抗生素类药物和人血清白蛋白相互作用的研究
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摘要
有关药物小分子与生物大分子方面的研究,是生物化学领域的重要研究内容,特别是血清蛋白与药物分子相互作用方面,研究甚为广泛。作为生物体血浆中含量最丰富的运输蛋白质,血清白蛋白具有维持血液胶体渗透压,清除自由基等生理学和药理学功能。它可以存储和运输许多内源性和外源性物质如氨基酸、阴阳离子、类固醇激素、药物等。因此,在毒理学和药代动力学上,对于药物等小分子与SA的相互作用机理的研究,具有十分重要的意义。本论文综合利用荧光光谱法、高效液相色谱法对药物小分子与血清蛋白相互作用进行研究。
第一章：抗生素药物与人血清白蛋白相互作用的文献综述。介绍了抗生素药物的定义及分类,人血清白蛋白的晶体结构及功能特点,并详细叙述了研究药物小分子与蛋白质相互作用所采用的方法,以及各种方法的原理。因抗生素药物发挥药效均需通过血清白蛋白的贮存与运输,到达受体部位,进而发生药理作用,所以研究抗生素药物与人血清白蛋白相互作用,对新药研发、配伍禁忌等方面提供参考。
第二章：在pH=7.30的Tris-HC1缓冲溶液,运用荧光光谱法研究了头孢哌酮(CPZ)和乳酸环丙沙星(CFLX)单独存在与同时存在时和人血清白蛋白(HSA)的相互作用机理,实验结果表明,头孢哌酮、乳酸环丙沙星单独与HSA相互作用时,药物与蛋白荧光的猝灭属于静态猝灭,测定了20℃和37℃时头孢哌酮、乳酸环丙沙星与HSA结合常数分别为(O.18X103L·mol-1,0.11X103L·mol-1)和(1.79X103L·mol01,0.42X103L·mol01)、热力学参数平均值(△HCPZ=-20.4kJ·mol-1,△HCFLX=-60.3kJ· mol-1)、作用位点数nCPZ (0.63和0.57),nCFLX(0.65和0.75)。本章还研究了头孢哌酮、乳酸环丙沙星共存时与HSA的相互作用。结果表明,头孢哌酮与乳酸环丙沙星之间存在相互作用,使得药物与蛋白间的结合常数增大,结合稳定性升高,游离药物含量减少,造成药效降低。
第三章：通过对色谱条件的选择及优化,建立了采用高效液相色谱-荧光检测分析法测定阿莫西林。本文所建立的样品分析方法线性范围为2.5μ g/ml～2000μ g/ml,线性回归方程：Y=1.5×106X+29.105,相关系数r=0.9995；日内和日间RSD<5.0%。与药典中高效液相色谱-紫外检测分析方法相比,线性范围更宽,检测限相当,响应时间短,方法更准确、可靠。
第四章：运用测定药物游离浓度的方法——超滤法,结合高效液相色谱荧光检测分析法对阿莫西林与人血清蛋白的结合率进行测定分析。经实验结果表明：阿莫西林与人血清白蛋白在20.0.50.0.80.0.120.0μ mol/L下的血浆蛋白结合率分别为37.5%、39.7%、36.15%、34.53%。同时测定了阿莫西林与人血清白蛋白相互作用的结合常数为0.679×103,结合位点数为1.04,与文献中采用荧光猝灭法测定的结果基本相符。
第五章：用紫外可见吸收光谱、荧光光谱研究了羟丙基-β-环糊精与头孢噻肟的包合作用。利用荧光光谱法测定了35℃、45℃和55℃下,羟丙基-β-环糊精对头孢噻肟的包合稳定常数为84.4L.mol-1,60.8L·mol-1,45.6L·mol-1,包合比为1：1。并探讨了pH为4.0,5.0,6.5,7.5时HP-B-CD与头孢噻肟的包合常数为31.9L·mol-1,29.8L·mol-1,32.8L·mol-1,17.3L·mol-1。从实验结果可以得知：羟丙基-β-环糊精对头孢噻肟的包合效果不理想。
It is important for investigation of interaction between Small drug molecules and biological macromolecule in the field of chemical biology, especially study on interaction between serum protein and drug molecular is wider. Serum albumin is the most abundant transport protein in the circulatory system, it possess many important physiological and pharmacological functions,such as maintaining blood pressure and removing free radicals. It serves as a transport and storage carrier for many endogenous and exogenous ligands such as fatty acids, amino acids, hormones, ions and drugs.Therefore, to study the mechanism and process of interactions of the toxicity of substances, drugs and other small ligand with SA has important significance in toxicology and pharmacokinetics.The thesis comprehensivly utilize of fluorescence spectroscopy, high-performance liquid chromatography to carry out my research。
