本文選題：白介素10 + PXR��； 參考：《南昌大學(xué)》2017年碩士論文

【摘要】：背景:氨氯地平主要在肝臟中由CYP3A4介導(dǎo)代謝。CYP3A4酶表達(dá)受孕烷X受體(PXR)等轉(zhuǎn)錄因子調(diào)控,而PXR的表達(dá)又與IL-10的表達(dá)水平具有相關(guān)性,且CYP3A4、PXR、IL-10的表達(dá)均存在基因多態(tài)性。氨氯地平的臨床療效個(gè)體差異是否與CYP3A4、PXR、IL-10的基因多態(tài)性關(guān)聯(lián),值得深入探討。目的:深入研究CYP3A4、PXR、IL-10的基因多態(tài)性對(duì)中國健康受試者空腹及餐后口服氨氯地平藥代動(dòng)力學(xué)特征的影響,為氨氯地平臨床合理用藥提供科學(xué)依據(jù)。方法:1.篩選并入組43名健康受試者(空腹給藥組22例與餐后給藥組各21例),口服10 mg氨氯地平后,在不同時(shí)間點(diǎn)采集系列血樣,采用已建立并進(jìn)行確證的LC-MS/MS方法測定血漿中氨氯地平的藥物濃度,應(yīng)用DAS2.1軟件計(jì)算相應(yīng)的藥動(dòng)學(xué)參數(shù)。2.同時(shí)采用PCR-RELP方法對(duì)43名受試者IL-10(1082 GA、819CT、592CA);PXR(24381AC、3'UTR10719GA、3'UTR 11193 TC);CYP3A4(13989AG、15820CG、17776 A insertion)九個(gè)突變點(diǎn)進(jìn)行基因檢測,在基因分型的基礎(chǔ)上,使用SPSS19.0和GraphPad Prism 5比較分析CYP3A4、PXR、IL-10基因多態(tài)性對(duì)中國健康受試者空腹及餐后口服氨氯地平藥代動(dòng)力學(xué)特征的影響。結(jié)果:1.IL-10在1082 GA、819 CT、592 CA位點(diǎn)的突變頻率分別為11.6%、23.2%、18.6%;PXR在24381AC、3'UTR10719GA、3'UTR 11193 TC位點(diǎn)突變頻率分別為27.9%、18.6%、25.5%;CYP3A4在13989AG、15820CG、17776 A insertion位點(diǎn)的突變頻率分別為16.5%、20.9%、11.6%。上述9個(gè)基因位點(diǎn)突變對(duì)空腹口服及餐后口服氨氯地平的主要藥動(dòng)學(xué)參數(shù)(C_(max)、AUC和t_(1/2))均無顯著影響(P0.05)。2.高脂高熱量飲食對(duì)氨氯地平在中國健康受試者體內(nèi)的吸收程度有明顯促進(jìn)作用,空腹與餐后AUC_(0-t)分別為212.09±40.53 ng·hml~(-1)與291.20±92.02ng·hml~(-1)(P0.05),AUC_(0-∞)分別為228.56±52.37 ng·hml~(-1)與313.209±103.471ng·hml~(-1)(P0.05)。結(jié)論:1.IL-10、PXR和CYP3A4基因突變對(duì)氨氯地平在中國健康受試者空腹及餐后口服氨氯地平藥代動(dòng)力學(xué)特征無明顯影響。2.高脂高熱量飲食能顯著促進(jìn)氨氯地平在中國健康受試者體內(nèi)的吸收。
[Abstract]:Background: amlodipine is mainly regulated by transcription factors such as CYP3A4 mediated metabolism. CYP3A4 gene expression of pregnancy X receptor (PXR), and the expression of PXR is correlated with the level of IL-10 expression, and the expression of CYP3A4 PXRRnIL-10 is polymorphic. Whether the individual difference in clinical efficacy of amlodipine is associated with the gene polymorphism of CYP3A4, PXRRnIL-10, is worth further study. Objective: to study the effect of CYP3A4 PXRnIL-10 gene polymorphism on the pharmacokinetics of amlodipine in healthy Chinese volunteers on fasting and postprandial oral administration of amlodipine, and to provide a scientific basis for rational clinical use of amlodipine. Method 1: 1. A series of blood samples were collected at different time points from 43 healthy subjects (22 patients in the fasting administration group and 21 patients in the postprandial administration group) who took 10 mg amlodipine orally. The concentration of amlodipine in plasma was determined by established and confirmed LC-MS/MS method. The pharmacokinetic parameters of amlodipine were calculated by DAS2.1 software. At the same time, PCR-RELP method was used to detect nine mutation sites of CYP3A4 (13989 AG15820CGN 17776A) in 43 subjects, PXRD24381AC3, UTR10719, GA3UR 11193 TCX, CYP3A4, AG13989, AG15820CGN, 17776A insertion.Based on the genotyping, nine mutation sites of CYP3A4, AG15820CGN, 17776A, were detected. SPSS19.0 and GraphPad Prism 5 were used to compare and analyze the effect of CYP3A4PXRr-10 gene polymorphism on the pharmacokinetics of Chinese healthy volunteers on fasting and postprandial oral amlodipine. Results the mutation frequencies of IL-10 at 1082 GAA819 CTN 592 CA locus were 11.6 and 23.2and 18.6A, respectively. The mutation frequencies at UTR10719GA3TX3UTR10719 UTR10719 UTR 11193 TC were 27.9C ~ 18.6C 25.5A respectively. The mutation frequencies of CYP3A4 at 13989 AGN 15820CGN 17776 A insertion were 16.50.20.9A and 11.611.9respectively. The mutation frequencies of CYP3A4 at 13989 AGN 15820CGN 17776A were 16.55.511.611.9. The above 9 locus mutations had no significant effect on the main pharmacokinetic parameters of fasting oral and postprandial oral amlodipine. The absorption of amlodipine in Chinese healthy volunteers was significantly promoted by high-fat and high-calorie diet, with fasting and postprandial AUCX 0-t being 212.09 鹵40.53 ng hml-1) and 291.20 鹵92.02ng hml-1 hml-1 (P 0.05hml-1), 228.56 鹵52.37 ng hml-1) and 313.209 鹵103.471ng hml-1, respectively. Conclusion 1. The mutation of PXR and CYP3A4 gene in IL-10 has no significant effect on the pharmacokinetic characteristics of amlodipine in Chinese healthy volunteers on fasting and postprandial oral administration of amlodipine. A high-fat and high-calorie diet significantly promotes the absorption of amlodipine in healthy Chinese volunteers.
【學(xué)位授予單位】：南昌大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R969.1

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