CYP3A5基因多态性、五酯胶囊对特发性膜性肾病患者他克莫司药代动力学指标的影响研究

发布时间：2018-06-04 19:41

本文选题：特发性膜性肾病 + 肾病综合征　；参考：《滨州医学院》2016年硕士论文

【摘要】：研究一:CYP3A5基因多态性对特发性膜性肾病患者他克莫司药代动力学指标的影响研究目的:观察不同CYP3A5基因型的特发性膜性肾病(idiopathic membranous nephropathy,IMN)患者在给予泼尼松联合他克莫司(tacrolimus,TAC)治疗6月,达到目标全血谷浓度时的用药剂量,推断不同基因型与他克莫司用药剂量之间的关系,初步探索由基因型指导的他克莫司个体化治疗模式。方法:所选病例均来自滨州医学院附属医院肾内科住院,临床表现为肾病综合征(nephrotic syndrome,NS),病理确诊为特发性膜性肾病(Idiopathic Membranous Nephropathy,IMN )的患者 60 例,荧光染色原位杂交(fluorescence in situ hybridization,FISH)技术检测CYP3A5基因型。依据基因型将患者分为AA、AG、GG3组。他克莫司的全血谷浓度(C0)应用均相酶扩大免疫分析法(EMIT)测定;比较3组患者用药后8周、12周、16周、24周时他克莫司全血谷浓度C0、用药剂量D、剂量-调整谷浓度C0/D。按照临床疗效分为完全缓解(CR),部分缓解(PR)和无效(NR) 3组,比较三组患者各访视点的TAC药代动力学指标变化。结果:60例特发性膜性肾病患者CYP3A5基因多态性(6986AG)G的基因频率为 53.33%,其中AA组 12 例(20%); 组 32 例(53.33%); GG 组 16 例(26.67%)。3组患者他克莫司用药8周、12周、16周、24周后的用药剂量(D)、剂量-调整谷浓度(C0/D)的差异有统计学意义(均p0.05)。AA组患者他克莫司用药剂量(D)约为GG组的2～3倍,AG组约为GG组的1～2倍。治疗24周AA组患者的缓解率显著低于AG、GG组(16.67%比81.25%、16.67%比87.25%,均p0.001)。CR、PR组的Co以及C0/D值均较NR组高,且随用药时间延长而提高,但组间差异无统计学意义(p0.05)。结论:对于IMN患者,不同CYP3A56986AG达到目标血药浓度时用药剂量不同,据此,可推断不同基因型患者的初始用药剂量,并结合TDM,具有一定的临床实用价值。研究二:五酯胶囊对CYP3A5基因表达型特发性膜性肾病患者他克莫司药代动力学指标的影响研究目的:针对CYP3A5基因表达型的特发性膜性肾病(IMN)患者,联合应用五酯胶囊(WZC),观察五酯胶囊对他克莫司药代动力学的影响,并注意联用后的稳定性和安全性,初步推断联合用药后他克莫司的用药剂量。方法:滨州医学院附属医院肾内科住院的患者,经肾穿刺病理活检诊断为特发性膜性肾病(IMN),且FISH检测CYP3A5基因分型均为CYP3A5基因表达型(即AA、AG),共68例,应用随机数字表进行分组,分别为治疗组(五酯胶囊联合他克莫司胶囊)、对照组(单用他克莫司胶囊),每组均为34例,实验组失访2例,对照组失访1例。对两组患者治疗开始8周、16周、24周时他克莫司用药剂量D、全血谷浓度C0、剂量-调整谷浓度C0/D进行比较,比较治疗24周两组患者的有效率和不良反应发生率。结果:对于CYP3A5基因表达型特发性膜性肾病而言,治疗开始8周、16周、24周的各访视点上,两组患者的C0无显著差异(p0.05);组间比较:治疗组的D较对照组显著降低(p0.001),C0/D较对照组显著升高(p0.001);两组患者组内比较时不同访视点D、C0/D的差异无统计学意义(p0.05),治疗组他克莫司的平均用药剂量为(0.037±0.002)mg.kg-1.d-1,约为对照组平均用药剂量的60%。治疗24周,两组患者的治疗有效率以及不良反应发生率的差异无统计学意义(p0.05),但治疗组的有效率较对照组有所升高。结论:五酯胶囊可减少CYP3A598G基因表达型(AA、AG) IMN患者他克莫司的用药剂量,作用安全、平稳,减轻了患者的经济负担,且不增加药物相关毒副作用。
[Abstract]:Study 1: the effect of CYP3A5 gene polymorphism on the pharmacokinetic index of tacrolimus in patients with idiopathic membranous nephropathy. Objective: To observe the specific CYP3A5 genotype of idiopathic membranous nephropathy (idiopathic membranous nephropathy, IMN) in patients with prednisone combined with tacrolimus, TAC (tacrolimus, TAC) for June, to achieve the target whole blood Valley concentration. The relationship between the different genotypes and the dose of tacrolimus was deduced, and the individualized treatment model of tacrolimus guided by genotyping was preliminarily explored. Methods: the selected cases were all from the hospitalized nephrology in Affiliated Hospital of Binzhou Medical College, the clinical manifestation was nephrotic syndrome, NS, and the pathological diagnosis was idiopathic. 60 patients with Idiopathic Membranous Nephropathy (IMN) were detected by fluorescence staining in situ hybridization (fluorescence in situ hybridization, FISH) technique for the detection of CYP3A5 genotypes. At 8 weeks, 12 weeks, 16 weeks and 24 weeks, the total blood Valley concentration of tacrolimus was C0, the dosage of the drug was D, and the dose adjustment Valley concentration C0/D. was divided into complete remission (CR), partial remission (PR) and ineffective (NR) 3 groups according to the clinical effect. The changes of the TAC pharmacokinetics index of the three groups of patients were compared. Results: 60 cases of idiopathic membranous nephropathy patients CYP3A5 The gene frequency of gene polymorphism (6986AG) G was 53.33%, of which 12 cases (20%) in group AA, 32 cases (53.33%), 16 cases in group GG, 16 (26.67%) in group.3, for 8 weeks, 12 weeks, 16 weeks, and 24 weeks, and the difference in dose adjustment Valley concentration (C0/D) was statistically significant (P0.05) the dosage of tacrolimus (D) in group.AA patients (D) was about 2~3 times in group GG and 1~2 times in group AG. The remission rate of group AA for 24 weeks was significantly lower than that of AG, group GG (16.67% to 81.25%, 16.67% ratio 87.25%, p0.001).CR, PR group Co and C0/D were higher than