喹胺醇蛋白结合率及其标示残留物研究
摘要
喹胺醇是中国农业科学院兰州畜牧与兽药研究所研制的一种新型药物饲料添加剂,属于喹喔啉类不同侧链结构的衍生化合物,前期研究结果表明毒性和残留均低于同类药品。本实验利用平衡透析法对喹胺醇在鸡体内蛋白结合率研究,利用反相高效液相色谱法分析喹胺醇在鸡体内的主要排泄途径和标示残留代谢物,旨在对喹胺醇的用药及残留检测提供实验数据,进而为喹胺醇临床安全性全面评价提供科学依据。
结果:(1)浓度为22.0、5.5、1.1μg/mL喹胺醇溶液,平衡透析时间为30±2 h,蛋白结合率分别为66.96±1.59%、75.30±1.92%、84.41±0.87%。(2)浓度为20.0、5.0、1.0μg/mL喹烯酮溶液,平衡透析时间为32±1 h,蛋白结合率分别为46.96±1.59%,55.30±1.92%,54.41±0.87%。(3)鸡口服喹胺醇200 mg/kg.B.W后,72 h内从粪中排泄原药的总量占总给药量的61%。(4)喹喔啉-2-羧酸可定为喹胺醇在鸡体内的一种标示残留物,其检测条件为:Agilent系列ZORBAX Eclipse XDB C18色谱柱(250 mm×4.6 mm,5μm),流动相为1%的甲酸水溶液:甲醇=(40:60),流速为1.0 mL/min,QCA的检测波长为320 nm。
结论:(1)喹胺醇、喹烯酮的透析平衡时间均为30±3h,这与二者结构、分子质量相近有关;(2)喹胺醇与血浆蛋白结合有一定的饱和度,饱和后血浆蛋白的结合率与浓度间呈反比;(3)喹胺醇的血浆蛋白结合率比喹烯酮高;(4)喹胺醇在鸡体内的排泄主要由胃肠道直接排出体外;(5)喹喔啉-2-羧酸可以确定为喹胺醇在鸡体内的残留检测标示物。
Kuianchun is a new drug of Quinoxlines developed by Lanzhou institute of animal sciences and veterinary pharmaceutics of Chinese academy of agricultural sciences. The previous studies showed that the toxicity and residue of Kuianchun were lower than those of olaquindox and others. In this study, the protein binding rate was evaluated by the equilibrium dialysis, the major excretion and the mark of residue were measured by RP-HPLC. The aims were to provide the data for clinic and residue detection and to provide evidences for evaluation of clinical safety on Kuianchun.
RESULTS: (1) At concentration of 22.0μg/mL, 5.5μg/mL and 1.1μg/mL in buffer, the protein binding rates of Kuianchun were 66.96±1.59%, 75.30±1.92%, 84.41±0.87%respectively. The equilibrium dialysis time was 30±2h. (2) At concentration of 20.0μg/mL,5.0μg/mL and 1.0μg/mL in buffer, the protein binding rates of Quinocetone were 46.96±1.59%, 55.30±1.92%, 54.41±0.87% respectively. The equilibrium dialysis time was 30±1 h. (3) At the dose of 200 mg/kg.B.W, over 61% Kuianchun in chicken was excreted with the feces during 72 hours. (4) The Quinoxaline-2-Carboxylic acid was one of the marker residues of Kuianchun. Measured conditions of RP-HPLC to Quinoxaline-2-Carboxylic acid in chicken were ZORBAX Eclipse XDB C18 chromatographic column (250 mm×4.6 mm, 5μm), the mobile phase of 1 % formic acid–methyl alcohol (40/60, v/v), the flow rate of 1.0 mL·min-1, the UV detecting wavelength of 320 nm.
CONCLUSION: (1) The equilibrium dialysis time was 30±3h both of Kuianchun and Quinocetone. There was a relationship among the equilibrium time and drug structure and molecular weight. (2) The protein combined with drug was terminated at the saturation. Then, the protein binding rate was decreased with increasing of drug concentration. (3) The protein binding rate of Quinocetone was lower than that of Kuianchun. (4) The much of Kuianchun in chicken was excreted with feces. (5) Quinoxaline-2-Carboxylic acid was one of the marker residues of Kuianchun.
