氟苯尼考论文：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.doc

氟苯尼考论文：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【中文摘要】本试验旨在研究氟苯尼考、恩诺沙星及替米考星的新型制剂微囊,给猪灌服之后,在猪体内的药物动力学参数。比较微囊制剂与其原粉的优缺点,为兽医临床合理用药提供理论依据。1.氟苯尼考微囊在猪体内的药物动力学试验分析氟苯尼考微囊（Florfenicol Microcapsules,FM）和氟苯尼考原粉（Florfenicol,FF）在猪体内的药物代谢动力学过程。猪单剂量分别灌服FF和FM 30 mgkg-1,36 h不同时间16次前腔静脉采血,高效液相色谱法（HPLC）测定血药中FF的浓度。结果表明,FM和FF在猪体内的药物动力学配置均符合有吸收因素一室开放模型,其药-时曲线最佳方程分别为:CFM=3.772 7(e0.047t-e0.8477t),CFF =0.375 9 (e0.2581t-e4.670 9t)。微囊及原粉的主要药物动力学参数:吸收半衰期t1/2Ka分别为（0.944 60.507 5） h,（0.155 00.030 1） h;消除半衰期t1/2Ke分别为（15.214 03.024 9） h,（2.694 50.169 5） h;药-时曲线下面积AUC分别为（77.311 113.312 7）mgL-1h,（1.374 70.606 0） mgL-1h;峰质量浓度分别为（2.937 10.232 2） mgL-1,（0.298 30.023 9） mgL-1;达峰时间分别为（3.951 01.533 9） h,（0.675 30.104 6） h。通过比较,说明FM口服给药吸收较慢但完全,达峰时间较长,消除缓慢,能够发挥长效作用。2.恩诺沙星微囊在猪体内的药物动力学试验分析了恩诺沙星微囊（Enrofloxacin Microcapsules, EM）和恩诺沙星原粉（Enrofloxacin, ENR）在猪体内的药物代谢动力学过程。猪单剂量分别灌服EM和ENR 30 mgkg-1,72 h不同时间18次前腔静脉采血,HPLC测定猪血浆中ENR的浓度。结果表明,6头猪灌服EM和ENR后,其药动学配置均符合有吸收因素二室药代动力学模型。最佳药时曲线方程为:CEM=11.326 3e-0.353 8t+5.420 6 e-0.0661t-16.746 9e-0.979 8t和CENR=11.251 1e-0.934 7t+5.330 1e-0.079 9t-16.581 2e-2.965 7t。EM在猪体内的吸收相半衰期t1/2ka为（0.769 50.250 9） h,分布相半衰期t1/2a为（2.160 30.704 1） h,消除相半衰期t1/2为（10.522 40.719 5） h,AUC为（92.924 35.308 4） mgL-1h。通过其与原粉的比较,表明EM在猪体内吸收缓慢,达峰时间长,消除相对较慢,能够较长时间维持血药浓度。3.替米考星微囊在猪体内的药物动力学试验分析了替米考星微囊（Tilmicosin Microcapsules,TM）和替米考星原粉（Tilmicosin,TMS）在猪体内的药物代谢动力学过程。猪单剂量分别灌服TM和TMS 30 mgkg-1,72 h不同时间18次前腔静脉采血,HPLC测定猪血浆中TMS的浓度。结果显示,6头猪灌服微囊和原粉后,其药动学配置均符合有吸收因素二室药代动力学模型。最佳药时曲线方程为:CTM =5.927 7e-0.444 8t+2.641 7e-0.051t-8.579 4e-2.471 4t和C TMS =5.083e-1.233t+2.366 4e-0.086 4t-7.449 4e-6.585 7t。TM在猪体内的t1/2ka为（0.2910.057） h,t1/2a为（1.9540.267） h,t1/2为（13.6020.611） h,AUC为（61.3443.371） mgL-1h。表明TM在猪体内吸收缓慢完全,消除相对较慢,能较长时间发挥药效。【英文摘要】The purpose of this study was to get the pharmacokinetic parameters of the new dosage forms of florfenicol, enrofloxacin, and tilmicosin, after a single oral administration in pigs. Compared with their original powder, then provided theoretical basis for rational drug use.1. Pharmacokinetic parameters of Florfenicol Microcapsules （FM） and Florfenicol in 6 pigs were calculated.Pigs were treated with a single dosage of FF (30 mgkg-1) orally, while the blood samples were collected from precaval vein within 36 hour after giving drug. The concentrations of FF in serum were determined by high performance liquid chromatography （HPLC）. The result showed that the one-compartment open modle with first-order absorption factor adequately describes concentrations of FM and FF in serum disposition and best concentration-time equations are: CFM=3.772 7 (e0.047t-e0.8477t), CFF=0.375 9(e-0.258 1t-e-4.670 9t). The primary pharmacokinetic parameters of FM and FF are: t1/2Ka=（0.944 60.507 5） h and （0.155 00.030 1） h, t1/2Ke=（15.214 03.024 9） h and （2.694 50.169 5） h, AUC=（77.311 113.312 7） mgL-1h and（1.374 70.606 0） mgL-1h, Cmax=（2.937 10.232 2） mgL-1 and （0.298 30.023 9） mgL-1h, Tmax=（3.951 01.533 9） h and （0.675 30.104 6） h. It will be seen that Florfenicol microcapsules was completely absorbed with a slowly absorption rate, and which was eliminated slowly in the blood after single oral administration.2. Pharmacokinetic parameters of Enrofloxacin Microcapsules（EM） and Enrofloxacin （ENR） in 6 pigs were calculated.Pigs were treated with a single dosage of ENR (30 mgkg-1) orally, while