本文選題：文拉法辛 + O-去甲文拉法辛　； 參考：《昆明醫(yī)科大學(xué)》2017年碩士論文

【摘要】：[目的]1.建立高效液相法同時測定大鼠血液和大腦、肝臟、腎臟、胃壁組織檢材中文拉法辛及其主要代謝產(chǎn)物O-去甲文拉法辛含量的方法。2.用所建立的方法,測定以鹽酸文拉法辛灌胃給藥后不同時間點文拉法辛、O-去甲文拉法辛在大鼠血液和大腦、肝臟、腎臟、胃壁組織檢材中的含量,探索文拉法辛、O-去甲文拉法辛和總活性成分(文拉法辛與O-去甲文拉法辛總和)在這些檢材中的分布變化規(guī)律。[方法]建立鹽酸文拉法辛灌胃給藥大鼠模型。分別于灌胃后1h、2h、4h、6h、8h麻醉采血,取大腦、肝臟、腎臟、胃壁組織器官。采用高效液相色譜法,利用外標校正曲線法同時測定灌胃給藥后大鼠血液及各組織中文拉法辛及其活性代謝產(chǎn)物O-去甲文拉法辛的含量。對比分析灌胃給藥鹽酸文拉法辛大鼠體內(nèi)文拉法辛、O-去甲文拉法辛及總活性成分在血液及各組織中的分布情況及隨時間的變化規(guī)律。[結(jié)果]文拉法辛與O-去甲文拉法辛在高效液相色譜條件下的出峰時間分別為7.1min、5.1min。檢測時雜質(zhì)對目標物干擾小。血液和大腦、肝臟、腎臟、胃壁組織中檢測文拉法辛的線性范圍分別為0.8～10.0μg/mL、0.8～20.0μg/g、0.8～40.0μg/g、1.0～40.0μg/g、1.0～200.Oμg/g,定量限為線性范圍最小值。O-去甲文拉法辛在血液和大腦、肝臟、腎臟、胃壁組織中的線性范圍分別為 0.8～10.0μg/mL、0.8～20.0μg/g、0.8～40.0μg/g、1.0～40.0μg/g、1.0～40.0μg/g,定量限為線性范圍最小值。血液中文拉法辛在1.0μg/mL、2.0μg/mL、4.0μg/mL、6.0μg/mL四個實際添加含量下的平均萃取回收率在83.73%～91.53%之間,平均準確度在95.00%～103.22%之間;血液中O-去甲文拉法辛在這四個實際添加含量下的平均萃取回收率在65.88%～71.66%之間,平均準確度在93.68%～102.89%之間。大腦組織中文拉法辛在2.0μg/g、4.0μg/g、6.0μg/g、20.0μg/g四個實際添加含量下的平均萃取回收率在78.74%～82.38%之間,平均準確度在93.95%～100.02%之間;大腦組織中O-去甲文拉法辛在這四個實際添加含量下的平均萃取回收率在66.70%～71.88%之間,平均準確度在93.97%～102.93%之間。肝臟組織中文拉法辛在2.0μg/g、4.0μg/g、6.0μg/g、20.Oμg/g四個實際添加含量下的平均萃取回收率在76.34%～81.85%之間,平均準確度在96.86%～106.02%之間;肝臟組織中O-去甲文拉法辛在這實際添加含量下的平均萃取回收率在60.99%～65.42%之間,平均準確度在94.86%～103.22%之間。腎臟組織中文拉法辛在2.0μg/g、4.Oμg/g、6.Oμg/g、20.0μg/g四個實際添加含量下的平均萃取回收率在70.19%～77.43%之間,平均準確度在104.93%～124.21%之間;腎臟組織中O-去甲文拉法辛在這四個實際添加含量下的平均萃取回收率在62.92%～68.03%之間,平均準確度在99.37%～123.20%之間。胃壁組織中文拉法辛在2.0μg/g、6.0μg/g、20.0μg/g、100.0μg/g四個實際添加含量下的平均萃取回收率在76.70%～92.23%之間,平均準確度在83.48%～105.42%之間;胃壁組織中O-去甲文拉法辛在2.0μg/g、6.0μg/g、20.Oμg/g三個實際添加含量下的平均萃取回收率在62.84%～70.20%之間,平均準確度在92.36%～104.17%之間。灌胃后4h內(nèi)文拉法辛、O-去甲文拉法辛在大鼠胃壁、肝臟、腎臟組織中含量較高,血液與大腦組織中含量相對較低。4h內(nèi)大鼠血液及各組織中以文拉法辛為主,4h后各組織中文拉法辛、O-去甲文拉法辛含量差異較小。大鼠腎臟中文拉法辛及O-去甲文拉法辛濃度長時間維持在較高水平。灌胃后文拉法辛在大鼠血液與胃壁組織中整體呈下降趨勢,其余各組織中呈先升后降趨勢。大鼠血液中文拉法辛代謝較快。大鼠各組織中文拉法辛含量在1h至2h內(nèi)變化不明顯,2h至4h內(nèi)排除較快,4小時后趨于平穩(wěn)。O-去甲文拉法辛在血液及各組織內(nèi)含量變化相對較小,整體呈先升后降趨勢,達峰時間與文拉法辛在各組織中達峰時間基本一致。各組織中總活性成分在1h至4h內(nèi)以文拉法辛為主,4h后文拉法辛與O-去甲文拉法辛在各組織中含量差異較小,各組織中總活性成分含量隨時間的變化趨勢與文拉法辛含量的變化趨勢基本一致。[結(jié)論]本課題建立了大鼠血液和大腦、肝臟、腎臟、胃壁幾種組織檢材中文拉法辛及其活性代謝產(chǎn)物O-去甲文拉法辛進行同時含量測定的高效液相色譜法,用以探索灌胃給藥鹽酸文拉法辛大鼠血液及各組織中文拉法辛的分布及代謝規(guī)律,方法學(xué)驗證顯示:該方法雜質(zhì)干擾小,定量測定穩(wěn)定準確,無殘留影響。通過本研究表明:腎臟組織可作為涉及文拉法辛中毒死亡案件檢測的首選檢材。灌胃后文拉法辛在大鼠血液中代謝較快。灌胃給藥4h內(nèi)文拉法辛在大鼠各組織中的含量較高,4h后文拉法辛與O-去甲文拉法辛含量差別較小。
[Abstract]:[Objective]1. to establish a high performance liquid phase method for simultaneous determination of blood and brain, liver, kidney, and gastric wall tissue for Chinese lafaxine and its main metabolite O- normethlafaxine content..2. was used for the determination of venlafaxine and O- de methavalafaxine in rat blood after intravenous administration of venlafaxine hydrochloride. Content of fluid and brain, liver, kidney, gastric wall tissue, and explore the distribution of venlafaxine, O- norafaxine and total active components (vlafaxine and O- normethlafaxine combined) in these samples. [Methods] the rat model of venlafaxine gavage was established. 