结果:(1)浓度为22.0、5.5、1.1μg/mL喹胺醇溶液,平衡透析时间为30±2 h,蛋白结合率分别为66.96±1.59%、75.30±1.92%、84.41±0.87%。(2)浓度为20.0、5.0、1.0μg/mL喹烯酮溶液,平衡透析时间为32±1 h,蛋白结合率分别为46.96±1.59%,55.30±1.92%,54.41±0.87%。(3)鸡口服喹胺醇200 mg/kg.B.W后,72 h内从粪中排泄原药的总量占总给药量的61%。(4)喹喔啉-2-羧酸可定为喹胺醇在鸡体内的一种标示残留物,其检测条件为:Agilent系列ZORBAX Eclipse XDB C18色谱柱(250 mm×4.6 mm,5μm),流动相为1%的甲酸水溶液:甲醇=(40:60),流速为1.0 mL/min,QCA的检测波长为320 nm。
结论:(1)喹胺醇、喹烯酮的透析平衡时间均为30±3h,这与二者结构、分子质量相近有关;(2)喹胺醇与血浆蛋白结合有一定的饱和度,饱和后血浆蛋白的结合率与浓度间呈反比;(3)喹胺醇的血浆蛋白结合率比喹烯酮高;(4)喹胺醇在鸡体内的排泄主要由胃肠道直接排出体外;(5)喹喔啉-2-羧酸可以确定为喹胺醇在鸡体内的残留检测标示物。
Kuianchun is a new drug of Quinoxlines developed by Lanzhou institute of animal sciences and veterinary pharmaceutics of Chinese academy of agricultural sciences. The previous studies showed that the toxicity and residue of Kuianchun were lower than those of olaquindox and others. In this study, the protein binding rate was evaluated by the equilibrium dialysis, the major excretion and the mark of residue were measured by RP-HPLC. The aims were to provide the data for clinic and residue detection and to provide evidences for evaluation of clinical safety on Kuianchun.
RESULTS: (1) At concentration of 22.0μg/mL, 5.5μg/mL and 1.1μg/mL in buffer, the protein binding rates of Kuianchun were 66.96±1.59%, 75.30±1.92%, 84.41±0.87%respectively. The equilibrium dialysis time was 30±2h. (2) At concentration of 20.0μg/mL,5.0μg/mL and 1.0μg/mL in buffer, the protein binding rates of Quinocetone were 46.96±1.59%, 55.30±1.92%, 54.41±0.87% respectively. The equilibrium dialysis time was 30±1 h. (3) At the dose of 200 mg/kg.B.W, over 61% Kuianchun in chicken was excreted with the feces during 72 hours. (4) The Quinoxaline-2-Carboxylic acid was one of the marker residues of Kuianchun. Measured conditions of RP-HPLC to Quinoxaline-2-Carboxylic acid in chicken were ZORBAX Eclipse XDB C18 chromatographic column (250 mm×4.6 mm, 5μm), the mobile phase of 1 % formic acid–methyl alcohol (40/60, v/v), the flow rate of 1.0 mL·min-1, the UV detecting wavelength of 320 nm.
CONCLUSION: (1) The equilibrium dialysis time was 30±3h both of Kuianchun and Quinocetone. There was a relationship among the equilibrium time and drug structure and molecular weight. (2) The protein combined with drug was terminated at the saturation. Then, the protein binding rate was decreased with increasing of drug concentration. (3) The protein binding rate of Quinocetone was lower than that of Kuianchun. (4) The much of Kuianchun in chicken was excreted with feces. (5) Quinoxaline-2-Carboxylic acid was one of the marker residues of Kuianchun.
引文
[1]沈建忠.药物饲料添加剂的应用及其展望[J].中国饲料.1994, 12(1):68～71.
[2]张宏伟,王喆，刘伟.动物源性食品中兽药和饲料添加剂残留及其对人体的危害[J].兽药与饲料添加剂. 2004, 9(4):1～3.
[3]徐士新.我国新兽药开发现状及存在问题[J].中国家禽.2001, 23(22):3～8.
[4] Tracy Hampton. Furan in Foods [J]. JAMA.2004, 291:29～33.
[5]张治平.抗生素与抗菌药发展史[M].首都医药出版社.北京:2004, 2:14～16.
[6]刘学剑.抗菌药物饲料添加剂的应用[J].饲料工业.1997, 18(3):29～31.
[7]刘培哲.人类可持续生存与毒理学的发展[J].中国药理学与毒理学杂志.1997, 11(2):85～86.
[8]张治平.抗生素与抗菌药发展史[M].首都医药出版社.北京:2004, 2:21～22.
[9]陈杖榴.兽医药理学[M].中国农业出版社.第二版.北京:2004, 3.
[10]曹随忠,张力,梁剑平,等.喹喔啉-1, 4-二氧化物类抗菌促生长剂特殊毒理学研究进展[J].动物医学进展.2001, 22(2):17～20.
[11]田少雪.英国上市药品安全评价指导原则[J].中国医药导刊.2002, 4(1):75-76.
[12]中华人民共和国农业部文件.农牧发[2003]38号动物源食品中兽药残留检测方法[Z].2003.
[13]孙永学,冯淇辉,董漓波,等.喹乙醇在鸡体内的毒物动力学及其生化毒性和病理学研究[J].畜牧兽医学报,1998, 29(5):385～391.
[14]何祖健.复方利菌净注射液体外抑菌和临床治疗试验[J].广西畜牧兽医,2001, 17(6):9～17.
[15]中国兽药监察所.新兽药质量标准[S]:33～35.
[16]李剑勇,赵荣材,李金善,等.喹烯酮在猪体内的药代动力学研究[J].中国兽医科技.2001, 31(8):31～33.
[17]李剑勇,赵荣材,李金善,等.口服喹烯酮代谢动力学研究[J].中国兽药杂志.2000, 35 (3):15～18.
[18]梁剑平,张力,曹随忠,等.新型饲料添加剂喹胺醇致突变性及其潜在致癌性预测[J].中国农业科学.2001, 34(6):679～685.
