kg.Therefore,a conclusion was given that it would take more than 1 200 degree-days for the total amount of Enrofloxacin and Ciprofloxacin in skin and muscle to reach the required limit if Carassius auratus gibelio was orally administered with Enrofloxacin at a dose of 60 mg/kg.b.w each time.Therefore,some data supports were provided by this study for scientific use of Enrofloxacin in carp breeding.
In recent years,the residues of Enrofloxacin that has been commonly used in aquaculture have become more serious in Carassius auratus gibelio,however,no any clear regulation on its withdrawal period has been developed by the state.In order to scientifically use the Enrofloxacin in carp breeding,the following experiment was carried out.Healthy Carassius auratus gibelio with body mass of(250±10)g was fed with Enrofloxacin at a dose of 60 mg/kg.b.w.under the water temperature of 12 to 15℃,and then incessantly sampled within 0 to 120 d to test by high performance liquid chromatography-tandem mass spectrometry(HPLC-MS),hence the metabolism mechanism was studied,as well as the elimination rule of Enrofloxacin and its metabolite(Ciprofloxacin)in gill,plasma,muscle,skin,liver and kidney,which could provide some references for defining its withdrawal period.The results showed that,after administration,the peak time(t_(max))of Enrofloxacin in plasma,muscle,liver,gill,kidney and skin was 9,18,24,24,48 and 48 h,respectively and the peak concentration(c_(max))was 16.636,18.715,21.372,15.157,30.490 and 11.663 mg/kg,respectively.The elimination half-life(t_(1/2β))in skin was the maximum,which was 338.2 h,and in plasma it was the minimum(93.303 h).The metabolism and elimination trend of Ciprofloxacin was similar to that of Enrofloxacin,specially,the peak value first appeared in plasma with t_(max) of 18 h,and the peak concentration reached the maximum in kidney with c_(max) of 547.26μg/kg.Therefore,a conclusion was given that it would take more than 1 200 degree-days for the total amount of Enrofloxacin and Ciprofloxacin in skin and muscle to reach the required limit if Carassius auratus gibelio was orally administered with Enrofloxacin at a dose of 60 mg/kg.b.w each time.Therefore,some data supports were provided by this study for scientific use of Enrofloxacin in carp breeding.
引文
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[4]刘春娥,林洪,曹立民,等.恩诺沙星酶联免疫吸附检测方法(ELISA)的建立及其与HPLC方法的比较研究[J].中国动物检疫,2009,26(9):44-46.
[5]臧莹安,李成梅,李春玲,等.链球菌2型对恩诺沙星耐药机制及耐药株毒力变化研究进展[J].中国动物检疫,2012,29(5):69-71.
[6]NAU M R,CARPENTER J W,KUKANICH B,et al.Pharmacokinetcs of a single dose of oral and subcutaneous enrofloxacin in Caribbean flamingos(Phoenicopterus rubber ruber)[J].Journal of zoo&wildlife medicine official publication of the American association of zoo veterinarians,2017,48(1):72-79.
[7]郭娇娇,潘红艳,杨虎,等.恩诺沙星在杂交鲟体内的药物代谢动力学[J].大连海洋大学学报,2011,26(4):362-366.
[8]DOWLING P M,WILSON R C,TYLER J W,et al.Pharmacokinetics of ciprofloxacin in ponies[J].Journal of veterinary pharmacology and therapeutics,1995,18(1):7-12.
[9]沈建忠.如何正确理解抗生素在动物养殖业上的地位和作用[J].兽医导刊,2017(8):6-8.
[10]张婷,李茂勇,范红照.恩诺沙星在水产动物体内药物代谢动力学研究进展[J].农林科技,2017(7):230-231.
[11]梁俊平,李健,张喆,等.肌注和口服恩诺沙星在大菱鲆体内的药代动力学比较[J].水生生物学报,2010,34(6):1122-1129.
