發(fā)布時(shí)間：2018-12-19 08:50

【摘要】：本論文對(duì)一種伊維菌素微乳新制劑在羊體內(nèi)的藥物動(dòng)力學(xué)特性與藥物殘留消除規(guī)律進(jìn)行了研究。研究建立了新型伊維菌素微乳在羊血漿內(nèi)的藥物濃度的測(cè)定方法,測(cè)定了其在羊體內(nèi)的藥代學(xué)數(shù)據(jù),分析了其藥動(dòng)學(xué)特特性;建立了新型伊維菌素微乳制劑在靶動(dòng)物羊不同組織的藥物殘留測(cè)定方法,獲得了其在不同組織內(nèi)的殘留消除規(guī)律,制定了伊維菌素微乳的休藥期。伊維菌素微乳的藥代動(dòng)力學(xué)試驗(yàn),建立了高效液相色譜-串聯(lián)質(zhì)譜法測(cè)定血漿中藥物濃度的方法,試驗(yàn)結(jié)果表明,前處理方法簡(jiǎn)單有效,最低定量限為0.5ng/mL,最低檢測(cè)限為0.3ng/mL,標(biāo)準(zhǔn)曲線線性良好,R2為0.9995,平均回收率大于90%,日內(nèi)精密度和日間精密度均小于10%,靈敏度高、干擾小、重復(fù)性好。通過(guò)皮下、肌肉、靜脈注射3種途徑對(duì)羊進(jìn)行給藥,試驗(yàn)結(jié)果顯示,皮下給藥組的AUC為1343.07±101.17h·ng/mL,達(dá)峰濃度Cmax為50.61±2.96ng/mL,達(dá)峰時(shí)間Tmax為7.14±0.80h,吸收半衰期T1/2(α)為4.46h,消除半衰期T1/2(β)為25.45h;肌肉給藥組的AUC為1814.24±56.06h·ng/mL,達(dá)峰濃度Cmax為70.34±1.89ng/mL,達(dá)峰時(shí)間Tmax為3.99±0.20,吸收半衰期T1/2(α)為4.52h,消除半衰期T1/2(β)為20.08h。肌肉注射與皮下注射伊維菌素微乳的絕對(duì)生物利用度分別為91.33%和67.62%。通過(guò)對(duì)不同的給藥方式進(jìn)行比較發(fā)現(xiàn),肌肉注射與皮下注射相比具有更高的達(dá)峰濃度,更快的達(dá)峰時(shí)間,更高的生物利用度。伊維菌素微乳藥物殘留消除試驗(yàn),建立了以高效液相色譜-串聯(lián)質(zhì)譜檢測(cè)羊各組織中伊維菌素殘留的方法。樣品使用乙腈提取,使用堿性氧化鋁固相萃取小柱凈化,以高效液相色譜-串聯(lián)質(zhì)譜進(jìn)行檢測(cè)。試驗(yàn)結(jié)果表明,伊維菌素基質(zhì)匹配標(biāo)準(zhǔn)曲線在1~3000ng/mL的藥物濃度范圍內(nèi),藥物峰面積與線性關(guān)系良好,R2均大于0.999;在頸部肌肉、腎臟、脂肪、背最長(zhǎng)肌和肝臟五種組織的最低檢測(cè)限均為0.3ng/mL,最低定量限均為0.5ng/mL,該方法的定量限低于歐盟、美國(guó)和我國(guó)對(duì)于伊維菌素殘留限量的規(guī)定。樣品的平均回收率大于70%,日內(nèi)精密度和日間精密度均小于10%,采用高效液相色譜串聯(lián)質(zhì)譜法檢測(cè)羊各組織中的伊維菌素殘留濃度,方法簡(jiǎn)單、快速、準(zhǔn)確、靈敏度高。結(jié)合實(shí)測(cè)濃度判斷法與采用WT1.4計(jì)算軟件擬合,頸部肌肉的休藥期計(jì)算為14.71d,肝臟的休藥期計(jì)算為18.27d,腎臟的休藥期計(jì)算為17.49d,脂肪的休藥期計(jì)算為18.61d,背長(zhǎng)肌的休藥期計(jì)算為12.90d。依據(jù)靶動(dòng)物羊體內(nèi)的消除規(guī)律研究數(shù)據(jù),結(jié)合伊維菌素在羊各組織中的休藥期結(jié)果,建議該伊維菌素微乳注射液在羊體內(nèi)的休藥期為19天。本研究為伊維菌素微乳的新藥評(píng)價(jià)和指導(dǎo)臨床應(yīng)用奠定了基礎(chǔ)。
[Abstract]:In this paper, the pharmacokinetic characteristics and drug residue elimination of a new Ivermectin microemulsion in sheep were studied. A new method for the determination of the concentration of ivermectin microemulsion in sheep plasma was established. The pharmacokinetic characteristics of ivermectin microemulsion in sheep were analyzed. A new method for determination of Ivermectin microemulsion in different tissues of target animal sheep was established. The law of its elimination in different tissues was obtained, and the withdrawal period of ivermectin microemulsion was established. The pharmacokinetic test of ivermectin microemulsion was carried out. A method for the determination of drug concentration in plasma by high performance liquid chromatography-tandem mass spectrometry (HPLC / MS) was established. The results showed that the pretreatment method was simple and effective, and the minimum quantitative limit was 0.5 ng / mL. The lowest detection limit was 0.3 ng 路mL ~ (-1), the linearity of the standard curve was good, R2 was 0.9995, the average recovery was more than 90, the