CYP3A5基因多态性对肾移植术后患者他克莫司代谢的影响

doi:10.13481/j.1671-587x.20180315

摘要/Abstract

摘要： 目的：探讨不同CYP3A5基因型对肾移植术后患者血他克莫司浓度的影响，为肾移植术后患者他克莫司个体化治疗提供依据。方法：回顾性分析115例肾移植术后患者的临床资料，根据CYP3A5基因型分为野生纯合子组（CYP3A5*1/*1型，11例）、突变杂合子组（CYP3A5*1/*3型，46例）和突变纯合子组（CYP3A5*3/*3型，58例），记录3组患者术后不同时间点（7d、1个月、3个月、6个月、1年和2年）有效的血他克莫司浓度/剂量（C₀/D）值。结果：3组患者体质量指数（BMI）、年龄构成比和性别构成比比较差异均无统计学意义（P>0.05）。与突变杂合子组比较，野生纯合子组患者术后7d、3个月、1年和2年他克莫司C₀/D值明显降低（P=0.011，P<0.01，P=0.022，P=0.024）；与突变纯合子组比较，野生纯合子组和突变杂合子组患者术后各个时段他克莫司C₀/D值均明显降低（P<0.01）。野生纯合子组术后7d患者他克莫司C₀/D值明显低于术后6个月、1年和2年（P=0.004，P=0.049，P=0.036）；突变杂合子组术后7d患者他克莫司C₀/D值明显低于术后1个月、3个月、6个月、1年和2年（P=0.006，P<0.01，P<0.01，P<0.01，P<0.01），术后1个月患者他克莫司C₀/D值明显低于术后6个月（P=0.013）；突变纯合子组术后7d患者他克莫司C₀/D值明显低于术后1个月、3个月、6个月、1年和2年（P=0.002，P<0.01，P<0.01，P<0.01，P<0.01）。结论：CYP3A5基因多态性对肾移植术后患者血他克莫司浓度有明显影响，且这种影响可持续至术后2年。

关键词: 肾移植, CYP3A5基因, 他克莫司, 基因多态性

Abstract: Objective: To investigate the effects of different CYP3A5 genotypes on the concentrations of tacrolimus in blood of the patients after kidney transplantation,and to provide the valuable evidence for personalized administration in the patients after kidney transplantation. Methods: The clinical materials of 115 patients after kidney transplantation were analyzed retrospectively.The patients were divided into three groups according to the CYP3A5 genotypes:CYP3A5*1/*1 group(11 cases), CYP3A5*1/*3 group(46 cases) and CYP3A5*3/*3 group(58 cases).The concentration/dosage (C₀/D) values of tacrolimus in blood of the patients in three groups at 7 d,1 month,3 months,6 months,1 year, and 2 years after operation were detected,respectively. Results: The differences of body mass index(BMI),age composition ratios and gender composition ratios of the patients were not significant between three groups(P>0.05).Compared with CYP3A5*1/*3 group,the C₀/D values of tacrolimus in blood of the patients in CYP3A5*1/*1 group at 7 d,3 months,1 year and 2 years after operation were decreased(P=0.011,P<0.01,P=0.022,P=0.024);compared with CYP3A5*3/*3 group,the C₀/D values of tacrolimus in blood of the patients in CYP3A5*1/*1 group and CYP3A5*1/*3 group at 7 d, 1 months,3 months,6 months,1 year and 2 years after operation were decreased(P<0.01).In CYP3A5*1/*1 group,the C₀/D value of tacrolimus in blood of the patients at 7 d after operation was significantly lower than those at 6 months,1 year and 2 years after operation (P=0.004,P=0.049,P=0.036); in CYP3A5*1/*3 group,the C₀/D value of tacrolimus in blood of the patients at 7 d after operation was significantly lower than those at 1 month,3 months,6 months,1 year and 2 years after operation(P=0.006,P<0.01,P<0.01,P<0.01,P<0.01),and the C₀/D value of tacrolimus in blood of the patients at 1 month after operation was significantly lower than that at 6 months after operation(P=0.013); in CYP3A5*3/*3 group,the C₀/D value of tacrolimus in blood of the patients at 7 d after operation was significantly lower than those at 1 month,3 months,6 months,1 year and 2 years after operation(P=0.002,P<0.01,P<0.01,P<0.01,P<0.01). Conclusion: The CYP3A5 genetic polymorphism has a significant impact on the metabolism of tacrolimus in blood of the patients after kidney transplantation,and the impact could last for two years.

Key words: kidney transplantation, CYP3A5 genotype, tacrolimus, genetic polymorphism

中图分类号:

R692.5

王明睿, 翟秀宇, 王钢, 张文岚, 高宝山, 周洪澜, 傅耀文. CYP3A5基因多态性对肾移植术后患者他克莫司代谢的影响[J]. 吉林大学学报(医学版), 2018, 44(03): 537-542.