1H, 2h, 4h, 6h, 8h anesthesia after gavage. The content of lafaxine and its active metabolite O-, lafaxine and its active metabolite in rats were measured by high performance liquid chromatography with high performance liquid chromatography, and the content of lafaxine and its active metabolite O- in the blood and tissues of rats after gavage were measured by high performance liquid chromatography. The contrast analysis of venlafaxine in venlafaxine hydrochloride rats, O- to Jia Wen The distribution of lafaxine and the total active components in blood and tissues and changes with time. [results] the peak time of venlafaxine and O- norvlafaxine at high performance liquid chromatography was 7.1min, and the interference of impurity to the target was small when 5.1min. was detected. The linear range of faraxin is 0.8 to 10 mu g/mL, 0.8 to 20 mu g/g, 0.8 to 40 mu g/g, 1 to 40 mu g/g, 1 to 200.O g/g, and the quantitative limit of the linear range of.O- normolafaxine in the blood and brain, the liver, the kidney and the gastric wall, respectively, 0.8 ~ 10, g/g, 0.8 ~ g/g, g/g. G/g, 1 ~ 40 mu g/g, the quantitative limit is the minimum of linear range. The average extraction recovery rate of blood Chinese lafaxine at 1 mu g/mL, 2 mu g/mL, 4 mu g/mL and 6 mu g/mL is between 83.73% to 91.53%, and the average accuracy is between 95% ~ 103.22%. The O- normethylafaxine in the blood is under these four added content. The average extraction recovery rate is from 65.88% to 71.66%, the average accuracy is from 93.68% to 102.89%. The average extraction recovery of Chinese lafaxine in the brain tissue is 2 u g/g, 4 g/g, 6, g/g, 20 mu g/g, and the average recovery rate is between 78.74% ~ 82.38%. The average accuracy is between 93.95% ~ 100.02% in the brain tissue, O- to Jia Wen The average extraction recovery rate of Rafasin was between 66.70% and 71.88%, with the average accuracy of 93.97% ~ 102.93%. The average extraction recovery rate of the liver tissue was between 2 g/g, 4, g/g, 6 mu g/g and 20.O mu g/g. The average extraction recovery rate was 76.34% to 81.85%, the average accuracy was 96.86%. Between 106.02% and 106.02%, the average extraction recovery of O- normethlafaxine in the liver was from 60.99% to 65.42%, with an average accuracy of 94.86% ~ 103.22%. The average extraction recovery of kidney tissue in Chinese Rafasin was 2 mu, 4.O mu g/g, 6.O UG g/g, 20 u g/g four solid intersections were 70.19% to 7. Between 7.43%, the average accuracy was between 104.93% and 124.21%. The average extraction recovery of O- norafaxine in the kidney tissues was 62.92% to 68.03%, with an average accuracy of 99.37% to 123.20%. The