2,3-二羟基苯甲酸十四烷基酯的药代动力学及组织分布研究

发布时间：2018-01-14 05:27

  本文关键词：2,3-二羟基苯甲酸十四烷基酯的药代动力学及组织分布研究　出处：《浙江大学》2014年硕士论文　论文类型：学位论文

  更多相关文章： 2 3-二羟基苯甲酸十四烷基酯 药代动力学 组织分布 高效液相色谱法 Ⅱ

【摘要】：阿尔兹海默病(Alzheimer's disease, AD)是老年人群中一种常发生的慢性疾病,目前还没有能从根本上治疗该病的药物。本课题组在龙胆苯甲酸酯的构效关系研究基础上,确定2,3-二羟基苯甲酸十四烷基酯(将该新化合物命名为ABG-001)为抗AD的先导化合物,并对其体内体外药效、体外作用机理和安全性进行了研究。为了进一步完善ABG-001的成药性评价,本文进行了ABG-001在大鼠体内药代动力学及组织分布研究。 本文建立了血浆中ABG-001的高效液相色谱分析法,并进行了方法学验证。所建立的血浆样品分析方法线性关系为y=1.7141x+0.05(r2=0.9992),线性范围为0.1-50μg/mL;日内和日间RSD均小于8%,准确度在93.1-107.2%之间,运用此方法对ABG-001的血浆药代动力学进行研究。结果表明,ABG-001(100mg/kg)口服给药后5小时在大鼠体内达到最高血药浓度0.81μg/mL,半衰期为3.40小时。静脉注射ABG-001(10mg/kg)后,半衰期为14.07分钟,说明ABG-001静脉给药后在体内分布与消除速率较快。根据所得到的ABG-001口服及静脉注射的药时曲线下面积计算结果,口服ABG-001的绝对生物利用度为8.88%。 本文还建立了高效液相色谱法分析ABG-001在大鼠组织中浓度的方法。对此方法在心脏、肺、胃、小肠、脾中的ABG-001分析进行了验证。用此法研究口服给药后大鼠体内的组织分布情况。大鼠灌胃给予100mg/kg ABG-001后,选择给药后2小时,5小时,7小时(涵盖吸收相,分布相和消除相)三个时间点后,分别处死大鼠,取脑组织、心脏、肝、脾、胃、肺、肾、小肠、睾丸、肌肉组织、脂肪组织以及胃容物,测定ABG-001在这些组织浓度或者部位的分布。结果表明,灌胃ABG-001后其在组织部位中的分布质量浓度由高到低依次为：胃容物、小肠、胃、心脏、脾、肺、肝及其他,提示化合物主要分布在消化道。在大多数分析的组织中,ABG-001在2小时达到较高水平,5小时到达峰值,提示药物在组织中有较快的分布速度；而在第7小时浓度明显下降,提示药物5小时后在各组织消除较快。
[Abstract]:Alzheimer's disease (Alzheimer's disease AD) is a frequent chronic diseases in the elderly, there is no drug can cure the disease fundamentally. The research group Gentiana benzoate structure-activity relationship on the basis of determining 2,3- two hydroxy benzoic acid alkyl ester fourteen (the new compound named ABG-001) as lead compounds against AD, and the in vitro and in vivo efficacy, mechanism and safety of in vitro were studied. In order to further improve the evaluation of ABG-001 medicine, the ABG-001 rats in vivo pharmacokinetics and tissue distribution of generation.
This paper established the analysis method of high performance liquid chromatography ABG-001 in plasma, and the method validation. The plasma samples were established by linear relationship analysis method for y=1.7141x+0.05 (r2=0.9992), the linear range is 0.1-50 ~ g/mL; intra day and inter day RSD were less than 8%, the accuracy between 93.1-107.2%, using this method to study the plasma pharmacokinetics of ABG-001. The results showed that ABG-001 (100mg/kg) 5 h after oral administration in rats reached the highest blood concentration of 0.81 g/mL, the half-life of 3.40 hours. After intravenous injection of ABG-001 (10mg/kg), the half-life of 14.07 minutes, ABG-001 after intravenous administration of in vivo distribution and elimination rate according to the results of ABG-001. The area of oral and intravenous injection of the drug time curve, the absolute bioavailability of oral ABG-001 use of 8.88%.
This paper also established the method of high performance liquid ABG-001 in rat tissues the concentration of chromatography analysis. This method is in the heart, lung, stomach, small intestine, spleen in ABG-001 analysis was verified. The study after oral administration in rats tissues. Rats were given 100mg/kg after ABG-001. In 2 hours, 5 hours after Administration for 7 hours (including the absorption phase, distribution and elimination phase) at three time points after the rats were killed, the brain, heart, liver, spleen, stomach, lung, kidney, intestine, testis, muscle, adipose tissue and gastric contents. Determination of ABG-001 in the distribution of these parts or tissue concentrations. The results showed that after intragastric administration of ABG-001 in the tissue distribution of concentration from high to low: stomach, small intestine, stomach, heart, spleen, lung, liver and other compounds, that is mainly distributed in the digestive tract. In most of the analysis in the organization, ABG-0 01, it reached a high level at 2 hours, reaching the peak in 5 hours, indicating that the drug had a faster distribution speed in the tissue, while the concentration decreased significantly in seventh hours, suggesting that the drug could be eliminated quickly in all tissues after 5 hours.

【学位授予单位】：浙江大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R969.1
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本文编号：1422233