CYP3A5基因多态性与肾移植受者他克莫司浓度/剂量的关系及个体化用药

Correlation of CY3A5 genetic polymorphism with concentration/dosage of tacrolimus and individualized administration of tacrolimus after kidney transplantation

背景:CYP3A5基因多态性可显著影响肾移植术后早期他克莫司血药浓度,国内许多的研究局限于肾移植后早期3个月内,缺乏对受者术后稳定期的影响。目的:探讨CYP3A5基因多态性与肾移植受者他克莫司浓度/剂量(C0/D)之间的关系,比较不同基因型之间的差异,为肾移植受者术后他克莫司个体化用药提供方案。方法:接受肾移植及术后均采用他克莫司(FK506)+霉酚酸酯(MMF)+泼尼松(Pred)免疫抑制治疗方案的65例成人受者,术前均检测受者CYP3A5基因型,按CYP3A5*1/*1、*1/*3、*3/*3型分为3组,监测受者术后他克莫司全血谷浓度C0指标,记录不同时间点3组受者他克莫司血药C0/D值。研究的治疗方案的实施符合北部战区空军医院的相关伦理要求。结果与结论:①CYP3A5*1/*1、*1/*3、*3/*3基因型的肾移植受者分别是6,25和34例;②CYP3A5*1/*1和*1/*3基因型受者组术后各个时间段他克莫司C0/D比值均明显低于*3/*3基因型受者组(P<0.05);*1/*1型受者组术后7,14 d时的他克莫司C0/D比值低于*1/*3型受者组(P=0.028,P=0.034);③*1/*1型受者组术后7d他克莫司C0/D值明显低于术后6个月、1年(P=0.35,P=0.41);*1/*3型受者组术后7 d时他克莫司C0/D值明显低于术后3,6个月及1年(P=0.029,P=0.07),术后14 d、1个月低于术后6个月、1年(P=0.04,P=0.39);*3/*3型受者术后7 d时他克莫司C0/D值明显低于术后3,6个月、1年(P=0.029,P=0.03),术后14 d明显低于术后6月、1年(P=0.022);④结果说明,CYP3A5基因多态性对肾移植受者术后的他克莫司C0/D值有显著影响,且可维持到移植术后长时间的稳定期。CYP3A5*1/*1、*1/*3型受者早期他克莫司代谢较快,要加大他克莫司给药剂量来维持目标血药浓度;*1/*3型受者剂量可适当比前者略少,后期应减慢减药速度;*3/*3型受者他克莫司代谢缓慢,早期应给予小剂量,后期应加快减药速度。

BACKGROUND:Polymorphism of CYP3A5 gene can significantly affect the blood concentration of tacrolimus in the early period after kidney transplantation.Many studies in China are limited to the early 3 months after kidney transplantation with no concern on the long-term effect of tacrolimus in recipients.OBJECTIVE:To investigate the relationship between the polymorphism of CYP3A5 gene and tacrolimus concentration/dose(C0/D)in kidney transplant recipients,and to compare the differences among different genotypes,so as to provide an individualized drug regimen of tacrolimus after kidney transplantation.METHODS:Sixty-five adult recipients who underwent kidney transplantation and postoperative administration of tacrolimus(FK506)+mycophenolate mofetil(MMF)+prednisone(Pred)immunosuppressive therapy were divided into three groups according to their CYP3A5 genotypes detected preoperatively:CYP3A5*1/*1,*1/*3,and*3/*3 groups.The whole blood concentration of tacrolimus was monitored in all the recipients,and C0/D value was recorded in each group at different time points after surgery.The study protocol was in line with the ethical requirements of Air Force Hospital of Northern Theater Command.RESULTS AND CONCLUSION:There were 6,25 and 34 recipients of CYP3A5*1/*1,*1/*3 and*3/*3,respectively.The C0/D value of tacrolimus in the CYP3A5*1/*1 and*1/*3 groups was significantly lower than that in the CYP3A5*3/*3 group(P<0.05).At 7 and 14 days after surgery,the C0/D value of tacrolimus in the CYP3A5*1/*1 group was lower than that in the CYP3A5*1/*3 group(P=0.028,P=0.034).In the CYP3A5*1/*1 group,the C0/D value of tacrolimus at 7 days after surgery was significantly lower than that at 6 months and 1 year after surgery(P=0.35,P=0.41).In the CYP3A5*1/*3 group,the C0/D value of tacrolimus at 7 days after surgery was significantly lower than that at 3 months,6 months and 1 year after surgery(P=0.029,P=0.07,P<0.01),and that at 14 days and 1 month after surgery was significantly lower than that at 6 months and 1 year after surgery(P=0.04,P=0.39).In the CYP3A5*3/*3 group,the C0/D value of tacrolimus at 7 days after surgery was significantly lower than that at 3 months,6 months and 1 year after surgery(P=0.029,P=0.03),and that at 14 days after surgery was significantly lower than that at 6 months and 1 year after surgery(P=0.022).Overall findings indicate that the polymorphism of CYP3A5 gene has a significant effect on the C0/D value of tacrolimus in kidney transplant recipients,which can be maintained for a long-term stable period after transplantation.For CYP3A5*1/*1 and*1/*3 recipients,the metabolism of tacrolimus is faster in the early stage,and the dosage of tacrolimus should be increased to maintain the target blood concentration,whereas for CYP3A5*1/*3 recipients,the dosage of tacrolimus may be moderately less than the former and the drug reduction rate should be slowed down in the later stage.CYP3A5*3/*3 recipients have a slow metabolism of tacrolimus,and should be given a small dose in the early stage,and the reduction rate should be accelerated in the later stage.