[19] Food and Agriculture organization. FAO Food and Nutrition Paper[R]. Rome, 1995, 41 (17):31～44.
[20]张力,梁剑平,程富胜,等.喹胺醇对断奶仔猪的亚急性毒性试验[J].中兽医医药杂志.2001, 20(2):11～12.
[21]孙晓平,张力,梁剑平,等.喹胺醇小白鼠急性毒性试验[J].中兽医医药杂志.1999, 18(2):17～18.
[22]张力,梁剑平,周丽霞,等.喹胺醇对肉用仔鸡亚急性毒性试验[J].中国兽医科技.2001, 31(1):27～30.
[23]张力,周丽霞,梁剑平,等.喹胺醇1号和3号体外抑菌试验[J].中国兽医科技.1998, 28(7): 24～25.
[24]梁剑平,张力,周丽霞,等.新型饲料添加剂喹胺醇致突变性及其潜在致癌性预测[J].中国农业科学.2001, 34(6):679~685.
[25]周丽霞,张力,梁剑平.药物饲料添加剂喹胺醇对仔猪的增重效果试验[J].中国兽医科技.2000, (1):15~16.
[26]周丽霞,张力,梁剑平.喹胺醇抗菌试验[J].预防兽医学进展.1999, (3):64.
[27]曹香林,杨志强,梁剑平,等.喹胺醇在鸡组织的消除及残留研究[J].中兽医医药杂志.2004, (3):5~7.
[28] Stasi R, Zinnani P L, Galieni P,et a1. Clinical implications of cytokine and soluble receptor measurements in patients with newly diagnosed agressive nonHodgKin’S mphomal[J].Eur J Haematal,1995, 54:9～17.
[29]曾经泽.生物药物分析[M].北京医科大学中国协和医科大学联合出版社.北京:1998, 247～252.
[30] Carbadox gains US tolerance[J]. Animal Pharm.1998, 39:5.
[31] Anonymous.Residues of some veterinary drugs in animals and food[Z]. FAO Food and Nutrition 85～96. 19～30. 53～62.
[32] MML Aerts,WMJ Beek,HJK eukens. Determination of residues of carbadox and some of its metabolites in swine tissues by high-performance liquid chromatography using on-line pre-column enrichment and post-column derivatization with UV-VIS detection[J]. Journal of Chromatography A.1986, 105～119.
[33] GMB innendijk,MML Aerts1,HJK eukens.Optimization and ruggedness testing of the determination of residues of carbadox and metabolites in products of animal origin [J]. Journal of Chromatography A.1991, 541:401～410.
[34] Della WM Sin,Lucy P K Chung,Martin M C Lai,et al. Determination of quinoxaline-2-carboxylic acid-the major metabolite of carbadox in porcine liver by isotope dilution gas chromatography electron capture negative ionization mass spectrometry [J]. Analytica Chimica Acta.2004, 508:147～158.
[35]张均田.现代药理实验方法[M].北京医科大学中国协和医科大学联合出版社.北京:1998,689.
[36] Mosmann T.Rapid colorime tricassay forcellar grow than survival:application to proliferation and cytotoxicity assays[J]. Immunol Methods.1983, 65(1):55～63.
[37]曾振灵,董漓波,陈杖榴.喹乙醇在鸡组织的消除及残留研究[J].畜牧兽医学报.1995, 26(4), 327～333.
[38]周学辉.不同喹喔啉类抗菌促生长剂对肉鸡生产性的影响[J].中兽医医药杂志.2006, 25 (2):16～18.
[39] Dean JH, Luster MI, Munson AE,et al. Immunotoxicology and Immunopharmacology[J]. NewYork Raven.1985, 24.
[40] McConnachie R. Archives of Environmental Health[J]. JAMA.1991, 47(4):249～253.
[41] Moszczynski P. Hyg Epidemiol Microbiol Immunol[J]. JAMA.1991, 35(4):351～360.
[42]曹随忠,张力,梁剑平,等.喹喔啉-1,4-二氧化物类抗菌促生长剂特殊毒理学研究进展[J].动物医学进展.2001, 22(2):17～20.
[43] FSIS. Carbadox metabolite in swine tissue [M]. Analytical Chemistry Laboratory Guidebook Residue Chemistry, 1991, 254.
[44] Lauridsen M G,Lund C,Jacobsen M,et al. Determination and depletion of residues of Carbadox,Tylosin,and Virginiamycin in kidney,liver,and muscle of pigs in feeding experiments[J]. J ASSOC OFF ANAL CHEM,1988, 7(5):921～925.
[45] Rose M D, Bygrave J, Tarbin J A.Determination of quinoxaline carboxylic acid(metabolite of Carbodox)in animal tissue by HPLC[J]. Food Addit Contam,1995, 12(2):177～183.
[46] The International SNP Map Working Group. A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms [J]. Nature.2001, 409:928～933.
[47]王玉春,严相林,赵荣材,等.新型药物饲料添加剂喹烯酮的一般毒性研究[J].中兽医医药杂志.1992, 18(1):16～19.
