双氯芬酸钠注射液在猪体内药动学及残留消除研究

发布时间：2018-05-12 10:07

本文选题：双氯芬酸钠 + 猪　；参考：《扬州大学》2015年硕士论文

【摘要】：双氯芬酸钠为第三代非甾体抗炎药,具有解热、镇痛和抗炎的作用。因其具有起效快、作用时间长、疗效好、副作用小、长期应用无积蓄性等特点,在医药行业中被广泛使用。双氯芬酸钠作用机制为抑制环氧化酶的活性,从而阻断花生四烯酸转化为前列腺素。同时它能促进花生四烯酸与甘油三酯结合,降低细胞内游离的花生四烯酸浓度,从而间接抑制白三烯的合成。本研究通过对双氯芬酸钠注射液在猪体内的药动学的研究,了解双氯芬酸在猪体内的过程和生物利用度,为制定临床合理给药方案提供依据；通过对双氯芬酸钠注射液在猪体内的残留消除规律研究,为制定其休药期提供依据,对确保动物性食品安全和消费者的健康具有重要的意义。1、双氯芬酸钠注射液在猪体内药动学研究8头体重相近的健康断奶仔猪随机分为两组,每组4头,公母各半。采用交叉试验设计,进行静脉注射和肌内注射给药药动学研究。静脉注射和肌内注射剂量均为2.5mg/kgb.W.,给药后按预定的时间采集血样分离血浆。血浆样品采用1 mol/L的盐酸溶液酸化,乙醚提取。双氯芬酸采用HPLC紫外检测器检测,流动相为1.5%冰醋酸：甲醇溶液。内标法定量。实测血药浓度-时间数据采用DAS2.1.1药动学分析软件计算药代动力学参数。猪单剂量静脉注射5%双氯芬酸钠注射液后,其平均消除半衰期(T1/2β)约为1.32 h,达峰时间(Tmax)和峰浓度(Cmax)分别约为0.10 h和37.69 μg/mL,平均滞留时间(MRT)约为1.60 h,平均药时曲线下面积(AUC)约为55.50hr·μg/ML表观分布容积(Vd)约为0.50L/kg,总体清除率(CLB)约为0.26 L/h/Kg。猪单剂量肌内注射5%双氯芬酸钠注射液后,其平均消除半衰期(T1/2β)约为1.87h,达峰时间(Tmax)和峰浓度(Cmax)分别约为1.19 h和11.61μg/mL,平均滞留时间(MRT)约为2.86h,平均药时曲线下面积(AUC)约为43.17hr·μg/mL,绝对生物利用度为78.50%。结果表明双氯芬酸在猪体内消除迅速,体内分布较差；肌内注射给药吸收迅速,且吸收程度良好。2、双氯芬酸钠注射液肌内注射给药在猪体内残留消除研究猪可食性组织中双氯芬酸残留采用乙酸乙酯提取,用液相色谱-串联质谱法测定,流动相为乙腈：0.2 mMl醋酸铵溶液(70:30,V/V/V),内标法定量。猪肌肉、肝脏、肾脏和皮脂空白组织添加水平为0.5、5和50μg/kg时,平均回收率均在70%-120%之间,批内、批间变异系数均小于10%。双氯芬酸在0.5-100ng/mL的浓度范围内呈良好的线性关系,相关系数均在0.99以上。猪各可食性组织中双氯芬酸的检测限和定量限分别为0.1μ g/kg和0.5 μgg/kg.本研究建立的检测方法适用于猪可食性组织中双氯芬酸残留量的测量。25头健康约克白商品猪(体重50 kg以上)用于残留消除试验(公母兼有)。双氯芬酸钠注射液按2.5mg/kg b.w.推荐剂量给猪肌内注射,每天一次,连用3天,分别于停药后第12 h、3 d、5 d、7 d和12 d时各屠宰5头猪,采集猪的肌肉(背最长肌)、肝脏、肾脏、皮脂及注射部位肌肉等可食性组织进行双氯芬酸残留量的检测。残留消除结果显示除注射部位外,停药后第12 h时双氯芬酸在肝脏中的残留量最高,其次是皮脂和肌肉,而肾脏的残留量最低。停药后第5 d时,5头猪肌肉中双氯芬酸残留量均低于定量限。停药后第7 d时,4头猪(4/5)皮脂中双氯芬酸残留量低于定量限,但5头猪肝脏和肾脏中双氯芬酸残留均高于定量限。残留消除结果表明双氯芬酸在肌肉中消除最快,其次是皮脂,肝脏和肾脏最慢,说明肝脏是双氯芬酸的残留靶组织。经WT1.4休药期软件计算,得出双氯芬酸在肝脏、肾脏、皮脂和肌肉组织和注射部位肌肉组织中休药期分别为9.892天、5.116天、14.205天、5.444天和8.818天。按双单侧95%置信区间计算双氯芬酸钠注射液按推荐用法与用量给药,建议其在猪的休药期可暂定为15天。
[Abstract]:Diclofenac sodium is the third generation nonsteroidal anti-inflammatory drug, which has the effect of antipyretic, analgesic and anti-inflammatory. It has the characteristics of quick effect, long time, good effect, small side effect and no accumulation in long term. The mechanism of diclofenac sodium is to inhibit the activity of cyclooxygenase and block the peanut four eNIC acid. It can be converted into prostaglandin. It can also promote the combination of peanut four enoic acid and triglyceride, reduce the intracellular free arachidic acid concentration, and indirectly inhibit the synthesis of leukotrienes. This study studies the process and bioavailability of dichlorofinic acid in pigs by studying the pharmacokinetics of Diclofenac Sodium Injection in pigs. In order to ensure the safety of animal food and the health of consumers, it is of great significance to ensure the safety of animal food and the health of consumers by studying the rule of residual elimination of Diclofenac Sodium Injection in pigs, which is of great significance to ensure the safety of animal food and the health of consumers. In the study of the pharmacokinetics of Diclofenac Sodium Injection in pigs, the 8 heads of Diclofenac Sodium Injection are similar. The healthy weanling piglets were randomly divided into two groups, with 4 heads in each group and half of the male and female. The cross test was designed to carry out the pharmacokinetic study of intravenous injection and intramuscular injection. The amount of intravenous injection and intramuscular injection were 2.5mg/kgb.W., and the blood samples were collected at a predetermined time after administration. The plasma samples were acidified with 1 mol/L hydrochloric acid and ether. Diclofenac was detected by HPLC UV detector, the mobile phase was 1.5% glacial acetic acid: the methanol solution. The internal standard was quantified. The measured blood concentration time data were measured by the DAS2.1.1 pharmacokinetic analysis software. The average half-life (T1/2 beta) of the pig was about 1.32 after a single dose