the blood samples were collected from precaval vein within 72 hour after giving drug. The concentrations of ENR in serum were determined by HPLC. The result showed that the two-compartment open modle with first-order absorption factor adequately describes concentrations of EM and ENR in serum disposition and best concentration-time equations are: CEM=11.326 3e-0.353 8t+5.420 6e-0.066 1t-16.746 9e-0.979 8t, CENR=11.251 1e-0.934 7t+5.330 1e-0.079 9t-16.581 2e-2.965 7t. The primary pharmacokinetic parameters of EM are: t1/2ka=（0.769 50.250 9） h; t1/2a=（2.160 30.704 1） h; t1/2=（10.522 40.719 5） h; AUC=（92.924 35.308 4） mgL-1h. It will be seen that EM was completely absorbed with a slowly absorption rate, and which was eliminated slowly in the blood after single oral administration.3. Pharmacokinetic parameters of Tilmicosin Microcapsules（TM） and Tilmicosin （TMS） in 6 pigs were calculated.Pigs were treated with a single dosage of TMS (30 mgkg-1) orally ,while the blood samples were collected from precaval vein within 72 hour after giving drug. The concentrations of TMS in serum were determined by HPLC. The result showed that the two-compartment open modle with first-order absorption factor adequately describes concentrations of TM and TMS in serum disposition and best concentration-time equations are: CTM =5.927 7e-0.444 8t+2.641 7e-0.051 0t-8.579 4e-2.471 4t, C TMS =5.083e-1.233 0t+2.366 4e-0.086 4t-7.449 4e-6.585 7t The primary pharmacokinetic parameters of tilmicosin microcapsules are: t1/2ka=（0.2910.057） h; t1/2a=（1.9540.267） h; t1/2=（13.6020.611） h; AUC=（61.3443.371） mgL-1h. It will be seen that tilmicosin microcapsules was completely absorbed with a slowly absorption rate, and which was eliminated slowly in the blood after single oral administration.【关键词】氟苯尼考 恩诺沙星 替米考星 微囊 药动学 猪【英文关键词】Florfenicol Enrofloxacin Tilmicosin Microcapsules Pharmacokinetics Pigs【目录】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摘要5-7ABSTRACT7-8第一章 文献综述13-301.1 氟苯尼考的研究概况13-171.1.1 氟苯尼考的理化性质131.1.2 氟苯尼考的化学结构13-141.1.3 氟苯尼考的抗菌活性141.1.4 氟苯尼考的作用机理141.1.5 氟苯尼考的药动学特点14-151.1.6 氟苯尼考的毒副作用15-161.1.7 氟苯尼考的检测方法161.1.8 氟苯尼考的临床应用16-171.2 恩诺沙星的研究概况17-221.2.1 恩诺沙星的理化性质171.2.2 恩诺沙星的化学结构17-181.2.3 恩诺沙星的抗菌活性18-191.2.4 恩诺沙星的作用机理191.2.5 恩诺沙星的药动学特点19-201.2.6 恩诺沙星的毒副作用20-211.2.7 恩诺沙星的检测方法211.2.8 恩诺沙星的临床应用21-221.3 替米考星的研究概况22-271.3.1 替米考星的理化性质221.3.2 替米考星的化学结构22-231.3.3 替米考星的抗菌活性23-251.3.4 替米考星的作用机理251.3.5 替米考星的药动学特点25-261.3.6 替米考星的毒副作用261.3.7 替米考星的检测方法26-271.3.8 替米考星的临床应用271.4 微囊的研究概况27-301.4.1 药物微囊制剂研究进展271.4.2 微囊发展史27-281.4.3 微囊的作用281.4.4 微囊在兽药新剂型方面应用28-291.4.5 展望29-30第二章 氟苯尼考微囊在猪体内的药物动力学研究30-382.1 试验材料302.1.1 试验仪器302.1.2 试验动物302.1.3 供试药品302.2 试验方法30-312.2.1 色谱条件302.2.2 给药方法及采血时间30-312.2.3 血浆样品预处理312.2.4 标准曲线的绘制312.2.5 精密度测定312.2.6 回收率的测定312.2.7 猪血浆中氟苯尼考浓度的测定312.2.8 药物动力学参数计算312.3 结果与分析31-362.3.1 标准曲线的绘制31-322.3.2 精密度的测定结果322.3.3 回收率的测定结果32-332.3.4 猪血浆中氟苯尼考浓度的实测值及血浆样品检测的色谱图33-342.3.5 猪体内血药浓度测定值34-352.3.6 氟苯尼考微囊和原粉在猪体内的药物动力学方程的拟合35-362.3.7 氟苯尼考微囊在猪体内的药物动力学参数的计算结果362.4 讨论与结论36-372.4.1 氟苯尼考血药浓度的测定36-372.4.2 氟苯尼考两种剂型在猪体内的药物动力学模型372.4.3 氟苯尼考微囊在猪体内的药动学特征372.5 小结37-38第三章 恩诺沙星微囊在猪体内的药物动力学研究38-463.1 材料与方法383.1.1 试验仪器383.1.2 试验动物383.1.3 供试药品383.2 试验方法38-393.2.1 色谱条件383.2.2 给药方法及采血时间383.2.3 血浆样品预处理38-393.2.4 标准曲线的绘制393.2.5 精密度测定393.2.6 回收率的测定393.2.7 猪血浆中恩诺沙星浓度的测定393.2.8 药物动力学参数计算393.3 结果与分析39-453.3.1 标准曲线的绘制39-403.3.2 精密度的测定结果403.3.3 回收率的测定结果40-413.3.4 猪血浆中恩