發(fā)布時間：2018-05-12 10:07

  本文選題：雙氯芬酸鈉 + 豬�。� 參考：《揚州大學(xué)》2015年碩士論文

【摘要】：雙氯芬酸鈉為第三代非甾體抗炎藥,具有解熱、鎮(zhèn)痛和抗炎的作用。因其具有起效快、作用時間長、療效好、副作用小、長期應(yīng)用無積蓄性等特點,在醫(yī)藥行業(yè)中被廣泛使用。雙氯芬酸鈉作用機制為抑制環(huán)氧化酶的活性,從而阻斷花生四烯酸轉(zhuǎn)化為前列腺素。同時它能促進花生四烯酸與甘油三酯結(jié)合,降低細胞內(nèi)游離的花生四烯酸濃度,從而間接抑制白三烯的合成。本研究通過對雙氯芬酸鈉注射液在豬體內(nèi)的藥動學(xué)的研究,了解雙氯芬酸在豬體內(nèi)的過程和生物利用度,為制定臨床合理給藥方案提供依據(jù)；通過對雙氯芬酸鈉注射液在豬體內(nèi)的殘留消除規(guī)律研究,為制定其休藥期提供依據(jù),對確保動物性食品安全和消費者的健康具有重要的意義。1、雙氯芬酸鈉注射液在豬體內(nèi)藥動學(xué)研究8頭體重相近的健康斷奶仔豬隨機分為兩組,每組4頭,公母各半。采用交叉試驗設(shè)計,進行靜脈注射和肌內(nèi)注射給藥藥動學(xué)研究。靜脈注射和肌內(nèi)注射劑量均為2.5mg/kgb.W.,給藥后按預(yù)定的時間采集血樣分離血漿。血漿樣品采用1 mol/L的鹽酸溶液酸化,乙醚提取。雙氯芬酸采用HPLC紫外檢測器檢測,流動相為1.5%冰醋酸：甲醇溶液。內(nèi)標(biāo)法定量。實測血藥濃度-時間數(shù)據(jù)采用DAS2.1.1藥動學(xué)分析軟件計算藥代動力學(xué)參數(shù)。豬單劑量靜脈注射5%雙氯芬酸鈉注射液后,其平均消除半衰期(T1/2β)約為1.32 h,達峰時間(Tmax)和峰濃度(Cmax)分別約為0.10 h和37.69 μg/mL,平均滯留時間(MRT)約為1.60 h,平均藥時曲線下面積(AUC)約為55.50hr·μg/ML表觀分布容積(Vd)約為0.50L/kg,總體清除率(CLB)約為0.26 L/h/Kg。豬單劑量肌內(nèi)注射5%雙氯芬酸鈉注射液后,其平均消除半衰期(T1/2β)約為1.87h,達峰時間(Tmax)和峰濃度(Cmax)分別約為1.19 h和11.61μg/mL,平均滯留時間(MRT)約為2.86h,平均藥時曲線下面積(AUC)約為43.17hr·μg/mL,絕對生物利用度為78.50%。結(jié)果表明雙氯芬酸在豬體內(nèi)消除迅速,體內(nèi)分布較差；肌內(nèi)注射給藥吸收迅速,且吸收程度良好。2、雙氯芬酸鈉注射液肌內(nèi)注射給藥在豬體內(nèi)殘留消除研究豬可食性組織中雙氯芬酸殘留采用乙酸乙酯提取,用液相色譜-串聯(lián)質(zhì)譜法測定,流動相為乙腈：0.2 mMl醋酸銨溶液(70:30,V/V/V),內(nèi)標(biāo)法定量。豬肌肉、肝臟、腎臟和皮脂空白組織添加水平為0.5、5和50μg/kg時,平均回收率均在70%-120%之間,批內(nèi)、批間變異系數(shù)均小于10%。雙氯芬酸在0.5-100ng/mL的濃度范圍內(nèi)呈良好的線性關(guān)系,相關(guān)系數(shù)均在0.99以上。豬各可食性組織中雙氯芬酸的檢測限和定量限分別為0.1μ g/kg和0.5 μgg/kg.本研究建立的檢測方法適用于豬可食性組織中雙氯芬酸殘留量的測量。25頭健康約克白商品豬(體重50 kg以上)用于殘留消除試驗(公母兼有)。雙氯芬酸鈉注射液按2.5mg/kg b.w.推薦劑量給豬肌內(nèi)注射,每天一次,連用3天,分別于停藥后第12 h、3 d、5 d、7 d和12 d時各屠宰5頭豬,采集豬的肌肉(背最長肌)、肝臟、腎臟、皮脂及注射部位肌肉等可食性組織進行雙氯芬酸殘留量的檢測。殘留消除結(jié)果顯示除注射部位外,停藥后第12 h時雙氯芬酸在肝臟中的殘留量最高,其次是皮脂和肌肉,而腎臟的殘留量最低。停藥后第5 d時,5頭豬肌肉中雙氯芬酸殘留量均低于定量限。停藥后第7 d時,4頭豬(4/5)皮脂中雙氯芬酸殘留量低于定量限,但5頭豬肝臟和腎臟中雙氯芬酸殘留均高于定量限。殘留消除結(jié)果表明雙氯芬酸在肌肉中消除最快,其次是皮脂,肝臟和腎臟最慢,說明肝臟是雙氯芬酸的殘留靶組織。經(jīng)WT1.4休藥期軟件計算,得出雙氯芬酸在肝臟、腎臟、皮脂和肌肉組織和注射部位肌肉組織中休藥期分別為9.892天、5.116天、14.205天、5.444天和8.818天。按雙單側(cè)95%置信區(qū)間計算雙氯芬酸鈉注射液按推薦用法與用量給藥,建議其在豬的休藥期可暫定為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.

【學(xué)位授予單位】：揚州大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2015
【分類號】：S859.79

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