【作者】 刘莹；

【导师】 张丽；

【作者基本信息】 南京理工大学 ， 环境工程， 2012， 硕士

【摘要】 抗肿瘤药物CG007是目前非常热门的一种PARP-1抑制剂。经体外和药效学研究可知,CG007具有一定的抗肿瘤效果,可以延长荷瘤动物的生存期。其作用机制主要是肿瘤细胞中PARP-1含量较正常细胞中高,可以通过PARP-1抑制剂来降低肿瘤细胞内DNA的修复功能,增强癌细胞对DNA损害因子的敏感度,从而提高化疗和放疗的效果。本文的研究目标是建立抗肿瘤药物CG007的体内药物分析方法,以及药物在小鼠体内的吸收及组织分布的研究,为后续的进一步研究提供参考数据。初步研究的实验结果如下：(1)建立抗肿瘤药物CG007的HPLC含量测定方法。色谱柱采用Krosmail-C18柱,流动相为甲醇：水(0.1%三氟乙酸)=60：40,流速=1.0ml/min,检测波长：276nm。(2)建立生物样品中的CG007测定方法。预处理方法采用甲醇作为血浆的蛋白沉淀和提取剂,酸化甲醇作为组织的蛋白沉淀剂和提取剂,效果良好,回收率在95.33%-110.96%范围内,日内RSD<5.92%,日间RSD<6.59%,内源性物质没有干扰生物样品中抗肿瘤药物CG007的测定。色谱条件与CG007含量测定方法一致。(3)研究抗肿瘤药物CG007在ICR小鼠体内吸收动力学和组织分布。抗肿瘤药物吸收动力学实验中给药方式采用静脉注射和灌胃两种,小鼠静脉给药10,20,30mg·kg-1后,分布半衰期t1/2α/h分别是0.031±0.002,0.163±0.021,0.079±0.003,消除半衰期t1/2β/h分别是0.498±0.015,1.950±0.543,3.027±1.032,时间-浓度下曲线面积AUC(0-∞)/ng·ml-1·h-1分别6003.394±678.432,13651.617±2830.345,21928.17±4213.246；小鼠灌胃给药10,20,30mg·kg-1后,分布半衰期t1/2α/h分别是1.126±0.298,1.279±0.135,2.075±0.458,消除半衰期t1/2β/h分别是1.128±0.056,1.283±0.034,3.873±1.232,时间-浓度下曲线面积AUC(0-∞)/ng·ml-1·h-1分别是132.049±560.322,6860.27±239.065,16128.6927±4309.453。抗肿瘤药物CG007吸收动力学符合二室模型,基本呈药剂依赖关系,消除过程呈非线性动力学,随着浓度的增大呈现饱和消除过程。抗肿瘤药物CG007在给药浓度为10mg·kg-1条件下的绝对生物利用度为52.17%。组织分布实验中小鼠静脉给药10mg·kg-1抗肿瘤药物CG007后,结果显示肾脏浓度最高,肝脏次之,心,脑,肺药物水平相近。更多还原

【Abstract】 Antitumor Drug CG007 is a kind of PARP-1 inhibitors which now are very popular. The vivo and pharmacodynamics study shows that CG007 has antitumor effect. It can prolong the survival time of tumor-bearing animals.The mechanism of CG007 is that PARP-1 in tumor cells is much more than normal cells, we can use PARP-1 inhibitors to reduce tumor cells’ DAN repair fuction and enhance the sensitivity of cancer cells to DNA damage factors, so as to improve the effect of chemotherapy and radiotherapy.The paper mainly studied how to estabilish the method of CG007 biopharmarmaeeutical analysis, and researched the conditions of the drug’s absorption and tisstue distribution in mice, in order to provide reference data for further study. Some conclusions were taken in the below:(1) Established a method for determination of CG007. CG007 was determined by a reversed phase high performance liquid chromatography method. CG007 could be quantitatively determined under such chromatographic conditions:Krosmail-C18 column (4.6 mm×250 mm,5μm), and mobile phase:methanol-deionized water, containing 0.1% TFA, (60:40,v:v).with a flow rate of 1.0 mL·min-1, and detection wavelength is 276nm, the column temperature was 20℃.(2) Established a method for determination of CG007 in biological smples. In the preprocess, we used methanol as plasma deproteination reagent, acidified methanl as tissue deproteination reagent. This method had good effect, recovery was between 95.33%-110.96%, intra-day RSD was less than 5.92%, inter-day RSD was less than 6.59%, and there was no interference of endogenous substances. The chromatographic conditions were the same to the determinantion of CG007.(3) Studied the vivo absorption kinetics and tissue distribution of drug CG007 in mice. Detection method was the same to the determination of CG007 in biological smple.In the absorption kinetics experiments, injection and oral administrations were given to the mice, and the administration dose was respectively 10,20,30mg·kg-1. After injection administration, t1/2α/h was respectively 0.031±0.002,0.163±0.021,0.079±0.003, t1/2β/h was respectively 0.498±0.015,1.950±0.543,3.027±1.032, AUC(0-∞)/ng·ml-1·h-1 is respectively 6003.394±678.432,13651.617±2830.345,21928.17±4213.246. After oral administration,t1/2α/h i was respectively 1.126±0.298,1.279±0.135,2.075±0.458, t1/2β/h was respectively 1.128±0.056,1.283±0.034,3.873±1.232, AUC(0-∞)/ng·ml-1·h-1 was respectively 3132.049± 560.322,6860.27±239.065,16128.6927±4309.453,5535.055±789.436,10133.45±2321.734. The results showed that the pharmacokinetics of CG007 in mice plasma agreed with two-compartment model. CG007 was dose-independent over the range of 250-2500 ng·ml-1 in mice. After i.v.administration of 10mg·kg-1, the absolute bioavaiabilty of antitumor drug CG007 was 51.17%.The distribution study of CG007 in mice showed that CG007 could be extensively distributed, After i.v administration with 10mg·kg-1, we found the highest concentration in kidney, liver was less and the concentration in heart, brain, lung was similar to each other.更多还原