[48] Hertzberg RC , MacDonell MM. Synergy and other ineffective mixture risk Definitions.Sci Total Environ [J]. JAMA.2002, 47(4): 31～42.
[49]王立.色谱分析样品处理[M].化学工业出版社.北京:2000, 52.
[50] Federal Register[Z]. 37 FR 20683. 1972.
[51] Food and Agriculture organization. FAO Food and Nutrition Paper[R]. Rome:1995, 41 (17): 31～44.
[52] Graaf G J, Spierenbury T J. Liquid chromatographic determination of cyadox in medicated feeds and in the contents of thporcine gastrointestinal tract with fluorescence detection[J]. ChromatogrB 1988, 44(7):244～248.
[53] Graaf G J, Jager L P, Baarsen A J, et al.Some pharmacokineti observation of carbadox medication in pigs [J]. Vet Quart.1988, 10(1):34～41.
[54] Macintosh A I, George A N. Liquid chromatographic determination of carbadox, desoxycarbodox and nitrofurazones in portissues[J]. J ASSOC OFF ANAL CHEM.1984, 67(5):958～962.
[55]乔莉萍.新兽药“喹胺醇”对小鼠免疫机能影响的研究[D].中国农业科学院研究生院,北京:2006, 32.
[56]张丰景.断奶仔猪饲料中添加剂痢菌净试验[J].上海畜牧兽医通讯,1998, 1:17～18.
[57]李剑勇,赵荣材,李金善,等.喹烯酮在猪体内的药代动力学研究[J].中国兽医科技.2001,31(8):31～33.
[58] Robin LS, Martinsky T, Schena M. Trends in microarray analysis [J]. Technology Trends ,2003 ,9(1):140～145.
[59] Heijne WH , Stierum RH , Slijper M, et al. Toxicogenomics of bromobenzene hepatotoxicity: acombined transcrip tomics and proteomics approach[J].Biochem Pharmacol.2003, 65(5) :857～875.
[60] Schmidt CW. Toxicogenomics an emerging discipline[J].Environ Health Perspect, 2002 ,110(12):750～755.
[61] Hutchinson M J, Young P B, Kennedy D G. Confirmation of carbadox and olaquindox metabolites in porcine liver using liquid chromatography-electrospray, tandem mass spectrometry[J]. J Chromatogr B, 2005, 816: 15～20.
[62]曹香林,杨志强,梁剑平,等.喹胺醇在鸡组织的消除及残留研究[J].中兽医医药杂志.2004, 28(3):5～7.
[63]周丽霞,张力,梁剑平,等.喹胺醇在鸡体内残留分析[J].中国预防兽医学报.2000, 22(1):75～76.
[64]李建喜,杨志强,梁剑平,等.喹胺醇在猪体内的药代动力学研究[A].中国畜牧兽医学会兽医药理毒理学分会第九次学术讨论会论文集[C].安徽:2005, 167.
[65]陈秋潮.实用临床新药手册[M].上海科技文献出版社.上海:1991, 386.
[66]张君仁.体内药物分析[M].化学工业出版社.北京:2002, 15～18.
[67]徐叔云,卞如濂,陈修.药理学实验方法[M].人民卫生出版社.北京:1982, 441～445
[68]罗芳洪,黄自强.13-甲基豆蔻酸在大鼠体内的药代动力学研究[J].西北药学杂志.2003, 31(1):16～19.
[69]王弘,陈济民,张清民.用高效液相色谱法测定人血浆中黄芩苷与血浆蛋白的结合率[J].沈阳药科大学学报.2000, 17(2):107～109.
[70] Midgley I, Chasseaud L F , Taylor T. The absorption and excretion of 14C-lofexidine hydrochloride in man [J]. Arzneim-forsch. / Drug Res, 1982, 32 (2):972～975.
[71] Boivin G, Deloffre P, Perrat B,et al.Strontium distribution and interactions with bonemineral in monkey iliac bone after strontium salt (S12911) adminstration[J].Bone Miner Res, 1996, 11:1302～1311.
[72]卢来春,蒋学华,杨俊毅,等.阿莫西林对格列美脲血浆蛋白结合率的影响[J].华西药学杂志.2004, 12 (4):246～250.
[73] Klimes J, Sochor J, Zahradnicek M, et al. Simultaneous high-performance chromatographic determination of salicylates in whole blood, plasma and isolated erthrcytes[J]. J Chromatogr, 1992, 584(2):221～281.
[74]李建喜.“喹胺醇”药代动力学及非临床毒理学研究[D].北京:中国农业科学院研究生院,2006, 54,69,87.
[75]商庆节,马云淑,程欣,等.克班宁与大鼠血浆蛋白结合的初步研究[J].云南中医学院学报.2006, 29(3):14～17.
[76]邱银生,袁宗辉,范盛先,等.高效液相色谱法测定猪血浆及组织中喹赛多及其脱二氧代谢物[J].中国兽医学报. 2003, 23(4)::363～365.
[77]张继瑜.动物专用新化学药物[M].甘肃科学技术出版社.兰州:2007,237.