[12]李娜,李健,王群.恩诺沙星在养殖大菱鲆体内的残留及消除规律[J].渔业科学进展,2009,30(2):26-33.
[13]常志强,李东利,李建.恩诺沙星在大菱鲆(Scophthalmusmaximus)、牙鲆(Paralichthysolivaceus)和半滑舌鳎(Cynoglossussemilaevis)体内的残留消除规律[J].渔业科学进展,2016,37(5):16-21.
[14]张德云,匡维华,郑映钦.恩诺沙星在日本鳗鲡体内残留消除规律研究[J].水产科学,2007,26(4):210-213.
[15]余培建.药浴给药恩诺沙星及其代谢产物在欧洲鳗鲡体内的药代动力学研究[J].福建水产,2007,12(4):38-43.
[16]房文红,于慧娟,蔡友琼,等.恩诺沙星及其代谢物环丙沙星在欧洲鳗鲡体内的代谢动力学[J].中国水产科学,2007,14(4):622-629.
[17]张乐,许宝青,刘超.恩诺沙星在乌鳢体内的代谢及其代谢产物消除的研究[J].安徽农学通报,2013,19(23):15-16.
[18]李佳蔚,刘慧慧,于召强,等.恩诺沙星在黑鲪体内的药物代谢动力学研究[J].中国渔业质量与标准,2012,2(1):52-57.
[19]徐维海,林黎明,朱校斌,等.恩诺沙星及其代谢产物在吉富罗非鱼、中国对虾体内的残留规律研究[J].水产科学,2004,23(7):5-8.
[20]孙慧宇,陈君义,王云飞,等.恩诺沙星和环丙沙星在泥鳅(Misgurnus anguillicaudatus)体内的残留和消除规律[J].渔业科学进展,2015,36(4):128-131.
[21]王习达,刘训猛,方苹,等.恩诺沙星在异育银鲫体内药代动力学研究[J].金陵科技学院学报,2013,29(1):78-81.
[22]赵英杰.盐酸氯苯胍和恩诺沙星在异育银鲫体内药动学研究[D].上海:上海海洋大学,2017.
[23]方星星,刘秀红,丁相卿,等.恩诺沙星在异育银鲫体内的组织分布及消除规律[J].南京农业大学学报,2012,35(4):110-114.
[24]赵海军,欧安,简纪常,等.恩诺沙星在凡纳滨对虾体内的代谢和残留消除规律[J].广东海洋大学学报,2012,30(6):31-34.
[25]郑宗林,叶金明,李代金,等.恩诺沙星及其代谢产物在中华绒螯蟹血淋巴中的比较药代动力学[J].海洋渔业,2011,33(1):75-85.
[26]农业部.诺氟沙星、恩诺沙星水产养殖使用规范:SCT 1083-2007[S].北京:农业部,2007.
[27]李宏.基于医学影像学的肾脏滤过模型研究[D].沈阳:东北大学,2011.
[28]简纪常,吴灶和,陈刚.恩诺沙星在眼斑拟石首鱼体内的药物代谢动力学[J].中国兽医学报,2005,25(2):195-197.
[29]李改娟,刘艳辉,戴欣,等.不同水温联合用药中恩诺沙星在鲤体内的药代动力学及残留的影响[J].吉林农业大学学报,2017,39(4):471-476.
[30]王洪艳,李兆新,邢丽红,等.恩诺沙星及其代谢产物环丙沙星在牙鲆体内代谢消除规律[J].渔业科学进展,2014,35(3):44-49.
[31]王广基.药物代谢动力学[M].北京:化学工业出版社,2005.
[32]潘红艳,郭娇娇,杨虎,等.氟苯尼考在鲟鱼体内的药物代谢动力学研究[J].水产科学,2011,30(7):373-377.
[33]汤菊芬,简纪常,鲁义善,等.恩诺沙星在红笛鲷体内的药代动力学[J].广东海洋大学学报,2012,32(4):28-33.
