新型三嗪类抗球虫药物AC4的药代动力学研究

发布时间：2018-06-07 09:28

本文选题：AC4 + 鸡　；参考：《中国农业科学院》2015年硕士论文

【摘要】：鸡球虫病是一种常见的原虫寄生虫病,以柔嫩艾美尔球虫和毒害艾美耳球虫危害最大,临床上会造成鸡体重下降、抵抗力下降、高死亡率,每年给养禽业带来巨大损失。AC4是中国农业科学院上海兽研究医所在地克珠利的结构基础上合成并筛选出的一种新型三嗪类抗球虫化合物,临床前研究表明其抗球虫效果优异,具有广谱、低毒的特点。本研究的目的是建立检测鸡和SD大鼠血浆内AC4的分析方法,考察高、中、低三个剂量的AC4在这两种动物的药代动力学和1.33mg/kg bw剂量下AC4在鸡体内的口服生物利用度,获得主要的药代动力学参数。在检测SD大鼠血浆内AC4含量的UPLC-UV方法中:使用乙酸乙酯作为提取溶剂,妥曲珠利亚砜作为内标,BEH C18色谱柱,采用梯度洗脱方式,每个样品进样时间为20 min;方法专属性良好,检测限和定量限分别为0.04、0.08μg/m L;标准曲线定量范围0.08-80μg/m L,线性方程y=0.091x+0.001,R2=1,线性关系良好;加标样品提取回收率在97.56-106.2%之间,日内、日间精密度均小于6.36%;样品至少在室温放置8 h或者反复冻融三次后稳定;该方法灵敏、准确,可以用于检测SD大鼠血浆内AC4含量。AC4在SD大鼠体内的药动学实验中,本文考察了1、2、10 mg/kg bw三个给药剂量分别在雌雄SD大鼠的药代动力学,结果表明:药时曲线下面积和最大血药浓度存在剂量依赖关系;给药后4-5 h达到最大血药浓度;生物消除半衰期在不同性别、不同剂量组之间存在较大差异;AC4在SD大鼠的药动学存在较为明显的性别和个体差异。在检测鸡血浆内AC4含量的UPLC-UV方法中:使用乙酸乙酯作为提取溶剂,妥曲珠利亚砜作为内标,BEH C18色谱柱,采用梯度洗脱方式,每个样品进样时间为10 min;方法专属性良好,检测限和定量限分别为0.02、0.04μg/m L;标准曲线定量范围0.04-50μg/m L,线性方程y=0.094x+0.002,R2=0.999,线性关系良好;加标样品提取回收率在92.97-109.5%之间,日内、日间精密度均小于7.84%;样品至少在室温放置8h或者反复冻融三次后稳定;该方法灵敏、准确,可以用于检测鸡血浆内AC4含量。AC4在鸡的药动学实验中,本文考察了0.45、0.9、4.5 mg/kg bw三个给药剂量,结果表明:药时曲线下面积和最大血药浓度存在剂量依赖关系;给药后平均4 h达到最大血药浓度;生物消除半衰期与给药剂量间无明显关系,平均消除半衰期为18.5 h,属于慢消除类药物。在AC4的生物利用度实验中,在给药剂量为1.33 mg/kg bw下:口服组AUC(0-t)为53.836mg/l*h,静注组AUC(0-t)为68.068 mg/l*h,由绝对生物利用度计算公式F=AUCpo/AUCiv×100%,得到AC4的口服生物利用度为79.1%。综上所述,本研究分别建立了检测鸡和SD大鼠血浆内AC4含量的UPLC-UV方法学,也分别对AC4在鸡、雌雄SD大鼠体内的药代动力学和AC4在鸡体内的口服生物利用度进行了研究,获得了AC4在鸡和SD大鼠体内的主要药动学参数,为AC4后续研究打下了基础。
[Abstract]:Chicken coccidiosis is a common parasite disease, especially Eimeria tenella and Eimeria poisoning, which will cause weight loss, resistance decline and high mortality. AC4 is a new type of triazine anti-coccidiosis compound synthesized and screened on the basis of the structure of the animal medicine in Shanghai, China Academy of Agricultural Sciences. Preclinical studies have shown that its anti-coccidiosis effect is excellent. It has broad spectrum and low toxicity. The aim of this study was to establish an analytical method for the determination of AC4 in plasma of chicken and SD rats, and to investigate the pharmacokinetics of high, medium and low doses of AC4 in both animals and the oral bioavailability of AC4 in chicken at 1.33mg/kg BW dose. The main pharmacokinetic parameters were obtained. In the UPLC-UV method for the determination of AC4 content in plasma of SD rats, ethyl acetate was used as the extraction solvent and totrezhulide sulfoxide as the internal standard. The gradient elution method was used, and the injection time of each sample was 20 min, the specificity of the method was good. The detection limit and the quantitative limit were 0.04 ~ 0.08 渭 g / mL, respectively, and the quantitative range of the standard curve was 0.08-80 渭 g / mL, and the linear equation was 0.091 x 0.001 ~ (-1) C ~ (2 +), the linear relationship was good, the recovery rate of the added standard sample was between 97.56-106.2%, within a day, The precision of day was less than 6.36; the samples were stable after