Chapter Ⅰ:Review.This chapter briefly introduced the definition and classification of antibiotic drugs,described the structure and function of the protein,at the same time,the research methods of the drug-HSA interaction in detail were summarized as well as the principle and application of a varitey of metheds.Because antibiotic drugs required the storage and transport of serum albumin before arriving at the receptor site to make efficacy,so study on interaction between antibiotic drugs and human serum albumin can provide the reference to the research and development of new drugs.
Chapter Ⅱ:The binding interaction of two antibiotics,cefoperazone(CPZ) and ciprofloxacinlactate(CFLX), with human serum albumin were investigated by fluorescence spectroscopy in this study.The results indicated that the combination reaction of them was a single static quenching process. In Tris-HCl buffer solution of pH=7.30,CPZ and CFLX combined strongly with HSA at26℃and37℃, respectively. The binding constants (0.18x103L·mol-1,0.11x103L·mol-1)and(1.79x103L·mol-1,0.42x103L·mol-1),th e average thermodynamic parameters (ΔHCPZ=-20.4kJ·mol-1ΔHCFLx=-60.3kJ·mol-1),the binding sites number nCPZ(0.63,0.57),nCFLx(0.65,0.75) were measured.Also the analysis of quenching of fluorescence of HSA is investigated when CPZ and CFLX coexisted.Under experiments, studies were established on the interaction between CPZ and CFLX by fluorescence spectrum. It was proved that the interaction between the drugs increase the binding stability of the drug and protein.At the same time, the prescence of one drug would make the binding of another drug with HSA easier,which indicated that free drug concentration at targets could decrease and the efficacy of the drugs could be reduced.
Chapter III:A high performance liquid chromatography-fluorescece detection method for the determination of amoxicillin is established.The standard curve was linear in the range from2.5μg to2000μg/ml,The recursive equation was shown in the following way:Y=1.5x106X+29.105, r=0.9991,The limit of quantitation (LOQ) of IQ in the samples was2.5μg/ml. The intra-day and inter-day RSDs were less than5.0%. Compared with the high performance liquid chromatography with UV detection,the developed method was more specific, accurate and sensitive.
Chapter IV:The ultrafiltration combined with the high performance chromatography-fluorescece detection was employed to determine the plasma protein binding rate of amoxicillin.The experimental results show that:the binding rate of amoxicillin with HSA at the concentration of20.0、50.0、80.0、120.0μmol/L were37.5%、39.7%、36.15%、34.53%,respectively.The binding constant of amoxicillin and HSA is0.679x103,the number of binding sites is1.04, which was similar to that reported with the method of fluorescece quenching in the literature.
