天麻、钩藤药对在肝脏摄取及消除的分子药物动力学机制初步研究

发布时间：2018-01-03 07:40

本文关键词：天麻、钩藤药对在肝脏摄取及消除的分子药物动力学机制初步研究　出处：《西南交通大学》2017年硕士论文　论文类型：学位论文

【摘要】：目的:初步研究天麻、钩藤药对在肝脏摄取及消除的分子药物动力学机制。方法:首先,大鼠预先给予异钩藤碱/天麻素,再静脉滴注天麻素/异钩藤碱,通过高效液相色谱仪(HPLC)检测不同时间点的天麻素血药浓度与肝药浓度,与对照组(直接静脉滴注天麻素/异钩藤碱)比较肝药浓度与血药浓度比值(Kp值)大小的变化,分析二者之间的相互影响,以此来研究天麻钩藤药对在肝脏摄取的分子药物动力学机制。其次,采用"Cocktail"探针药物法,同时给予大鼠一系列微量探针药物(茶碱、氨苯砜、氯唑沙宗、奥美拉唑、甲苯磺丁脲、右美沙芬),在给药后 5min、15min、30min、1h、2h、3h、5h、6h、12h、24h 十个时间点采血,建立利用HPLC同时检测大鼠血液中6种探针药物浓度的分析方法,计算并比较天麻组、钩藤组、天麻钩藤组和对照组各探针药物的药代动力学参数,阐明天麻、钩藤以及二者配伍对CYP450主要6种亚型CYP1A2、CYP3A4、CYP2E1、CYP2C19、CYP2C9、CYP2D6体内代谢活性的影响,以此来对天麻、钩藤药对在肝脏消除的分子药物动力学机制进行初步研究。结果:1)Kp天麻素组小于Kp 天麻素+异钩藤碱组,说明给予异钩藤碱后,天麻素从血液摄取到肝脏的过程受到促进;Kp异钩藤碱组大于Kp 异钩藤喊+天麻素组,说明给予天麻素后,异钩藤碱从血液摄取到肝脏的过程受到抑制。2)建立了利用高效液相色谱仪(HPLC)同时检测大鼠血液中6种探针药物浓度的分析方法(梯度洗脱,多波长同时检测),证实该方法稳定性好,精密度高,回收率高。3)天麻组的各组数据与空白组相比无明显差异,说明天麻对CYP450的主要6种亚型没有明显的影响;钩藤组与空白组相比,氨苯砜与甲苯磺丁脲两个探针药物的AUC减小,t1/2减小,CL增大(P0.05),说明钩藤组中这两种探针药物的代谢加快,对应的CYP3A4和CYP2C9两种亚型活性增大;天麻钩藤药对组与空白组相比,天麻钩藤药对组中氨苯砜与甲苯磺丁脲两种探针药物的AUC减小,t1/2减小,CL增大(P0.05),表明天麻钩藤药对组中这两种探针药物的代谢加快,探针药物对应的CYP3A4和CYP2C9两种亚型活性增大,而探针药物氯唑沙宗的AUC增大,t1/2增大,CL减小(P0.05),表明天麻钩藤药对组中氯唑沙宗的代谢减慢,探针药物对应的CYP2E1活性降低。结论:1)天麻素可能是异钩藤碱肝脏摄取的抑制剂。2)异钩藤碱可能是天麻素肝脏摄取的诱导剂。3)天麻对CYP450的主要6种亚型没有明显的影响。4)钩藤对CYP3A4和CYP2C9有一定的诱导作用。5)天麻、钩藤药对对CYP2E1有一定的抑制作用,而对CYP3A4和CYP2C9有一定的诱导作用。
[Abstract]:Objective: To study medicine in Uncaria Tianma, liver uptake and elimination of drug molecular dynamics mechanism. Methods: firstly, in rats pretreated with isorhy / gastrodin, then intravenous infusion of gastrodin / isorhy, by high performance liquid chromatography (HPLC) at different time points were detected in Tianma blood concentration with the drug concentration in liver, and the control group (direct intravenous injection of gastrodin / isorhy) hepatic drug concentration and blood concentration ratio (Kp value) size changes, the mutual influence between the two analysis, in order to study the molecular dynamics of Gastrodia and Uncaria medicine drug mechanism in liver uptake. Secondly, using the the "Cocktail" probe drugs, at the same time, the rats were given a series of micro probe drug (theophylline, dapsone, chlorzoxazone and omeprazole, tolbutamide, dextromethorphan), 5min, after the administration of 15min, 30min, 1H, 2h, 3h, 5h, 6h, 12h, 24h ten time points blood, establish A method for the simultaneous determination of 6 probe drugs concentration in blood of rats with HPLC, calculate and compare the Tianma Group, Uncaria group, Tianmagoutengyin group and control group of probe drug pharmacokinetics parameters, clarify the gastrodin, as well as the two Uncaria combination on CYP450 main 6 subtypes of CYP1A2, CYP3A4, CYP2E1, CYP2C19. CYP2C9, effects of activity in vivo metabolism of CYP2D6, in order to study medicine Gastrodia elata, Uncaria on molecular dynamics mechanism in liver drug elimination. Results: 1) Kp gastrodin gastrodin group than Kp + isorhy group that treated with Sinomenine hook, gastrodin from the blood to the liver uptake by promoting Kp; isorhy group than Kp + isorhynchophylline shout gastrodin group that given gastrodin, isorhynchophylline from the blood to the liver uptake was inhibited by.2) was established by high performance liquid chromatography (HPLC) detection and blood of rats Analysis of 6 kinds of probe drug concentration (gradient elution, multi wavelength detection), confirmed that the method has good stability, high precision, high recovery rate of.3 group) Gastrodia data was compared with the control group had no significant difference, indicating that the main 6 subtypes of CYP450 have no obvious effect compared with gastrodia Uncaria; group and blank control group, dapsone and tolbutamide two probe drugs of AUC decreased, t1/2 decreased, CL increased (P0.05), which indicates that these two kinds of probe drugs in the RTA group to speed up metabolism, the corresponding CYP3A4 and two subtypes of CYP2C9 activity increased; compared to day Ma Uncaria medicine group and blank group Tianmagouteng medicine on ammonia benzene group sulfone and tolbutamide two probe drugs of AUC decreased, t1/2 decreased, CL increased (P0.05), surface medicine Tian Ma Gou Teng of these two kinds of probe drugs in the group to speed up metabolism, increase the activity of the two subtypes of probe drugs corresponding to CYP3A4 and CYP2C9, The probe drug chlorzoxazone AUC increased, t1/2 increased, CL decreased (P0.05), surface medicine slow metabolism of Tian Ma Gou Teng group of chlorzoxazone, reduce the corresponding CYP2E1 probe drug activity. Conclusion: 1) gastrodin may be isorhy liver uptake inhibitor.2) sinomenine may be induced by different hook agent.3 the effect of gastrodin on hepatic uptake).4 6 subtypes of CYP450) have no obvious Gastrodia Uncaria induced by.5 on the CYP3A4 and CYP2C9) Tianma, Uncaria medicine has certain inhibitory effect on the CYP2E1, and induced the activity of CYP3A4 and CYP2C9.

【学位授予单位】：西南交通大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R285.5

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