at least 8 h at room temperature or three times of repeated freezing and thawing. The method was sensitive and accurate, and could be used to detect the AC4 content. AC4 in SD rats' plasma in pharmacokinetic experiments. The pharmacokinetics of three doses of 10 mg/kg BW in male and female Sprague-Dawley rats was investigated. The results showed that there was a dose-dependent relationship between the area under the drug time curve and the maximum blood drug concentration, and the maximum blood drug concentration was reached at 4-5 hours after administration. There were significant differences in pharmacokinetics of AC4 in SD rats with different sex and different dosage groups in biological elimination half-life, and there were obvious gender and individual differences in pharmacokinetics of AC4 in SD rats. In the UPLC-UV method for the determination of AC4 content in chicken plasma, ethyl acetate was used as the extraction solvent and totrezoli sulfoxide was used as the internal standard. The gradient elution method was used. The injection time of each sample was 10 min, the specificity of the method was good. The detection limit and quantification limit were 0.02n 0.04 渭 g / mL and 0.04-50 渭 g / mL, respectively. The linear equation was 0.094 x 0.002 渭 g / mL, and the linear relationship was good. The recovery rate of the added standard sample was 92.97-109.5%. The precision between day and day was less than 7.84. The samples were stable after at least 8 hours at room temperature or three times of repeated freezing and thawing. The method was sensitive and accurate, and could be used to detect the content of AC4. AC4 in chicken plasma in pharmacokinetic experiments. In this paper, the dose-dependent relationship between the area under the drug time curve and the maximum blood drug concentration was found, and the drug concentration reached the maximum concentration in the average of 4 hours after administration. There was no significant relationship between the half-life of biological elimination and the dosage of the drug, and the average half-life of elimination was 18.5 h, which was a slow elimination drug. In the bioavailability test of AC4, under the dosage of 1.33 mg/kg BW, the oral dose of AUC 0-t was 53.836 mg / L ~ (-1) h, and that of the intravenous group was 68.068 mg / L ~ (-1) h. The bioavailability of AC4 was 79.1 mg 路L ~ (-1) by calculating the absolute bioavailability formula F=AUCpo/AUCiv 脳 100. To sum up, the UPLC-UV methodology for the determination of AC4 in plasma of chicken and SD rats was established, and the pharmacokinetics of AC4 in chicken, male and female SD rats and the oral bioavailability of AC4 in chicken were also studied. The main pharmacokinetic parameters of AC4 in chicken and SD rats were obtained, which laid a foundation for further study of AC4.
【学位授予单位】：中国农业科学院
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：S859.795

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