Chapter V:The formation of the inclusion complex of cefotaxime with hydroxypropyl-β-cyclodextrin(HP-β-CD) was studied by steady-state fluorescence,UV-vis absorption spectroscopy.The stability constants(K) between HP-β-CD and cefotaxime were84.4L·mol-1,60.8L·mor01,45.6L·mol-1at35℃、45℃and55℃, inclusion ratio was1:1.The effect of pH on the complexation process was also quantitatively assessed,the stability constants were31.9L·mol-1,29.8L·mol-1,32.8L·mol-1,17.3L·mol-1at pH of4.0,5.0,6.5,7.5.The experimental results showed that the inclusion effect on complexation of cefotaxime and HP-P-CD was not ideal.
第一章：抗生素药物与人血清白蛋白相互作用的文献综述。介绍了抗生素药物的定义及分类,人血清白蛋白的晶体结构及功能特点,并详细叙述了研究药物小分子与蛋白质相互作用所采用的方法,以及各种方法的原理。因抗生素药物发挥药效均需通过血清白蛋白的贮存与运输,到达受体部位,进而发生药理作用,所以研究抗生素药物与人血清白蛋白相互作用,对新药研发、配伍禁忌等方面提供参考。
第二章：在pH=7.30的Tris-HC1缓冲溶液,运用荧光光谱法研究了头孢哌酮(CPZ)和乳酸环丙沙星(CFLX)单独存在与同时存在时和人血清白蛋白(HSA)的相互作用机理,实验结果表明,头孢哌酮、乳酸环丙沙星单独与HSA相互作用时,药物与蛋白荧光的猝灭属于静态猝灭,测定了20℃和37℃时头孢哌酮、乳酸环丙沙星与HSA结合常数分别为(O.18X103L·mol-1,0.11X103L·mol-1)和(1.79X103L·mol01,0.42X103L·mol01)、热力学参数平均值(△HCPZ=-20.4kJ·mol-1,△HCFLX=-60.3kJ· mol-1)、作用位点数nCPZ (0.63和0.57),nCFLX(0.65和0.75)。本章还研究了头孢哌酮、乳酸环丙沙星共存时与HSA的相互作用。结果表明,头孢哌酮与乳酸环丙沙星之间存在相互作用,使得药物与蛋白间的结合常数增大,结合稳定性升高,游离药物含量减少,造成药效降低。
第三章：通过对色谱条件的选择及优化,建立了采用高效液相色谱-荧光检测分析法测定阿莫西林。本文所建立的样品分析方法线性范围为2.5μ g/ml～2000μ g/ml,线性回归方程：Y=1.5×106X+29.105,相关系数r=0.9995；日内和日间RSD<5.0%。与药典中高效液相色谱-紫外检测分析方法相比,线性范围更宽,检测限相当,响应时间短,方法更准确、可靠。
第四章：运用测定药物游离浓度的方法——超滤法,结合高效液相色谱荧光检测分析法对阿莫西林与人血清蛋白的结合率进行测定分析。经实验结果表明：阿莫西林与人血清白蛋白在20.0.50.0.80.0.120.0μ mol/L下的血浆蛋白结合率分别为37.5%、39.7%、36.15%、34.53%。同时测定了阿莫西林与人血清白蛋白相互作用的结合常数为0.679×103,结合位点数为1.04,与文献中采用荧光猝灭法测定的结果基本相符。
第五章：用紫外可见吸收光谱、荧光光谱研究了羟丙基-β-环糊精与头孢噻肟的包合作用。利用荧光光谱法测定了35℃、45℃和55℃下,羟丙基-β-环糊精对头孢噻肟的包合稳定常数为84.4L.mol-1,60.8L·mol-1,45.6L·mol-1,包合比为1：1。并探讨了pH为4.0,5.0,6.5,7.5时HP-B-CD与头孢噻肟的包合常数为31.9L·mol-1,29.8L·mol-1,32.8L·mol-1,17.3L·mol-1。从实验结果可以得知：羟丙基-β-环糊精对头孢噻肟的包合效果不理想。
It is important for investigation of interaction between Small drug molecules and biological macromolecule in the field of chemical biology, especially study on interaction between serum protein and drug molecular is wider. Serum albumin is the most abundant transport protein in the circulatory system, it possess many important physiological and pharmacological functions,such as maintaining blood pressure and removing free radicals. It serves as a transport and storage carrier for many endogenous and exogenous ligands such as fatty acids, amino acids, hormones, ions and drugs.Therefore, to study the mechanism and process of interactions of the toxicity of substances, drugs and other small ligand with SA has important significance in toxicology and pharmacokinetics.The thesis comprehensivly utilize of fluorescence spectroscopy, high-performance liquid chromatography to carry out my research。
Chapter Ⅰ:Review.This chapter briefly introduced the definition and classification of antibiotic drugs,described the structure and function of the protein,at the same time,the research methods of the drug-HSA interaction in detail were summarized as well as the principle and application of a varitey of metheds.Because antibiotic drugs required the storage and transport of serum albumin before arriving at the receptor site to make efficacy,so study on interaction between antibiotic drugs and human serum albumin can provide the reference to the research and development of new drugs.
