【作者】 李剑勇；

【导师】 赵荣材；

【作者基本信息】 中国农业科学院 ， 临床兽医学， 2000， 硕士

【摘要】 六茜素（Pyroline）是氢醌类的新型抗菌兽药，具有抗菌谱广、作用强、低毒、无残留、不易产生耐药性等特点，临床用于治疗奶牛乳房炎、猪水肿病、猪丹毒以及多种病原菌引起的畜禽消化道疾病，效果显著。本实验一方面研究六茜素在猪体内的代谢动力学，为临床合理用药、新药研制与剂型改进提供理论依据；另一方面研究六茜素抗菌活性的定量构效关系，以便筛选出更加理想的抗菌新兽药，改善我国兽药品种少及长期依赖人药的局面。 1．实验猪5头，分别单剂量30mg·kg^-1静脉注射、85mg·kg^-1肌肉注射六茜素后，采用反相HPLC法检测六茜素的血浆浓度。美国waters高效液相色谱仪系列，YWG-C₁₈柱（5μm）4.6mm×250mm。以香草醛为内标，流动相为甲醇—水（40:60），流动速度为0.7ml·min^-1，检测波长220nm。用MCPKP处理数据，结果所得的六茜素血药时程两者都符合二室开放模型，它们的药物动力学参数为：iv,T_1/2μ=1.52min,T_1/2β=66.05min,AUC=880.07mg·min·L^-1；im,T_1/2α=0.37min,T_1/2μ=3.45min,T_1/2β=76.87min,AUC=570.17mg·min·L^-1,Tp=1.53min,Cmax=11.34μg·ml^-1。结果表明：六茜素iv和im给药后，其在体内吸收迅速，分布快和广，消除快，而且生物利用度低。结合临床实际情况，可以推断出六茜素是以抗菌药后效应等机理发挥作用。 2．以六茜素为先导化合物，合成了14个新化合物。经过抗菌活性的测定，确定以氢醌为母核进行Hansch法定量构效关系的研究。结合临床用药特点，选取金葡萄球菌84184为活性常数提取的致病菌。结果所得QSAR方程为：lgl/MIC=0.0350π-0.0153π²+0.1784σ+0.0020MR-1.6213I+4.4415 n=13 r=0.8089F=2.65（α=0.05），以异丙基氢醌进行验证，发现该方程对化合物的活性预测有一定的参考意义。通过挑选作用显著的参数，发现指示变量Ⅰ与抗菌活性的58％相关，从而提出：氢醌类化合物是通过氧化还原的反应而显示其抗菌活性的作用机理。本实验对进一步寻找更有效的六茜素衍生物和阐明其作用机理，提供了一定的线索和依据。 六茜素在猪体内的药代动力学研究国内外未见报道；氢醌化合物的定量构效关系的研究前人有报道，本研究首次以指示变量（Ⅰ）为参数进行构效关系研究并提出相应的作用机理。更多还原

【Abstract】 Pyroline attached to hydroquinones is a novel antibacterial animal medicine. Its characters are wide antibacterial ranges strong action low toxicity no residual .~ not easy Produced antidrug effect and so on. Pyroline effect is of great significance when it is applied to cure cow mastitis.. porcine water fats porcine erysipelas and husbandry animal chylopoietic disease by many pathogenic bacteria in veterinary clinical practice. One hand, the experiment was to study the pharmacokinetics of pyroline in pigs in order to provide the theoretical basis for rational pharmacotherapy~ new animal medicine research and formulation improvement. On the other hand, the experiment was to study antibacterial quantitative structureactivity relationship of pyroline in order to pick out new bacterial animal medicine better than pyroline and to improve Chinese situation that animal medicines are short of many types and often dependent on man ones.1 . Five normal pigs were given pyroline iv 30mg kg?and im 85mg kg? The concentrations of pyroline in porcine plasma were determined with RP-HPLC method developed in our laboratory. A waters model 480 instrument was used throughout the experiment. Vanillin was used as the internal standard at absorption wavelength of38220nm.A mixture of methanol and water(40:60) was used as the mobile phase with aflow rate of 0.7ml. min-’,and YWG-C., as stationary phase. Plasma drugconcentration-time course of pyroline aIier iv and im administration of pyroline wereboth tbulld to be fitted to two col11partmel1t opel1 1nodel and their pharmacokineticalwt ase wty as tbIlowrf iv, T. (. =l.52 nd. tl =66.05min,AUC=880.07mg. min. L-’; il11, T,;,.,,=0.37min, T.,, (. =3.45min, T,,, t) =76.87min,AUC=570. l7mg,1lin t-’, Tp=l .53n1i11, Cn1ax=l l .34 ll g,nl-’. The results reveal thatPyrolille was absorbed rapidly. distribtlted wide. eliminated fast and its biovailabilitywas low. Combined with clinic cases, it was followed that pyroline effect was carriedout by such many mechanisms as antibiotic effect prolonged.2.Pyroline was acted as a lead compound and new fourteen compounds weresynthesized. After antibacterial effects were measured, hydroquine was acted asmother structure to study QSAR. Con1bined with clinic practice, staphylococcus wasselected as a pathogenic bacterium by which et1bctive coefficients were measured. Ittbllowed’ QSAR equation was lgl/MIC=0.0350 rr -0.0l53 rr 2+0. l784 o +0.0020MR-l .62l3l+4.44l5 n=l3 r=0.8089 F=2.65(u =0.05),When iso-propylhydroquinonewere used to prove the equatiol1,tl1erc werc solne certain effective significance fOr itsequatiol1 tbrecasting compotll1d’s activity. Tl1rough selecting significant actionpara111cters, it was tbllowed that tl1ere was 58% correlation between order variance (I)al1d antibacterial activity. TherefOr, al1tibacterial mechanism of hydroquinones wascarried out by oxidization and reduction reaction. The experiment provided somecertain clue and basis fOr finding thrther etTective pyrolines and explaining its actionmechanism.Study on the pharmacokinetics in pigs of pyroline has never reported in the world.AIthough research on QSAR of hydroquinones has ever reported by forefather, theexperiment finished QSAR first with order variance (I) and accordingly producedaction lnechanism.更多还原