of 5% Diclofenac Sodium Injection was injected into the pig. H, the peak time (Tmax) and peak concentration (Cmax) were about 0.10 h and 37.69 mu g/mL respectively. The average retention time (MRT) was about 1.60 h, and the area under the average drug time curve (AUC) was about 55.50hr. G/ML apparent distribution volume (Vd) was about 0.50L/kg, and the total clearance rate was about 0.26 after single dose of intramuscular injection of 5% Diclofenac Sodium Injection. The half-life (T1/2 beta) was about 1.87h, the peak time (Tmax) and peak concentration (Cmax) were about 1.19 h and 11.61 micron g/mL respectively. The average retention time (MRT) was about 2.86h, and the area under the average drug time curve (AUC) was about 43.17hr. G/mL. The absolute bioavailability of the 78.50%. knots showed that diclofenac was eliminated rapidly in pigs and the body was poorly distributed. The absorption of the internal injection was rapid, and the absorption degree was good.2. The residue of Diclofenac Sodium Injection intramuscular injection in pigs was eliminated. The residue of diclofenac in the edible tissues of pigs was extracted with ethyl acetate and determined by liquid chromatography tandem mass spectrometry. The mobile phase was acetonitrile: 0.2 mMl ammonium acetate solution (70:30, V/V/V), and the internal standard method was used. The average recovery rate of the pig muscle, liver, kidney and sebum blank was 0.5,5 and 50 g/kg, and the average recovery rate was between 70%-120%. In batch, the coefficient of variation in batch was less than that of 10%. diclofenac in 0.5-100ng/mL concentration range, and the correlation coefficient was above 0.99. The detection of diclofenac in the edible tissues of pigs The limits and limits of quantitative limit are 0.1 g/kg and 0.5 gg/kg. respectively. The detection method established in this study is suitable for the measurement of diclofenac residues in the edible tissues of pigs..25 head healthy York white commodity pigs (weight over 50 kg) are used for residual elimination test (both male and female). Diclofenac Sodium Injection is recommended to pig intramuscular injection according to the recommended dose of 2.5mg/kg b.w.. Once a day, 3 days after 3 days, 5 pigs were slaughtered at twelfth h, 3 D, 5 d, 7 d and 12 d, respectively. The muscle (the longest muscle of the back), the liver, kidney, sebum and the muscle of the injection site were detected. The residual elimination of the fruit showed that diclofenac was in the liver at twelfth h except the injection site. The residual amount in the viscera was the highest, followed by sebum and muscle, and the remnants of the kidney were the lowest. At fifth d after stopping the 5 pigs, the diclofenac residues in the muscles of 5 pigs were lower than the quantitative limit. The residue of diclofenac in the sebum of 4 pigs (4/5) was lower than the quantitative limit at seventh d after stopping the drug, but the residue of diclofenac in the liver and kidney of 5 pigs were all higher than that of the quantitative limit. The elimination results showed that diclofenac was the fastest in the muscles, followed by sebum, liver and kidney was the slowest, indicating that the liver was a residual target tissue of diclofenac. After the WT1.4 phase software, it was concluded that diclofenac was 9.892 days, 5.116 days, 14.20 in the liver, kidney, sebum, muscle tissue and intramuscular tissue, respectively, 14.20. 5 days, 5.444 days and 8.818 days. According to the double unilateral 95% confidence interval, Diclofenac Sodium Injection is given the recommended dosage and dosage, and it is suggested that it should be tentatively fixed for 15 days in the period of taking the pig's medicine.

【学位授予单位】：扬州大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：S859.79

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