[34]INTORRE L,CECCHINI S,BERTINI S,et al.Pharmacokinetics of enrofloxacin in the seabass(Dicentrarchus labrax)[J].Aquaculture,2000,182(1):49-59.
[35]宋维彦,苏永全,潘滢,等.磺胺甲基噁唑和恩诺沙星在日本囊对虾体内的药代动力学研究[J].海洋科学,2010,34(7):22-27.
[36]GORE S R,HARMS C A,KUKANICH B,et al.Enrofloxacin pharmacokinetics in the European cuttlefish,sepia officinalis,after a single iv injection and bath administration[J].Journal of veterinary pharmacology and therapeutics,2005,28(5):433-439.
[37]唐锡招,李兆新,邢利红,等.恩诺沙星代谢产物研究进展[J].中国渔业质量与标准,2015,5(2):65-74.
[38]邢丽红,孙伟红,冷凯凉,等.阿维菌素在鲈组织中的富集及消除研究规律研究[J].中国渔业质量与标准,2013,3(4):63-69.
[2]郭娇娇,杨虎,潘红艳,等.恩诺沙星对鲟鱼的急性毒性研究[J].现代农业科技,2010(20):311-315.
[3]宓晓黎,李利东,黄丽俊,等.恩诺沙星免疫抗原的制备与鉴定[J].中国动物检疫,2010,27(6):43-45.
[4]刘春娥,林洪,曹立民,等.恩诺沙星酶联免疫吸附检测方法(ELISA)的建立及其与HPLC方法的比较研究[J].中国动物检疫,2009,26(9):44-46.
[5]臧莹安,李成梅,李春玲,等.链球菌2型对恩诺沙星耐药机制及耐药株毒力变化研究进展[J].中国动物检疫,2012,29(5):69-71.
[6]NAU M R,CARPENTER J W,KUKANICH B,et al.Pharmacokinetcs of a single dose of oral and subcutaneous enrofloxacin in Caribbean flamingos(Phoenicopterus rubber ruber)[J].Journal of zoo&wildlife medicine official publication of the American association of zoo veterinarians,2017,48(1):72-79.
[7]郭娇娇,潘红艳,杨虎,等.恩诺沙星在杂交鲟体内的药物代谢动力学[J].大连海洋大学学报,2011,26(4):362-366.
[8]DOWLING P M,WILSON R C,TYLER J W,et al.Pharmacokinetics of ciprofloxacin in ponies[J].Journal of veterinary pharmacology and therapeutics,1995,18(1):7-12.
[9]沈建忠.如何正确理解抗生素在动物养殖业上的地位和作用[J].兽医导刊,2017(8):6-8.
[10]张婷,李茂勇,范红照.恩诺沙星在水产动物体内药物代谢动力学研究进展[J].农林科技,2017(7):230-231.
[11]梁俊平,李健,张喆,等.肌注和口服恩诺沙星在大菱鲆体内的药代动力学比较[J].水生生物学报,2010,34(6):1122-1129.
[12]李娜,李健,王群.恩诺沙星在养殖大菱鲆体内的残留及消除规律[J].渔业科学进展,2009,30(2):26-33.
[13]常志强,李东利,李建.恩诺沙星在大菱鲆(Scophthalmusmaximus)、牙鲆(Paralichthysolivaceus)和半滑舌鳎(Cynoglossussemilaevis)体内的残留消除规律[J].渔业科学进展,2016,37(5):16-21.
[14]张德云,匡维华,郑映钦.恩诺沙星在日本鳗鲡体内残留消除规律研究[J].水产科学,2007,26(4):210-213.
[15]余培建.药浴给药恩诺沙星及其代谢产物在欧洲鳗鲡体内的药代动力学研究[J].福建水产,2007,12(4):38-43.
[16]房文红,于慧娟,蔡友琼,等.恩诺沙星及其代谢物环丙沙星在欧洲鳗鲡体内的代谢动力学[J].中国水产科学,2007,14(4):622-629.