[78] Lynch M J, Bartolucci S R. Confirmatory identification of Car-badox-related residues in swine liver by Gas-Liquid Chro-matography/Mass Spectrometry with Selected Ion Monitoring[J]. J ASSOC OFF ANAL CHEM, 1982, 65(1):66～70.
[79] Lynch M J, Mosher F R, Scheeider R P,et al. Determination of Carbadox-related residues in swine liver by Gas Chromatogra-phy/Mass Spectrometry with Ion Trap Detection[J]. J ASSOC OFF ANAL CHEM,1991, 74(4):611～618.
[80] Graaf G J, Spierenbury T J. Liquid chromatographic determination of cyadox in medicated feeds and in the contents of thporcine gastrointestinal tract with fluorescence detection[J]. Chromatogr, 1988, 447:244～248.
[81]高迎春,魏秀丽.规模化养鸡场的用药现状及对策[J].中国兽药杂志.2006, 40(11):25～28.
[82] Li F B, Zhong J H, Tan J. Environmental impact and its control of intensive industrialized piggery in Guangdong Province[J]. Soil of the Total Environmental Sciences, 1999, 8(4):245～249.
[83] Garbarino A J, Bednar J R, Rutherford D W,et al. Environmental fate of roxrsone in poultry litter I: Degradation of roxrsone during composting[J]. Environmental Science and Technology, 2003, 37:1509～1514.
[84] Kennedy D G, Cannavan A, Robert M J. Regulatory problems caused by contamination,a frequently overlooked cause of veterinary drug residues[J]. Journal of Chromatography A,2000, 882(1/2):37～52.
[85] FSIS. Carbadox metabolite in swine tissue [M].Analytical Chemistry Laboratory Guidebook Residue Chemistry,1991, 652.
[86]陈杖榴,杨桂香,孙永学,等.兽药残留的毒性与生态毒理研究进展[J].华南农业大学学报.2001, 22(1):88～91.
[87] Liu WK. Activation of peritoneal macrophages by polysaccharopeptide from the mushroom, coriolus versicolor[J]. Immunopharmacol.1993, 26:139.
[88] Lorshach RB, Russel SW. A specific sequence of stimulation is required to induce synthesis of the antimicrobial molecule nitric oxide by mouse macrophage[J]. Infect Immun. 1992, 267:109.
[89] John SH, Femando QC, Guy HN, et al. Induction of nitric oxide sythesis in J774 cells lowers intracellular glutathione:Effect of modulated glutathione redox status on nitric oxide synthase induction[J]. Biochem J. 1997, 322:477.
[90]李剑勇,赵荣材,李金善,等.喹烯酮在猪体内的药代动力学研究[J].中国兽医科技. 2001,31(8):31～33.
[91]动物性食品中卡巴氧标示残留物检测方法——高效液相色谱法(S)农业部2003.01.22.
[92] Cox JS, Chen B, McNeil M & Jacobs WR (1999) Complex lipid determines tissue specific replication of Mycobacterium tuberculosis in mice. Nature 402: 79～83.
[93] Daffe M & Draper P (1998) The envelope layers of mycobacteria with reference to their pathogenicity. Adv Microb Physiol 39:131～203.
[94]李建晴,董川,冯小花.四种喹诺酮类药物滤纸基质室温磷光法研究[M].分析化学简报.2002, 30(6):716～760.
[95]中华人民共和国农业部(1997年).动物性食品中兽药最高残留限量(试行)[S].
[96] Rutalj M, Bazulic D, Sapunar-Postruzink J,et al. Quinoxaline-2-Carboxylic Acid (QCA) in swine liver and muscle[J]. Food Ad-dit Contam. 1996,13(8):879～882.
[97]出口肉中卡巴氧残留量检验方法.中华人民共和国进出口商品检验行业标准[S].SN 0194.1-93.
[98] De Vrics H, Bojarski J, Donker AA. Photochemical reactions of quindoxin, olaquidox, carbadox and cyadox with protein, indicating photo allergic properties[J]. Toxicology. 1990, 63: 85～95.
[2]张宏伟,王喆，刘伟.动物源性食品中兽药和饲料添加剂残留及其对人体的危害[J].兽药与饲料添加剂. 2004, 9(4):1～3.
[3]徐士新.我国新兽药开发现状及存在问题[J].中国家禽.2001, 23(22):3～8.
[4] Tracy Hampton. Furan in Foods [J]. JAMA.2004, 291:29～33.
[5]张治平.抗生素与抗菌药发展史[M].首都医药出版社.北京:2004, 2:14～16.
[6]刘学剑.抗菌药物饲料添加剂的应用[J].饲料工业.1997, 18(3):29～31.
[7]刘培哲.人类可持续生存与毒理学的发展[J].中国药理学与毒理学杂志.1997, 11(2):85～86.
[8]张治平.抗生素与抗菌药发展史[M].首都医药出版社.北京:2004, 2:21～22.
[9]陈杖榴.兽医药理学[M].中国农业出版社.第二版.北京:2004, 3.
[10]曹随忠,张力,梁剑平,等.喹喔啉-1, 4-二氧化物类抗菌促生长剂特殊毒理学研究进展[J].动物医学进展.2001, 22(2):17～20.