intra-day precision and inter-day precision were less than 10, the sensitivity was high, the interference was small, and the repeatability was good. The AUC of the subcutaneous administration group was 1343.07 鹵101.17 h ng/mL, peak concentration (Cmax) was 50.61 鹵2.96 ng / mL, and the peak time Tmax was 7.14 鹵0.80 h. Absorption half life T 1 / 2 (偽) was 4.46 h, elimination half life T 1 / 2 (尾) was 25.45 h; In the intramuscular administration group, AUC was 1814.24 鹵56.06 h, Cmax was 70.34 鹵1.89 ng / mL, Tmax was 3.99 鹵0.20, absorption half life T 1 / 2 (偽) was 4.52 h, elimination half life T 1 / 2 (尾) was 20.08 h. The absolute bioavailability of ivermectin microemulsion by intramuscular injection and subcutaneous injection was 91.33% and 67.62%, respectively. It was found that intramuscular injection had higher peak concentration, faster peak time and higher bioavailability than subcutaneous injection. A method for the determination of ivermectin residues in sheep tissues by HPLC-tandem mass spectrometry (HPLC-MS) was established by the drug residue elimination test of ivermectin microemulsion. The samples were extracted by acetonitrile and purified by alkaline alumina solid phase extraction column. The results showed that the peak area of ivermectin matrix matching standard curve was linear in the range of 1~3000ng/mL concentration, and R2 was greater than 0.999. In neck muscle, kidney, fat, longissimus dorsi muscle and liver, the minimum detection limit is 0.3 ng / mL, and the minimum quantitative limit is 0.5 ng / mL. the quantitative limit of this method is lower than that of the European Union. Ivermectin residue limits in the United States and China. The average recovery of the sample was more than 70 and the intra-day precision and inter-day precision were less than 100.The method was simple, rapid, accurate and sensitive for the determination of Ivermectin residues in sheep tissues by HPLC tandem mass spectrometry (HPLC / MS). Combined with the method of judging the measured concentration and using WT1.4 software, the discontinuation period of neck muscle, liver, kidney, fat and fat were 14.71 days, 18.27 days, 17.49 days and 18.61 days, respectively. The discontinuation period of the dorsal longus muscle was calculated to be 12.90 days. According to the study data of the elimination rule in the sheep of target animal and the results of the discontinuation period of ivermectin in sheep tissues, it is suggested that the drug withdrawal period of Ivermectin microemulsion injection in sheep body should be 19 days. This study laid a foundation for the new drug evaluation and clinical application of ivermectin microemulsion.
【學(xué)位授予單位】：中國(guó)農(nóng)業(yè)科學(xué)院
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2016
【分類(lèi)號(hào)】：S859.79

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