环糊精包合氟苯尼考在猪体内的药代动力学研究

doi:10.16431/j.cnki.1671-7236.2020.06.033

摘要/Abstract

摘要： 为评价采用新包被工艺生产的氟苯尼考（受试制剂F）与国外同类产品（R1）、国内同类产品（R2）在猪体内的生物等效性并探索其药代动力学特性，本试验采用随机三制剂、三周期自身交叉试验设计，选取6头健康的阉割小公猪（体重15 kg±2 kg），分别灌胃给药3种制剂，给药剂量为20 mg/（kg·BW），采用高效液相色谱法测定血浆中氟苯尼考浓度，利用Kinetica 5.0软件分析药代动力学特性，SAS统计软件进行生物等效性评价。结果显示，受试制剂在猪体内的药时曲线符合带时滞的一级吸收一室开放模型，F、R1、R2的峰浓度（C_max）分别为16.0845、18.3287和21.1678 μg/mL，药物达峰时间（T_max）分别为5.0、1.9、1.5 h；药-时曲线下面积_（0-∞）（AUC_0-∞）分别为144.7327、118.2670和123.3715 μg/mL·h；受试制剂相比于两种参比制剂的相对生物利用度分别为122.51%（R1）和117.52%（R2）。结果表明，环糊精包被氟苯尼考有更好的缓释作用，具有更好的生物安全性，药效维持时间长，生物利用度有效提高。

关键词: 环糊精包合氟苯尼考; 猪; 高效液相色谱法; 药代动力学; 生物等效性

Abstract: In order to evaluate the bioequivalence of flufenicol (test reagent F) produced by the new coating process with the similar foreign products (R1) and domestic products (R2),and to explore its pharmacokinetic characteristics in pigs.The design of random triplet and triplet self-crossing test was adopted.Six healthy castrated male pigs (15 kg±2 kg) were respectively to take three formulations by oral administration (20 mg/kg).Flufenicol plasma concentration was analyzed by high performance liquid chromatography.Pharmacokinetic characteristics were analyzed by Kinetica 5.0,and bioequivalence was evaluated by SAS statistical software.The results showed that the drug time curve of the tested preparation in pigs conformd to the first-order absorption one-chamber open model.The C_max of F,R1 and R2 were 16.0845,18.3287 and 21.1678 μg/mL respectively,T_max were 5.0,1.9 and 1.5 h respectively;AUC_0-∞ were 144.7327,118.2670 and 123.3715 μg/mL·h,respectively.The relative bioavailability of the two reference preparations was 122.51% (R1) and 117.52% (R2),respectively.The results showed that cyclodextrin coated with flurbenicol had better sustained-release effect,better biosafety,longer duration of efficacy,and higher bioavailability.

Key words: cyclodextrin inclusion flurbenicol; pig; high performance liquid chromatography; pharmacokinetics; bioequivalence

中图分类号:

S859.79

张乐, 张广峰, 朱崇淼, 吴植, 朱善元, 于生兰, 封琦, 邢晓玲, 赵倩楠. 环糊精包合氟苯尼考在猪体内的药代动力学研究[J]. 中国畜牧兽医, 2020, 47(6): 1934-1941.

ZHANG Le, ZHANG Guangfeng, ZHU Chongmiao, WU Zhi, ZHU Shanyuan, YU Shenglan, FENG Qi, XING Xiaoling, ZHAO Qiannan. Study on Pharmacokinetics of Cyclodextrin-encapsulated Flufenicol in Pigs[J]. China Animal Husbandry and Veterinary Medicine, 2020, 47(6): 1934-1941.

