文拉法辛在大鼠体内的分布与代谢

发布时间：2018-04-26 02:39

本文选题：文拉法辛 + O-去甲文拉法辛　；参考：《昆明医科大学》2017年硕士论文

【摘要】：[目的]1.建立高效液相法同时测定大鼠血液和大脑、肝脏、肾脏、胃壁组织检材中文拉法辛及其主要代谢产物O-去甲文拉法辛含量的方法。2.用所建立的方法,测定以盐酸文拉法辛灌胃给药后不同时间点文拉法辛、O-去甲文拉法辛在大鼠血液和大脑、肝脏、肾脏、胃壁组织检材中的含量,探索文拉法辛、O-去甲文拉法辛和总活性成分(文拉法辛与O-去甲文拉法辛总和)在这些检材中的分布变化规律。[方法]建立盐酸文拉法辛灌胃给药大鼠模型。分别于灌胃后1h、2h、4h、6h、8h麻醉采血,取大脑、肝脏、肾脏、胃壁组织器官。采用高效液相色谱法,利用外标校正曲线法同时测定灌胃给药后大鼠血液及各组织中文拉法辛及其活性代谢产物O-去甲文拉法辛的含量。对比分析灌胃给药盐酸文拉法辛大鼠体内文拉法辛、O-去甲文拉法辛及总活性成分在血液及各组织中的分布情况及随时间的变化规律。[结果]文拉法辛与O-去甲文拉法辛在高效液相色谱条件下的出峰时间分别为7.1min、5.1min。检测时杂质对目标物干扰小。血液和大脑、肝脏、肾脏、胃壁组织中检测文拉法辛的线性范围分别为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,定量限为线性范围最小值。O-去甲文拉法辛在血液和大脑、肝脏、肾脏、胃壁组织中的线性范围分别为 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,定量限为线性范围最小值。血液中文拉法辛在1.0μg/mL、2.0μg/mL、4.0μg/mL、6.0μg/mL四个实际添加含量下的平均萃取回收率在83.73%～91.53%之间,平均准确度在95.00%～103.22%之间;血液中O-去甲文拉法辛在这四个实际添加含量下的平均萃取回收率在65.88%～71.66%之间,平均准确度在93.68%～102.89%之间。大脑组织中文拉法辛在2.0μg/g、4.0μg/g、6.0μg/g、20.0μg/g四个实际添加含量下的平均萃取回收率在78.74%～82.38%之间,平均准确度在93.95%～100.02%之间;大脑组织中O-去甲文拉法辛在这四个实际添加含量下的平均萃取回收率在66.70%～71.88%之间,平均准确度在93.97%～102.93%之间。肝脏组织中文拉法辛在2.0μg/g、4.0μg/g、6.0μg/g、20.Oμg/g四个实际添加含量下的平均萃取回收率在76.34%～81.85%之间,平均准确度在96.86%～106.02%之间;肝脏组织中O-去甲文拉法辛在这实际添加含量下的平均萃取回收率在60.99%～65.42%之间,平均准确度在94.86%～103.22%之间。肾脏组织中文拉法辛在2.0μg/g、4.Oμg/g、6.Oμg/g、20.0μg/g四个实际添加含量下的平均萃取回收率在70.19%～77.43%之间,平均准确度在104.93%～124.21%之间;肾脏组织中O-去甲文拉法辛在这四个实际添加含量下的平均萃取回收率在62.92%～68.03%之间,平均准确度在99.37%～123.20%之间。胃壁组织中文拉法辛在2.0μg/g、6.0μg/g、20.0μg/g、100.0μg/g四个实际添加含量下的平均萃取回收率在76.70%～92.23%之间,平均准确度在83.48%～105.42%之间;胃壁组织中O-去甲文拉法辛在2.0μg/g、6.0μg/g、20.Oμg/g三个实际添加含量下的平均萃取回收率在62.84%～70.20%之间,平均准确度在92.36%～104.17%之间。灌胃后4h内文拉法辛、O-去甲文拉法辛在大鼠胃壁、肝脏、肾脏组织中含量较高,血液与大脑组织中含量相对较低。4h内大鼠血液及各组织中以文拉法辛为主,4h后各组织中文拉法辛、O-去甲文拉法辛含量差异较小。大鼠肾脏中文拉法辛及O-去甲文拉法辛浓度长时间维持在较高水平。灌胃后文拉法辛在大鼠血液与胃壁组织中整体呈下降趋势,其余各组织中呈先升后降趋势。大鼠血液中文拉法辛代谢较快。大鼠各组织中文拉法辛含量在1h至2h内变化不明显,2h至4h内排除较快,4小时后趋于平稳。O-去甲文拉法辛在血液及各组织内含量变化相对较小,整体呈先升后降趋势,达峰时间与文拉法辛在各组织中达峰时间基本一致。各组织中总活性成分在1h至4h内以文拉法辛为主,4h后文拉法辛与O-去甲文拉法辛在各组织中含量差异较小,各组织中总活性成分含量随时间的变化趋势与文拉法辛含量的变化趋势基本一致。[结论]本课题建立了大鼠血液和大脑、肝脏、肾脏、胃壁几种组织检材中文拉法辛及其活性代谢产物O-去甲文拉法辛进行同时含量测定的高效液相色谱法,用以探索灌胃给药盐酸文拉法辛大鼠血液及各组织中文拉法辛的分布及代谢规律,方法学验证显示:该方法杂质干扰小,定量测定稳定准确,无残留影响。通过本研究表明:肾脏组织可作为涉及文拉法辛中毒死亡案件检测的首选检材。灌胃后文拉法辛在大鼠血液中代谢较快。灌胃给药4h内文拉法辛在大鼠各组织中的含量较高,4h后文拉法辛与O-去甲文拉法辛含量差别较小。
[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.

【学位授予单位】：昆明医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：D919.4

【参考文献】