WANG Mingrui, ZHAI Xiuyu, WANG Gang, ZHANG Wenlan, GAO Baoshan, ZHOU Honglan, FU Yaowen. Effects of CYP3A5 genetic polymorphisms on metabolism of tacrolimus in patients after kidney transplantation[J]. Journal of Jilin University Medicine Edition, 2018, 44(03): 537-542.

参考文献

[1] 戴立波,杨宏昕,韩晓芳,等.他克莫司治疗药物监测与合理用药分析[J]. 世界最新医学信息文摘,2017,17(57):109,112.
[2] Chen JS,Li LS,Cheng DR,et al.Effect of CYP3A5 genotype on renal allograft recipients treated with tacrolimus[J].Transplant Proc,2009,41(5):1557-1561.
[3] 付生军,刘静,李涛,等.CYP3A5基因型与肾移植患者他克莫司血药浓度关系的系统评价[J].中国循证医学杂志,2013,13(12):1440-1445.
[4] Hirano K,Naito T,Mino Y,et al.Impact of CYP3A5 genetic polymorphism on cross-reactivity in tacrolimus chemiluminescent immunoassay in kidney transplant recipients[J].Clin Chim Acta,2012,414:S120-S124.
[5] Coto E,Tavira B.Pharmacogenetics of calcineurin inhibitors in renal transplantation[J].Transplantation,2009,88(3 Suppl):S62-S67.
[6] 赵富磊,李骞,张峻.基因多态性对肾移植患者他克莫司药代动力学影响的研究现状[J].中国临床药理学杂志,2017,33(23):2489-2491.
[7] Meier-Kriesche HU,Li S,Gruessner RW,et al.Immunosuppression:evolution in practice and trends,1994-2004[J].Am J Transplant,2006,6(5pt2):1111-1131.
[8] 中华人民共和国国家卫生和计划生育委员会.药物代谢酶和药物作用靶点基因检测技术指南(试行)概要[J].实用器官移植电子杂志,2015,3(5):257-267.
[9] Li D,Zhang GL,Lou YQ,et al.Genetic polymorphisms in MDR1 and CYP3A5 and MDR1 haplotype in mainland Chinese Han,Uygur and Kazakh ethnic groups[J].Clin Pharm Ther,2007,32(1):89-95.
[10] 李敏,李峰,高鑫.基因多态性对他克莫司血药浓度影响的研究进展[J].实用医药杂志,2017,34(2):162-164.
[11] 丁晴,冯端浩.CYP3A5基因多态性与临床合理用药[J].解放军药学学报,2015,31(5):435-438.
[12] 陈晨,张晏洁,贺小露,等.他克莫司个体化用药指南解读[J].医学研究生学报,2017,30(4):342-347.
[13] 张小东,张际青,尹航,等.CYP3A5基因型对肾移植受者术后早期血他克莫司浓度的影响[J].中华器官移植杂志,2009,30(12):717-721.
[14] 林玲,宋文利,沈中阳,等.肾移植受者C YP3A5*3和CYP3A4*18B对他克莫司药动学的影响[J].中华器官移植杂志,2012,33(4):220-224.
[15] 潘晓东,陈文伟,倪晓洁,等.药物代谢酶CYP3A5基因多态性与肾移植术后他克莫司和环孢素A早期临床疗效的相关性[J].中国药理学与毒理学杂志,2014,28(6):892-897.
[16] 程晓莉,李志荣,颜学滔.CYP3A5*3基因多态性对环孢素药动学的影响[J].中国医院药学杂志,2010,30(8):636-639.
[17] 孙搏,郭彦琨,高君伟,等.CYP3A基因多态性与肾移植术后不同时期环孢素浓度剂量个体差异的相关性研究[J].中国药师,2017,20(1):91-93.
[18] 何霞,童荣生,肖开春,等.他克莫司血药浓度影响因素的研究进展[J].中国药业,2011,20(11):80.
[19] Hu RH,Lee PH,Tsai MK.Clinical influencing factors for daily dose,trough level,and relative clearance of tacrolimus in renal transplant recipients[J].Transplant Proc,2000,32(7):1689-1692.
[20] Zahir H,McLachlan AJ,Nelson A,et al.Population pharmacokinetic estimation of tacrolimus apparent clearance in adult liver transplant recipients[J].Ther Drug Monit,2005,27(4):422-430.
[21] 张关敏,李良,陈文倩,等.他克莫司在中国肾移植患者中的群体药物动力学研究[J].药学学报,2008, 43(7):695-701.
[22] 张鑫,刘志红,郑敬民,等.肾移植患者他克莫司血药浓度的影响因素[J].肾脏病与透析肾移植杂志, 2005,14(4):333-338.
[23] Chow FS,Piekoszewski W,Jusko WJ.Effect of hematocrit and albumin concentration on hepatic clearance of tacrolimus (FK 506) during rabbit liver perfusion[J].Drug Metab Dispos,1997,25(5):610-616.
[24] 张大伟,许亮,徐俊楠,等.肾移植受者术前甘油三酯代谢对移植肾早期功能恢复的影响[J].解放军医学杂志,2017,42(5):427-431.