Chapter Ⅱ:The binding interaction of two antibiotics,cefoperazone(CPZ) and ciprofloxacinlactate(CFLX), with human serum albumin were investigated by fluorescence spectroscopy in this study.The results indicated that the combination reaction of them was a single static quenching process. In Tris-HCl buffer solution of pH=7.30,CPZ and CFLX combined strongly with HSA at26℃and37℃, respectively. The binding constants (0.18x103L·mol-1,0.11x103L·mol-1)and(1.79x103L·mol-1,0.42x103L·mol-1),th e average thermodynamic parameters (ΔHCPZ=-20.4kJ·mol-1ΔHCFLx=-60.3kJ·mol-1),the binding sites number nCPZ(0.63,0.57),nCFLx(0.65,0.75) were measured.Also the analysis of quenching of fluorescence of HSA is investigated when CPZ and CFLX coexisted.Under experiments, studies were established on the interaction between CPZ and CFLX by fluorescence spectrum. It was proved that the interaction between the drugs increase the binding stability of the drug and protein.At the same time, the prescence of one drug would make the binding of another drug with HSA easier,which indicated that free drug concentration at targets could decrease and the efficacy of the drugs could be reduced.
Chapter III:A high performance liquid chromatography-fluorescece detection method for the determination of amoxicillin is established.The standard curve was linear in the range from2.5μg to2000μg/ml,The recursive equation was shown in the following way:Y=1.5x106X+29.105, r=0.9991,The limit of quantitation (LOQ) of IQ in the samples was2.5μg/ml. The intra-day and inter-day RSDs were less than5.0%. Compared with the high performance liquid chromatography with UV detection,the developed method was more specific, accurate and sensitive.
Chapter IV:The ultrafiltration combined with the high performance chromatography-fluorescece detection was employed to determine the plasma protein binding rate of amoxicillin.The experimental results show that:the binding rate of amoxicillin with HSA at the concentration of20.0、50.0、80.0、120.0μmol/L were37.5%、39.7%、36.15%、34.53%,respectively.The binding constant of amoxicillin and HSA is0.679x103,the number of binding sites is1.04, which was similar to that reported with the method of fluorescece quenching in the literature.
Chapter V:The formation of the inclusion complex of cefotaxime with hydroxypropyl-β-cyclodextrin(HP-β-CD) was studied by steady-state fluorescence,UV-vis absorption spectroscopy.The stability constants(K) between HP-β-CD and cefotaxime were84.4L·mol-1,60.8L·mor01,45.6L·mol-1at35℃、45℃and55℃, inclusion ratio was1:1.The effect of pH on the complexation process was also quantitatively assessed,the stability constants were31.9L·mol-1,29.8L·mol-1,32.8L·mol-1,17.3L·mol-1at pH of4.0,5.0,6.5,7.5.The experimental results showed that the inclusion effect on complexation of cefotaxime and HP-P-CD was not ideal.
引文
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