[11]田少雪.英国上市药品安全评价指导原则[J].中国医药导刊.2002, 4(1):75-76.
[12]中华人民共和国农业部文件.农牧发[2003]38号动物源食品中兽药残留检测方法[Z].2003.
[13]孙永学,冯淇辉,董漓波,等.喹乙醇在鸡体内的毒物动力学及其生化毒性和病理学研究[J].畜牧兽医学报,1998, 29(5):385～391.
[14]何祖健.复方利菌净注射液体外抑菌和临床治疗试验[J].广西畜牧兽医,2001, 17(6):9～17.
[15]中国兽药监察所.新兽药质量标准[S]:33～35.
[16]李剑勇,赵荣材,李金善,等.喹烯酮在猪体内的药代动力学研究[J].中国兽医科技.2001, 31(8):31～33.
[17]李剑勇,赵荣材,李金善,等.口服喹烯酮代谢动力学研究[J].中国兽药杂志.2000, 35 (3):15～18.
[18]梁剑平,张力,曹随忠,等.新型饲料添加剂喹胺醇致突变性及其潜在致癌性预测[J].中国农业科学.2001, 34(6):679～685.
[19] Food and Agriculture organization. FAO Food and Nutrition Paper[R]. Rome, 1995, 41 (17):31～44.
[20]张力,梁剑平,程富胜,等.喹胺醇对断奶仔猪的亚急性毒性试验[J].中兽医医药杂志.2001, 20(2):11～12.
[21]孙晓平,张力,梁剑平,等.喹胺醇小白鼠急性毒性试验[J].中兽医医药杂志.1999, 18(2):17～18.
[22]张力,梁剑平,周丽霞,等.喹胺醇对肉用仔鸡亚急性毒性试验[J].中国兽医科技.2001, 31(1):27～30.
[23]张力,周丽霞,梁剑平,等.喹胺醇1号和3号体外抑菌试验[J].中国兽医科技.1998, 28(7): 24～25.
[24]梁剑平,张力,周丽霞,等.新型饲料添加剂喹胺醇致突变性及其潜在致癌性预测[J].中国农业科学.2001, 34(6):679~685.
[25]周丽霞,张力,梁剑平.药物饲料添加剂喹胺醇对仔猪的增重效果试验[J].中国兽医科技.2000, (1):15~16.
[26]周丽霞,张力,梁剑平.喹胺醇抗菌试验[J].预防兽医学进展.1999, (3):64.
[27]曹香林,杨志强,梁剑平,等.喹胺醇在鸡组织的消除及残留研究[J].中兽医医药杂志.2004, (3):5~7.
[28] Stasi R, Zinnani P L, Galieni P,et a1. Clinical implications of cytokine and soluble receptor measurements in patients with newly diagnosed agressive nonHodgKin’S mphomal[J].Eur J Haematal,1995, 54:9～17.
[29]曾经泽.生物药物分析[M].北京医科大学中国协和医科大学联合出版社.北京:1998, 247～252.
[30] Carbadox gains US tolerance[J]. Animal Pharm.1998, 39:5.
[31] Anonymous.Residues of some veterinary drugs in animals and food[Z]. FAO Food and Nutrition 85～96. 19～30. 53～62.
[32] MML Aerts,WMJ Beek,HJK eukens. Determination of residues of carbadox and some of its metabolites in swine tissues by high-performance liquid chromatography using on-line pre-column enrichment and post-column derivatization with UV-VIS detection[J]. Journal of Chromatography A.1986, 105～119.
[33] GMB innendijk,MML Aerts1,HJK eukens.Optimization and ruggedness testing of the determination of residues of carbadox and metabolites in products of animal origin [J]. Journal of Chromatography A.1991, 541:401～410.
[34] Della WM Sin,Lucy P K Chung,Martin M C Lai,et al. Determination of quinoxaline-2-carboxylic acid-the major metabolite of carbadox in porcine liver by isotope dilution gas chromatography electron capture negative ionization mass spectrometry [J]. Analytica Chimica Acta.2004, 508:147～158.
[35]张均田.现代药理实验方法[M].北京医科大学中国协和医科大学联合出版社.北京:1998,689.
[36] Mosmann T.Rapid colorime tricassay forcellar grow than survival:application to proliferation and cytotoxicity assays[J]. Immunol Methods.1983, 65(1):55～63.
[37]曾振灵,董漓波,陈杖榴.喹乙醇在鸡组织的消除及残留研究[J].畜牧兽医学报.1995, 26(4), 327～333.
[38]周学辉.不同喹喔啉类抗菌促生长剂对肉鸡生产性的影响[J].中兽医医药杂志.2006, 25 (2):16～18.
[39] Dean JH, Luster MI, Munson AE,et al. Immunotoxicology and Immunopharmacology[J]. NewYork Raven.1985, 24.
[40] McConnachie R. Archives of Environmental Health[J]. JAMA.1991, 47(4):249～253.
[41] Moszczynski P. Hyg Epidemiol Microbiol Immunol[J]. JAMA.1991, 35(4):351～360.
