IL-10、PXR和CYP3A4基因多态性对中国健康受试者空腹及餐后口服氨氯地平药代动力学特征的影响

发布时间：2018-04-23 22:38

本文选题：白介素10 + PXR　；参考：《南昌大学》2017年硕士论文

【摘要】：背景:氨氯地平主要在肝脏中由CYP3A4介导代谢。CYP3A4酶表达受孕烷X受体(PXR)等转录因子调控,而PXR的表达又与IL-10的表达水平具有相关性,且CYP3A4、PXR、IL-10的表达均存在基因多态性。氨氯地平的临床疗效个体差异是否与CYP3A4、PXR、IL-10的基因多态性关联,值得深入探讨。目的:深入研究CYP3A4、PXR、IL-10的基因多态性对中国健康受试者空腹及餐后口服氨氯地平药代动力学特征的影响,为氨氯地平临床合理用药提供科学依据。方法:1.筛选并入组43名健康受试者(空腹给药组22例与餐后给药组各21例),口服10 mg氨氯地平后,在不同时间点采集系列血样,采用已建立并进行确证的LC-MS/MS方法测定血浆中氨氯地平的药物浓度,应用DAS2.1软件计算相应的药动学参数。2.同时采用PCR-RELP方法对43名受试者IL-10(1082 GA、819CT、592CA);PXR(24381AC、3'UTR10719GA、3'UTR 11193 TC);CYP3A4(13989AG、15820CG、17776 A insertion)九个突变点进行基因检测,在基因分型的基础上,使用SPSS19.0和GraphPad Prism 5比较分析CYP3A4、PXR、IL-10基因多态性对中国健康受试者空腹及餐后口服氨氯地平药代动力学特征的影响。结果:1.IL-10在1082 GA、819 CT、592 CA位点的突变频率分别为11.6%、23.2%、18.6%;PXR在24381AC、3'UTR10719GA、3'UTR 11193 TC位点突变频率分别为27.9%、18.6%、25.5%;CYP3A4在13989AG、15820CG、17776 A insertion位点的突变频率分别为16.5%、20.9%、11.6%。上述9个基因位点突变对空腹口服及餐后口服氨氯地平的主要药动学参数(C_(max)、AUC和t_(1/2))均无显著影响(P0.05)。2.高脂高热量饮食对氨氯地平在中国健康受试者体内的吸收程度有明显促进作用,空腹与餐后AUC_(0-t)分别为212.09±40.53 ng·hml~(-1)与291.20±92.02ng·hml~(-1)(P0.05),AUC_(0-∞)分别为228.56±52.37 ng·hml~(-1)与313.209±103.471ng·hml~(-1)(P0.05)。结论:1.IL-10、PXR和CYP3A4基因突变对氨氯地平在中国健康受试者空腹及餐后口服氨氯地平药代动力学特征无明显影响。2.高脂高热量饮食能显著促进氨氯地平在中国健康受试者体内的吸收。
[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 卤40.53 ng hml-1) and 291.20 卤92.02ng hml-1 hml-1 (P 0.05hml-1), 228.56 卤52.37 ng hml-1) and 313.209 卤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.
【学位授予单位】：南昌大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R969.1

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