that of NR group, and increased with the duration of drug use, but there was no statistical difference between the groups. Conclusion: for the patients, there is no statistical difference. Conclusion: for the patients, there is no statistical difference. Conclusion: for the patients, there is no statistical difference. Conclusion: the difference between the groups is not statistically significant. Conclusion: the difference between the groups is not statistically significant. Conclusion: for the patients, there is no statistical difference. Conclusion: the difference between the groups is not statistically significant. Conclusion: the difference between the groups is not statistically significant. Conclusion: for the patients, there is no statistical difference. Conclusion: the difference between the groups is not statistically significant. Conclusion: the difference between the groups is not statistically significant. Conclusion: for the patients, there is no statistical difference. Conclusion: the difference between the groups is not statistically significant. Conclusion: for the patients, there is no statistical difference. Conclusion: for patients, there is no statistical difference. Conclusion: The dosage of G is different when it reaches the target blood concentration. According to this, we can infer the initial dosage of different genotype patients and combine with TDM, it has certain clinical practical value. Study two: the effect of five ester capsule on the pharmacokinetic index of tacrolimus in patients with CYP3A5 gene expression type idiopathic membranous nephropathy: aim at the CYP3A5 gene The expression type of idiopathic membranous nephropathy (IMN) patients, combined with five ester capsule (WZC), observed the effect of five ester capsule on the pharmacokinetics of tacrolimus, and paid attention to the stability and safety after combined use. The dosage of tacrolimus after combined use was preliminarily deduced. Pathological biopsy was diagnosed as idiopathic membranous nephropathy (IMN), and the FISH genotyping of CYP3A5 was CYP3A5 gene expression type (AA, AG). A total of 68 cases were divided into the treatment group (five ester capsule combined with Tacrolimus Capsules), the control group (single Tacrolimus Capsules), 34 cases in each group, and 2 cases in the experimental group. The two groups of patients were treated for 1 cases. At 8 weeks, 16 weeks and 24 weeks, the dosage of tacrolimus was D, the whole blood Valley concentration was C0, the dose adjusted Valley concentration C0/D was compared, and the rates of efficiency and adverse reactions were compared for two groups of patients in the 24 weeks. Results: for the CYP3A5 gene expression type idiopathic membranous nephropathy, the treatment began for 8 weeks, 16 weeks, 24 There was no significant difference in C0 between the two groups of patients (P0.05). Compared with the control group, the D in the treatment group was significantly lower than that in the control group (p0.001), and C0/D was significantly higher than the control group (p0.001). The difference of view point D in the two group was not statistically significant (P0.05), and the average dosage of tacrolimus in the treatment group was (0.037 + 0.002). Mg.kg-1.d-1, the average dose of 60%. in the control group was about 24 weeks. There was no significant difference in the effective rate of treatment and the incidence of adverse reactions between the two groups (P0.05), but the effective rate of the treatment group was higher than that of the control group. Conclusion: five ester capsules can reduce the dosage of tacrolimus in the CYP3A598G gene expression type (AA, AG) IMN patients. The dosage is safe and stable, which reduces the economic burden of patients and does not increase the side effects of drugs.
【学位授予单位】：滨州医学院
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R692

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