CYP3A5联合CYP3A4基因多态性对肾移植受者他克莫司个体化用药的指导

发布时间：2018-03-16 07:48

本文选题：CYP3A5　切入点：CYP3A4　出处：《山西医科大学》2015年硕士论文　论文类型：学位论文

【摘要】：目的:了解CYP3A4和CYPA5对FK506代谢与清除的影响,比较传统给药和根据基因分型进行个体化给药的优劣,了解CYP3A4和CYPA5联合基因分型的临床应用价值。方法:选取2014年5月至12月在解放军第309医院随诊的75例肾移植受者为研究对象,随机入组(实验组和对照组),所有纳入实验组的肾移植受者于术前采用荧光原位杂交法测定肾移植受体CYP3A5、CYP3A4的基因型,实验组根据CYP3A5-CYP3A4基因型进行分组并给予不同的FK506初始剂量。对照组三个月后进行回顾性基因分型。结果:①我研究所肾移植受者CYP3A5*3和CYP3A4*18B等位基因突变频率分别为67.3%和20%,与国内外研究数据结果相似,说明中国人种CYP3A5*3和CYP3A4*18B基因分布稳定。②肾移植受者CYP3A5*3和CYP3A4*18B基因多态性影响FK506的药代动学。CYP3A5*1和CYP3A4*18B促进代谢,CYP3A5*3和CYP3A4*1延缓代谢。③肾移植术后早期根据基因型调整给予个体化精细他克莫司治疗可以使肾移植受者更快地达到标准血药浓度范围。④术后早期联合高表达的肾移植受者为达到目标血药浓度范围所需药物剂量较高,个体化给药能够使移植受者迅速有效达到目标血药浓度,而传统给药剂量往往无法达标,诱发排斥反应的风险较高,有统计学显著差异。结论:与传统方法相比,根据基因型的不同调整FK506的初始剂量的个体化给药方案可以明显提高肾移植术后早期FK506药物血药浓度和达到标准血药浓度范围的百分比,为降低因药物浓度过高或者过低引起的药物不良反应、急性排斥反应的发生提供了可能。
[Abstract]:Objective: to investigate the effects of CYP3A4 and CYPA5 on the metabolism and clearance of FK506 and compare the advantages and disadvantages of traditional administration and individualized administration according to genotyping. To understand the clinical application value of CYP3A4 and CYPA5 combined genotyping. Methods: 75 renal transplant recipients who were followed up from May 2014 to December in the 309th Hospital of PLA were selected as the study subjects. The genotypes of CYP3A5 and CYP3A4 were determined by fluorescence in situ hybridization (FISH) in all the renal transplant recipients of the experimental group and the control group, and the genotypes of CYP3A5 and CYP3A4 were determined by fluorescence in situ hybridization. The experimental group was divided into groups according to CYP3A5-CYP3A4 genotype and given different initial doses of FK506. The control group was genotyped retrospectively after three months. Results the frequencies of CYP3A5*3 and CYP3A4*18B alleles were 67.3% and 67.3% respectively in the recipients of kidney transplantation in the study group. 20, similar to domestic and foreign research data, The results indicate that the polymorphism of CYP3A5*3 and CYP3A4*18B genes in Chinese ethnic CYP3A5*3 and CYP3A4*18B gene distribution is stable. 2. The pharmacokinetics of FK506. CYP3A5A5O1 and CYP3A4*18B promote metabolism. CYP3A5A5K3 and CYP3A4*1 delay metabolism 3 early after renal transplantation according to genotypic adjustment. Chemotherapy with tacrolimus could enable renal transplant recipients to reach the standard plasma drug concentration range faster. 4. 4 early postoperative high expression renal transplant recipients needed higher doses of drugs to reach the target blood drug concentration range. Individualized administration can quickly and effectively reach the target blood drug concentration in the transplant recipients, but the traditional dose often fails to meet the standard, and the risk of inducing rejection is higher. Conclusion: compared with the traditional method, the risk of inducing rejection is significantly higher. The individualized regimen of adjusting the initial dose of FK506 according to different genotypes could significantly increase the blood concentration of FK506 and the percentage of reaching the standard range of serum drug concentration in the early stage of renal transplantation. In order to reduce the adverse drug reaction caused by too high or too low drug concentration, the occurrence of acute rejection is possible.
【学位授予单位】：山西医科大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R699.2

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