[42]曹随忠,张力,梁剑平,等.喹喔啉-1,4-二氧化物类抗菌促生长剂特殊毒理学研究进展[J].动物医学进展.2001, 22(2):17～20.
[43] FSIS. Carbadox metabolite in swine tissue [M]. Analytical Chemistry Laboratory Guidebook Residue Chemistry, 1991, 254.
[44] Lauridsen M G,Lund C,Jacobsen M,et al. Determination and depletion of residues of Carbadox,Tylosin,and Virginiamycin in kidney,liver,and muscle of pigs in feeding experiments[J]. J ASSOC OFF ANAL CHEM,1988, 7(5):921～925.
[45] Rose M D, Bygrave J, Tarbin J A.Determination of quinoxaline carboxylic acid(metabolite of Carbodox)in animal tissue by HPLC[J]. Food Addit Contam,1995, 12(2):177～183.
[46] The International SNP Map Working Group. A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms [J]. Nature.2001, 409:928～933.
[47]王玉春,严相林,赵荣材,等.新型药物饲料添加剂喹烯酮的一般毒性研究[J].中兽医医药杂志.1992, 18(1):16～19.
[48] Hertzberg RC , MacDonell MM. Synergy and other ineffective mixture risk Definitions.Sci Total Environ [J]. JAMA.2002, 47(4): 31～42.
[49]王立.色谱分析样品处理[M].化学工业出版社.北京:2000, 52.
[50] Federal Register[Z]. 37 FR 20683. 1972.
[51] Food and Agriculture organization. FAO Food and Nutrition Paper[R]. Rome:1995, 41 (17): 31～44.
[52] Graaf G J, Spierenbury T J. Liquid chromatographic determination of cyadox in medicated feeds and in the contents of thporcine gastrointestinal tract with fluorescence detection[J]. ChromatogrB 1988, 44(7):244～248.
[53] Graaf G J, Jager L P, Baarsen A J, et al.Some pharmacokineti observation of carbadox medication in pigs [J]. Vet Quart.1988, 10(1):34～41.
[54] Macintosh A I, George A N. Liquid chromatographic determination of carbadox, desoxycarbodox and nitrofurazones in portissues[J]. J ASSOC OFF ANAL CHEM.1984, 67(5):958～962.
[55]乔莉萍.新兽药“喹胺醇”对小鼠免疫机能影响的研究[D].中国农业科学院研究生院,北京:2006, 32.
[56]张丰景.断奶仔猪饲料中添加剂痢菌净试验[J].上海畜牧兽医通讯,1998, 1:17～18.
[57]李剑勇,赵荣材,李金善,等.喹烯酮在猪体内的药代动力学研究[J].中国兽医科技.2001,31(8):31～33.
[58] Robin LS, Martinsky T, Schena M. Trends in microarray analysis [J]. Technology Trends ,2003 ,9(1):140～145.
[59] Heijne WH , Stierum RH , Slijper M, et al. Toxicogenomics of bromobenzene hepatotoxicity: acombined transcrip tomics and proteomics approach[J].Biochem Pharmacol.2003, 65(5) :857～875.
[60] Schmidt CW. Toxicogenomics an emerging discipline[J].Environ Health Perspect, 2002 ,110(12):750～755.
[61] Hutchinson M J, Young P B, Kennedy D G. Confirmation of carbadox and olaquindox metabolites in porcine liver using liquid chromatography-electrospray, tandem mass spectrometry[J]. J Chromatogr B, 2005, 816: 15～20.
[62]曹香林,杨志强,梁剑平,等.喹胺醇在鸡组织的消除及残留研究[J].中兽医医药杂志.2004, 28(3):5～7.
[63]周丽霞,张力,梁剑平,等.喹胺醇在鸡体内残留分析[J].中国预防兽医学报.2000, 22(1):75～76.
[64]李建喜,杨志强,梁剑平,等.喹胺醇在猪体内的药代动力学研究[A].中国畜牧兽医学会兽医药理毒理学分会第九次学术讨论会论文集[C].安徽:2005, 167.
[65]陈秋潮.实用临床新药手册[M].上海科技文献出版社.上海:1991, 386.
[66]张君仁.体内药物分析[M].化学工业出版社.北京:2002, 15～18.
[67]徐叔云,卞如濂,陈修.药理学实验方法[M].人民卫生出版社.北京:1982, 441～445
[68]罗芳洪,黄自强.13-甲基豆蔻酸在大鼠体内的药代动力学研究[J].西北药学杂志.2003, 31(1):16～19.
[69]王弘,陈济民,张清民.用高效液相色谱法测定人血浆中黄芩苷与血浆蛋白的结合率[J].沈阳药科大学学报.2000, 17(2):107～109.
[70] Midgley I, Chasseaud L F , Taylor T. The absorption and excretion of 14C-lofexidine hydrochloride in man [J]. Arzneim-forsch. / Drug Res, 1982, 32 (2):972～975.
[71] Boivin G, Deloffre P, Perrat B,et al.Strontium distribution and interactions with bonemineral in monkey iliac bone after strontium salt (S12911) adminstration[J].Bone Miner Res, 1996, 11:1302～1311.