Chinese lafaxine in the gastric wall was 2 u g/ g, 6 mu g/g, 20 mu g/g, 100 mu g/g four actual additions. The average extraction recovery was between 76.70% and 92.23%, the average accuracy was between 83.48% and 105.42%. The average extraction recovery of O- normethylafaxine at 2 mu, 6 g/g and 20.O mu g/g was 62.84% to 70.20% in the gastric wall tissue, and the average accuracy was from 92.36% to 104.17%. After gavage, the internal 4H was used. Rafasin, O- normethlafaxine content in rat's stomach wall, liver, kidney tissue is high, blood and brain tissue are relatively low in the blood and brain tissue in.4h rats and all tissues are mainly venlafaxine, after 4h, the differences in Chinese Rafasin, normethlafaxine content are small. Rat kidney of rat kidney and O- normethlafaxine The concentration of Vin Rafa Sin in the rat blood and the stomach wall decreased after gavage for a long time, and the rest of the tissues showed a rising trend. The metabolism of Chinese lafaxine in the rat blood was faster. The changes of Chinese rapafaxin content in the rat tissues from 1H to 2H were not obvious, 2h to 4h were quickly excluded, and then tended to be 4 hours later. The content of.O- normethylene Vin Rafa Sin in the blood and each tissue is relatively small, the whole is first rising and then descending, and the peak time is basically the same as the peak time of Vin Rafa Sin in each tissue. The total active components in each tissue are mainly in the 1H to 4h, and the content of lafaxine and O- deacon Vin Rafa Sin in each tissue is poor. The variation trend of the total active component content in each tissue with time is basically the same as that of venlafaxine. [Conclusion] this subject has established the Chinese Rafasin and the active metabolite O- of the rat blood and brain, the liver, the kidney, the gastric wall and its active metabolite O- to the high performance liquid for the simultaneous determination of the content of the active metabolites of the rat. Chromatography was used to explore the distribution and metabolism of Chinese lafaxine in the blood and various tissues of venlafaxine hydrochloride rats. Methodological verification showed that the method has little interference, the quantitative determination is stable and accurate, and there is no residual effect. This study shows that kidney tissue can be used as the first detection of cases of venlafaxine poisoning death. After gavage, the metabolism of Vin Rafa Sin was faster in the blood of rats. The content of 4h Neven Rafa Sin in the rat tissues was higher, and the difference between the content of Vin Rafa Sin and O- and the normethylene Vin Rafa Sin was small after 4H.

【學(xué)位授予單位】：昆明醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：D919.4

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