本文關鍵詞：天麻、鉤藤藥對在肝臟攝取及消除的分子藥物動力學機制初步研究　出處：《西南交通大學》2017年碩士論文　論文類型：學位論文

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【摘要】：目的:初步研究天麻、鉤藤藥對在肝臟攝取及消除的分子藥物動力學機制。方法:首先,大鼠預先給予異鉤藤堿/天麻素,再靜脈滴注天麻素/異鉤藤堿,通過高效液相色譜儀(HPLC)檢測不同時間點的天麻素血藥濃度與肝藥濃度,與對照組(直接靜脈滴注天麻素/異鉤藤堿)比較肝藥濃度與血藥濃度比值(Kp值)大小的變化,分析二者之間的相互影響,以此來研究天麻鉤藤藥對在肝臟攝取的分子藥物動力學機制。其次,采用"Cocktail"探針藥物法,同時給予大鼠一系列微量探針藥物(茶堿、氨苯砜、氯唑沙宗、奧美拉唑、甲苯磺丁脲、右美沙芬),在給藥后 5min、15min、30min、1h、2h、3h、5h、6h、12h、24h 十個時間點采血,建立利用HPLC同時檢測大鼠血液中6種探針藥物濃度的分析方法,計算并比較天麻組、鉤藤組、天麻鉤藤組和對照組各探針藥物的藥代動力學參數(shù),闡明天麻、鉤藤以及二者配伍對CYP450主要6種亞型CYP1A2、CYP3A4、CYP2E1、CYP2C19、CYP2C9、CYP2D6體內(nèi)代謝活性的影響,以此來對天麻、鉤藤藥對在肝臟消除的分子藥物動力學機制進行初步研究。結(jié)果:1)Kp天麻素組小于Kp 天麻素+異鉤藤堿組,說明給予異鉤藤堿后,天麻素從血液攝取到肝臟的過程受到促進;Kp異鉤藤堿組 大于Kp 異鉤藤喊+天麻素組,說明給予天麻素后,異鉤藤堿從血液攝取到肝臟的過程受到抑制。2)建立了利用高效液相色譜儀(HPLC)同時檢測大鼠血液中6種探針藥物濃度的分析方法(梯度洗脫,多波長同時檢測),證實該方法穩(wěn)定性好,精密度高,回收率高。3)天麻組的各組數(shù)據(jù)與空白組相比無明顯差異,說明天麻對CYP450的主要6種亞型沒有明顯的影響;鉤藤組與空白組相比,氨苯砜與甲苯磺丁脲兩個探針藥物的AUC減小,t1/2減小,CL增大(P0.05),說明鉤藤組中這兩種探針藥物的代謝加快,對應的CYP3A4和CYP2C9兩種亞型活性增大;天麻鉤藤藥對組與空白組相比,天麻鉤藤藥對組中氨苯砜與甲苯磺丁脲兩種探針藥物的AUC減小,t1/2減小,CL增大(P0.05),表明天麻鉤藤藥對組中這兩種探針藥物的代謝加快,探針藥物對應的CYP3A4和CYP2C9兩種亞型活性增大,而探針藥物氯唑沙宗的AUC增大,t1/2增大,CL減小(P0.05),表明天麻鉤藤藥對組中氯唑沙宗的代謝減慢,探針藥物對應的CYP2E1活性降低。結(jié)論:1)天麻素可能是異鉤藤堿肝臟攝取的抑制劑。2)異鉤藤堿可能是天麻素肝臟攝取的誘導劑。3)天麻對CYP450的主要6種亞型沒有明顯的影響。4)鉤藤對CYP3A4和CYP2C9有一定的誘導作用。5)天麻、鉤藤藥對對CYP2E1有一定的抑制作用,而對CYP3A4和CYP2C9有一定的誘導作用。
[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.

【學位授予單位】：西南交通大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R285.5

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