[17]张乐,许宝青,刘超.恩诺沙星在乌鳢体内的代谢及其代谢产物消除的研究[J].安徽农学通报,2013,19(23):15-16.
[18]李佳蔚,刘慧慧,于召强,等.恩诺沙星在黑鲪体内的药物代谢动力学研究[J].中国渔业质量与标准,2012,2(1):52-57.
[19]徐维海,林黎明,朱校斌,等.恩诺沙星及其代谢产物在吉富罗非鱼、中国对虾体内的残留规律研究[J].水产科学,2004,23(7):5-8.
[20]孙慧宇,陈君义,王云飞,等.恩诺沙星和环丙沙星在泥鳅(Misgurnus anguillicaudatus)体内的残留和消除规律[J].渔业科学进展,2015,36(4):128-131.
[21]王习达,刘训猛,方苹,等.恩诺沙星在异育银鲫体内药代动力学研究[J].金陵科技学院学报,2013,29(1):78-81.
[22]赵英杰.盐酸氯苯胍和恩诺沙星在异育银鲫体内药动学研究[D].上海:上海海洋大学,2017.
[23]方星星,刘秀红,丁相卿,等.恩诺沙星在异育银鲫体内的组织分布及消除规律[J].南京农业大学学报,2012,35(4):110-114.
[24]赵海军,欧安,简纪常,等.恩诺沙星在凡纳滨对虾体内的代谢和残留消除规律[J].广东海洋大学学报,2012,30(6):31-34.
[25]郑宗林,叶金明,李代金,等.恩诺沙星及其代谢产物在中华绒螯蟹血淋巴中的比较药代动力学[J].海洋渔业,2011,33(1):75-85.
[26]农业部.诺氟沙星、恩诺沙星水产养殖使用规范:SCT 1083-2007[S].北京:农业部,2007.
[27]李宏.基于医学影像学的肾脏滤过模型研究[D].沈阳:东北大学,2011.
[28]简纪常,吴灶和,陈刚.恩诺沙星在眼斑拟石首鱼体内的药物代谢动力学[J].中国兽医学报,2005,25(2):195-197.
[29]李改娟,刘艳辉,戴欣,等.不同水温联合用药中恩诺沙星在鲤体内的药代动力学及残留的影响[J].吉林农业大学学报,2017,39(4):471-476.
[30]王洪艳,李兆新,邢丽红,等.恩诺沙星及其代谢产物环丙沙星在牙鲆体内代谢消除规律[J].渔业科学进展,2014,35(3):44-49.
[31]王广基.药物代谢动力学[M].北京:化学工业出版社,2005.
[32]潘红艳,郭娇娇,杨虎,等.氟苯尼考在鲟鱼体内的药物代谢动力学研究[J].水产科学,2011,30(7):373-377.
[33]汤菊芬,简纪常,鲁义善,等.恩诺沙星在红笛鲷体内的药代动力学[J].广东海洋大学学报,2012,32(4):28-33.
[34]INTORRE L,CECCHINI S,BERTINI S,et al.Pharmacokinetics of enrofloxacin in the seabass(Dicentrarchus labrax)[J].Aquaculture,2000,182(1):49-59.
[35]宋维彦,苏永全,潘滢,等.磺胺甲基噁唑和恩诺沙星在日本囊对虾体内的药代动力学研究[J].海洋科学,2010,34(7):22-27.
[36]GORE S R,HARMS C A,KUKANICH B,et al.Enrofloxacin pharmacokinetics in the European cuttlefish,sepia officinalis,after a single iv injection and bath administration[J].Journal of veterinary pharmacology and therapeutics,2005,28(5):433-439.
[37]唐锡招,李兆新,邢利红,等.恩诺沙星代谢产物研究进展[J].中国渔业质量与标准,2015,5(2):65-74.
[38]邢丽红,孙伟红,冷凯凉,等.阿维菌素在鲈组织中的富集及消除研究规律研究[J].中国渔业质量与标准,2013,3(4):63-69.