[72]卢来春,蒋学华,杨俊毅,等.阿莫西林对格列美脲血浆蛋白结合率的影响[J].华西药学杂志.2004, 12 (4):246～250.
[73] Klimes J, Sochor J, Zahradnicek M, et al. Simultaneous high-performance chromatographic determination of salicylates in whole blood, plasma and isolated erthrcytes[J]. J Chromatogr, 1992, 584(2):221～281.
[74]李建喜.“喹胺醇”药代动力学及非临床毒理学研究[D].北京:中国农业科学院研究生院,2006, 54,69,87.
[75]商庆节,马云淑,程欣,等.克班宁与大鼠血浆蛋白结合的初步研究[J].云南中医学院学报.2006, 29(3):14～17.
[76]邱银生,袁宗辉,范盛先,等.高效液相色谱法测定猪血浆及组织中喹赛多及其脱二氧代谢物[J].中国兽医学报. 2003, 23(4)::363～365.
[77]张继瑜.动物专用新化学药物[M].甘肃科学技术出版社.兰州:2007,237.
[78] Lynch M J, Bartolucci S R. Confirmatory identification of Car-badox-related residues in swine liver by Gas-Liquid Chro-matography/Mass Spectrometry with Selected Ion Monitoring[J]. J ASSOC OFF ANAL CHEM, 1982, 65(1):66～70.
[79] Lynch M J, Mosher F R, Scheeider R P,et al. Determination of Carbadox-related residues in swine liver by Gas Chromatogra-phy/Mass Spectrometry with Ion Trap Detection[J]. J ASSOC OFF ANAL CHEM,1991, 74(4):611～618.
[80] Graaf G J, Spierenbury T J. Liquid chromatographic determination of cyadox in medicated feeds and in the contents of thporcine gastrointestinal tract with fluorescence detection[J]. Chromatogr, 1988, 447:244～248.
[81]高迎春,魏秀丽.规模化养鸡场的用药现状及对策[J].中国兽药杂志.2006, 40(11):25～28.
[82] Li F B, Zhong J H, Tan J. Environmental impact and its control of intensive industrialized piggery in Guangdong Province[J]. Soil of the Total Environmental Sciences, 1999, 8(4):245～249.
[83] Garbarino A J, Bednar J R, Rutherford D W,et al. Environmental fate of roxrsone in poultry litter I: Degradation of roxrsone during composting[J]. Environmental Science and Technology, 2003, 37:1509～1514.
[84] Kennedy D G, Cannavan A, Robert M J. Regulatory problems caused by contamination,a frequently overlooked cause of veterinary drug residues[J]. Journal of Chromatography A,2000, 882(1/2):37～52.
[85] FSIS. Carbadox metabolite in swine tissue [M].Analytical Chemistry Laboratory Guidebook Residue Chemistry,1991, 652.
[86]陈杖榴,杨桂香,孙永学,等.兽药残留的毒性与生态毒理研究进展[J].华南农业大学学报.2001, 22(1):88～91.
[87] Liu WK. Activation of peritoneal macrophages by polysaccharopeptide from the mushroom, coriolus versicolor[J]. Immunopharmacol.1993, 26:139.
[88] Lorshach RB, Russel SW. A specific sequence of stimulation is required to induce synthesis of the antimicrobial molecule nitric oxide by mouse macrophage[J]. Infect Immun. 1992, 267:109.
[89] John SH, Femando QC, Guy HN, et al. Induction of nitric oxide sythesis in J774 cells lowers intracellular glutathione:Effect of modulated glutathione redox status on nitric oxide synthase induction[J]. Biochem J. 1997, 322:477.
[90]李剑勇,赵荣材,李金善,等.喹烯酮在猪体内的药代动力学研究[J].中国兽医科技. 2001,31(8):31～33.
[91]动物性食品中卡巴氧标示残留物检测方法——高效液相色谱法(S)农业部2003.01.22.
[92] Cox JS, Chen B, McNeil M & Jacobs WR (1999) Complex lipid determines tissue specific replication of Mycobacterium tuberculosis in mice. Nature 402: 79～83.
[93] Daffe M & Draper P (1998) The envelope layers of mycobacteria with reference to their pathogenicity. Adv Microb Physiol 39:131～203.
[94]李建晴,董川,冯小花.四种喹诺酮类药物滤纸基质室温磷光法研究[M].分析化学简报.2002, 30(6):716～760.
[95]中华人民共和国农业部(1997年).动物性食品中兽药最高残留限量(试行)[S].
[96] Rutalj M, Bazulic D, Sapunar-Postruzink J,et al. Quinoxaline-2-Carboxylic Acid (QCA) in swine liver and muscle[J]. Food Ad-dit Contam. 1996,13(8):879～882.
[97]出口肉中卡巴氧残留量检验方法.中华人民共和国进出口商品检验行业标准[S].SN 0194.1-93.
[98] De Vrics H, Bojarski J, Donker AA. Photochemical reactions of quindoxin, olaquidox, carbadox and cyadox with protein, indicating photo allergic properties[J]. Toxicology. 1990, 63: 85～95.