参考文献

[1] 李洪权,柏玉冰,宋忠祥,等.动物源性食品中氟苯尼考残留水平和分布情况分析[J].食品安全质量检测学报,2019,10(2):426-433. LI H Q,BAI Y B,SONG Z X,et al.Analysis of the levels and distribution of florfenicol residue in animal-origin food[J].Journal of Food Safety and Quality,2019,10(2):426-433.(in Chinese)
[2] 张春辉,邢广旭,胡骁飞,等.动物专用药物氟苯尼考的研究进展[J].中兽医医药杂志,2019,38(5):95-98. ZHANG C H,XING G X,HU X F,et al.Reviewed on the animal medicine florfenicol[J].Journal of Traditional Chinese Veterinary Medicine,2019,38(5):95-98.(in Chinese)
[3] ORLANDO E A,COSTA R A G,LOSEKANN M E,et al.UPLC-MS/MS determination of florfenicol and florfenicol amine antimicrobial residues in tilapia muscle[J].Journal of Chromatography B,2016,1035:8-15.
[4] BARRETO F,RIBEIRO C,BARCELLOS H R,et al.Determination of chloramphenicol,thiamphenicol,florfenicol and florfenicol amine in poultry,swine,bovine and fish by liquid chromatography-tandem mass spectrometry[J].Journal of Chromatography. A,2016,1449:48-53.
[5] DOREY L,HOBOSON S,LEES P.Potency of marbofloxacin for pig pneumonia pathogens Actinobacillus pleuropneumoniae and Pasteurella multocida:Comparison of growth media[J].Research in Veterinary Science,2017,111:43-48.
[6] DAWAR R,NAGARJUNA D,GUPTA R,et al.Actinobacillus ureae:An unusual cause of tree-in-bud pattern in a case of pneumonia on lung computed tomographic scan-first clinical case report and review of the literature from India[J].New Microbes and New Infections,2016,14:69-72.
[7] WANG G T,WAN B,ZHAO X,et al.Determination of thiamphenicol,florfenicol and florfenicol amine residues in poultry meat and pork via ASE-UPLC-FLD[J].Journal of Food Composition and Analysis,2019,81:19-27.
[8] ACHARD D,CARUSO V A,COLLIN J F,et al.Treatment of experimentally induced bovine respiratory disease in young calves with a single administration of a combination of florfenicol and meloxicam[J].Veterinary Record,2018,183(17):535.
[9] OULTRAM J,PHIPPS E,TEIXEIRA A G V,et al.Effects of antibiotics (oxytetracycline,florfenicol or tulathromycin on neonatal calves faecal microbial diversity[J].Veterinary Record,2015,177(23):598.
[10] YANG F,LIN Z,RIVIERE J E,et al.Development and application of a population physiologically based pharmacokinetic model for florfenicol and its metabolite florfenicol amine in cattle[J].Food and Chemical Toxicology,2019,126:285-294.
[11] 程培培,杨亚军,刘希望,等.新型复方氟苯尼考注射液中氟尼辛葡甲胺含量测定方法研究[J].河南农业科学,2014,43(3):142-146. CHENG P P,YANG Y J,LIU X W,et al.Content determination of flunixin meglumin in a novel compound florfenicol injection by high performance liquid chromatography[J].Journal of Henan Agricultural Sciences,2014,43(3):142-146.(in Chinese)
[12] 刘芳.两种氟苯尼考粉剂在鸡体内的药动学比较研究[D].扬州:扬州大学,2016. LIU F.Two kinds of forfenicol powder in pharmacokinetics studies in chickens[D].Yangzhou:Yangzhou University,2016.(in Chinese)
[13] 杨宝亭,王庚南,黄康东,等.氟苯尼考-羟丙基-β-环糊精包合物的研制[J].中国畜牧兽医,2017,44(6):1854-1860. YANG B T,WANG G N,HUANG K D,et al.Preparation and identification of florfenicol-hydroxypropyl-β-cyclodextrin[J].China Animal Husbandry & Veterinary Medicine,2017,44(6):1854-1860.(in Chinese)
[14] WANG B,XIE X,ZHAO X.Development of an accelerated solvent extraction-ultra-performance liquid chromatography-fluorescence detection method for quantitative analysis of thiamphenicol,florfenicol and florfenicol amine in poultry eggs[J].Molecules (Basel,Switzerland),2019,24(9):1830.
[15] 刁志祥,张培杨,王旭堂,等.加速溶剂萃取/超高效液相色谱-荧光法检测猪肉中氟苯尼考和氟苯尼考胺残留[J].中国畜牧兽医,2019,46(9):2753-2759. DIAO Z Y,ZHANG P Y,WANG X T,et al.Determination of flufenicol and flufenicol residues in pork by accelerated solvent extraction/ultra high performance liquid chromatography-fluorescence[J].China Animal Husbandry & Veterinary Medicine,2019,46(9):2753-2759.(in Chinese)
[16] NASIM A,ASLAM B,JAVED I,et al. Determination of florfenicol residues in broiler meat and liver samples using RP-HPLC with UV-visible detection(Article)[J].Journal of the Science of Food and Agriculture,2016,96(4):1284-1288.
[17] ROSA E G,CAROLINA N,EWELINA P,et al.Determination of florfenicol,thiamfenicol and chloramfenicol at trace levels in animal feed by HPLC-MS/MS[J].Antibiotics (Basel),2019,8(2):59.
[18] 李广.氟苯尼考及氟苯尼考胺药物残留检测方法及应用[J].辽宁农业科学,2019,5:59-62. LI G.Method and application of florfenicol and florfenicol drug residue detection[J].Liaoning Agricultural Sciences,2019,5:59-62.(in Chinese)
[19] 时菲菲,王婧,秦枫,等.新型兽用纳米乳载药系统在大鼠体内的药代动力学研究[J].中国畜牧兽医,2019,46(4):1236-1243. SHI F F,WANG J,QIN F,et al.Study on pharmacokinetics of a novel veterinary nanoemulsion drug loading system in rats[J].China Animal Husbandry & Veterinary Medicine,2019,46(4):1236-1243.(in Chinese)
[20] 刘凡.氟苯尼考纳米制剂的制备及其药效学评价[D].长沙:湖南农业大学,2016. LIU F.Preparation of flufenicol nano-agents and its pharmacodynamics evaluation[D].Changsha:Hunan Agricultural University,2016.(in Chinese)
[21] 刘怀珠,张建平,胡海英,等.高效氟苯尼考粉剂研究[J].中国兽医杂志,2014,50(6):76-79. LIU H Z,ZHANG J P,HU H Y,et al.Study on high efficiency flufenicol powder[J].Chinese Journal of Veterinary Medicine,2014,50(6):76-79.(in Chinese)
[22] 胡亚南.氟苯尼考、恩诺沙星及替米考星微囊在猪体内的药物动力学研究[D].杨凌:西北农林科技大学,2011. HU Y N.Study on the pharmacokinetics of flurbenicol,enoxacin and timicorin microcapsules in pigs[D].Yangling:Northwest A&F University,2011.(in Chinese)
[23] VOORSPOELS J,D'HAESE E,DE CRAENE B A,et al.Pharmacokinetics of florfenicol after treatment of pigs with single oral or intramuscular doses or with medicated feed for three days[J].Veterinary Record,1999,145(14):397-399.