本文關(guān)鍵詞：2,3-二羥基苯甲酸十四烷基酯的藥代動(dòng)力學(xué)及組織分布研究　出處：《浙江大學(xué)》2014年碩士論文　論文類(lèi)型：學(xué)位論文

  更多相關(guān)文章： 2 3-二羥基苯甲酸十四烷基酯 藥代動(dòng)力學(xué) 組織分布 高效液相色譜法 Ⅱ

【摘要】：阿爾茲海默病(Alzheimer's disease, AD)是老年人群中一種常發(fā)生的慢性疾病,目前還沒(méi)有能從根本上治療該病的藥物。本課題組在龍膽苯甲酸酯的構(gòu)效關(guān)系研究基礎(chǔ)上,確定2,3-二羥基苯甲酸十四烷基酯(將該新化合物命名為ABG-001)為抗AD的先導(dǎo)化合物,并對(duì)其體內(nèi)體外藥效、體外作用機(jī)理和安全性進(jìn)行了研究。為了進(jìn)一步完善ABG-001的成藥性評(píng)價(jià),本文進(jìn)行了ABG-001在大鼠體內(nèi)藥代動(dòng)力學(xué)及組織分布研究。 本文建立了血漿中ABG-001的高效液相色譜分析法,并進(jìn)行了方法學(xué)驗(yàn)證。所建立的血漿樣品分析方法線(xiàn)性關(guān)系為y=1.7141x+0.05(r2=0.9992),線(xiàn)性范圍為0.1-50μg/mL;日內(nèi)和日間RSD均小于8%,準(zhǔn)確度在93.1-107.2%之間,運(yùn)用此方法對(duì)ABG-001的血漿藥代動(dòng)力學(xué)進(jìn)行研究。結(jié)果表明,ABG-001(100mg/kg)口服給藥后5小時(shí)在大鼠體內(nèi)達(dá)到最高血藥濃度0.81μg/mL,半衰期為3.40小時(shí)。靜脈注射ABG-001(10mg/kg)后,半衰期為14.07分鐘,說(shuō)明ABG-001靜脈給藥后在體內(nèi)分布與消除速率較快。根據(jù)所得到的ABG-001口服及靜脈注射的藥時(shí)曲線(xiàn)下面積計(jì)算結(jié)果,口服ABG-001的絕對(duì)生物利用度為8.88%。 本文還建立了高效液相色譜法分析ABG-001在大鼠組織中濃度的方法。對(duì)此方法在心臟、肺、胃、小腸、脾中的ABG-001分析進(jìn)行了驗(yàn)證。用此法研究口服給藥后大鼠體內(nèi)的組織分布情況。大鼠灌胃給予100mg/kg ABG-001后,選擇給藥后2小時(shí),5小時(shí),7小時(shí)(涵蓋吸收相,分布相和消除相)三個(gè)時(shí)間點(diǎn)后,分別處死大鼠,取腦組織、心臟、肝、脾、胃、肺、腎、小腸、睪丸、肌肉組織、脂肪組織以及胃容物,測(cè)定ABG-001在這些組織濃度或者部位的分布。結(jié)果表明,灌胃ABG-001后其在組織部位中的分布質(zhì)量濃度由高到低依次為：胃容物、小腸、胃、心臟、脾、肺、肝及其他,提示化合物主要分布在消化道。在大多數(shù)分析的組織中,ABG-001在2小時(shí)達(dá)到較高水平,5小時(shí)到達(dá)峰值,提示藥物在組織中有較快的分布速度；而在第7小時(shí)濃度明顯下降,提示藥物5小時(shí)后在各組織消除較快。
[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.

【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類(lèi)號(hào)】：R969.1
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本文編號(hào)：1422233