CAJ | 학술논문

目的研究肾移植受者细胞色素P450 3A(CYP3A)酶系中CYP3A5基因多态性指导他克奠司的个体化用药.方法 2011年1月至2012年10月间254例尿毒症患者接受了肾移植,将接受首次肾移植及术后采用他克莫司+吗替麦考酚酯+泼尼松方案的成人受者172例纳入研究.术前均采用聚合酶链反应及限制性片段长度多态性分析法测定受者CYP3A5基因型,依据CYP3A5基因型结果给予不同初始剂量的他克莫司,其中CYP3A5* 1/*1型(Ⅰ组,17例)为0.15 mg·kg-1 ·d-1,*1/*3型(Ⅱ组,77例)为0.13～0.15 mg·kg-1·d-1,*3/*3型(Ⅲ组,78例)为0.10～0.12 mg*kg-1 ·d-1.术后1周、2周、1个月、3个月、6个月和12月时,采用荧光偏振免疫分析法监测全血他克奠司浓度谷值(C0),同时依据C0和移植肾功能等指标调整他克莫司剂量,统计各组C0与剂量的比值;检测各组受者肾功能等指标.结果肾移植后随着受者服用他克莫司时间的延长,他克莫司的剂量逐渐减少,C0也逐渐下降.Ⅰ组受者术后他克莫司C0与剂量比值缓慢升高,1个月后趋于稳定;Ⅱ组和Ⅲ组受者他克莫司C0与剂量比值随时间的延长逐渐升高.术后前3个月,Ⅰ组和Ⅱ组受者他克莫司C0与剂量比值间的差异无统计学意义(P＞0.05),3个月后,二者间差异有统计学意义(P＜0.05);术后1年内,Ⅱ组和Ⅲ组受者他克莫司C0与剂量比值间的差异有统计学意义(P＜0.05),1年后二者间差异无统计学意义(P＞0.05).结论 CYP3A5*1/*1型受者对他克莫司的代谢快,肾移植后早期应适当加大他克莫司剂量以达到目标浓度;*1/*3型受者对他克莫司的代谢先慢后快,早期剂量应加大,并控制后期减量速度,3个月后可适当加快减量速度;*3/*3型受者对他克莫司的代谢慢,早期应给予低剂量,后期药物减量速度应适当加快.
목적 연구신이식수자세포색소P450 3A(CYP3A)매계중CYP3A5기인다태성지도타극전사적개체화용약.방법 2011년1월지2012년10월간254례뇨독증환자접수료신이식,장접수수차신이식급술후채용타극막사+마체맥고분지+발니송방안적성인수자172례납입연구.술전균채용취합매련반응급한제성편단장도다태성분석법측정수자CYP3A5기인형,의거CYP3A5기인형결과급여불동초시제량적타극막사,기중CYP3A5* 1/*1형(Ⅰ조,17례)위0.15 mg·kg-1 ·d-1,*1/*3형(Ⅱ조,77례)위0.13～0.15 mg·kg-1·d-1,*3/*3형(Ⅲ조,78례)위0.10～0.12 mg*kg-1 ·d-1.술후1주、2주、1개월、3개월、6개월화12월시,채용형광편진면역분석법감측전혈타극전사농도곡치(C0),동시의거C0화이식신공능등지표조정타극막사제량,통계각조C0여제량적비치;검측각조수자신공능등지표.결과 신이식후수착수자복용타극막사시간적연장,타극막사적제량축점감소,C0야축점하강.Ⅰ조수자술후타극막사C0여제량비치완만승고,1개월후추우은정;Ⅱ조화Ⅲ조수자타극막사C0여제량비치수시간적연장축점승고.술후전3개월,Ⅰ조화Ⅱ조수자타극막사C0여제량비치간적차이무통계학의의(P＞0.05),3개월후,이자간차이유통계학의의(P＜0.05);술후1년내,Ⅱ조화Ⅲ조수자타극막사C0여제량비치간적차이유통계학의의(P＜0.05),1년후이자간차이무통계학의의(P＞0.05).결론 CYP3A5*1/*1형수자대타극막사적대사쾌,신이식후조기응괄당가대타극막사제량이체도목표농도;*1/*3형수자대타극막사적대사선만후쾌,조기제량응가대,병공제후기감량속도,3개월후가괄당가쾌감량속도;*3/*3형수자대타극막사적대사만,조기응급여저제량,후기약물감량속도응괄당가쾌.
Objective To investigate the individualized administration of Tacrolimus in renal transplant recipients and the gene polymorphism of CYP3A5 in cytochrorme P450 3A (CYP3A) enzymes.Method 254 uremia patients received kidney transplants from January 2011 to October 2012,and 172 adult recipients who received kidney transplants for the first time and treated with Tacrolimus + myeophenolate mofetil + prednisone triple immunosuppressive regimen after renal transplantation were enrolled in this study.CYP3A5 genotype was determined by polymemse chain reaction and restriction fragment length polymorphism analysis.Different initial Tacrolimus doses were given according to CYP3A5 genotype of the recipients:0.15 rmg·kg-1 ·d-1 for CYP3A5 * 1/* 1 type (group Ⅰ,17 cases),0.13-0.15 rmg·kg-1 ·d-1 for * 1/* 3 type (group Ⅱ,77 cases),and 0.10-0.12 mg·kg-1 ·d-1 for * 3/* 3 type (group Ⅲ,78 cases).At 1st week,2nd week,1st month,3rd momh,6th month and 12th month post-operation,fluorescence polarization immunoassay was used to measure the whole blood trough concentration of Tacrolimus (C0),while according to Tacrolimus trough levels (C0),kidney function and other indicators were applied to adjust the tacrolimus dosage and calculate Tacrolimus trough concentration (C0)/dose ratio in each group.At the same time,kidney function and other indicators were detected.Results With time of Tacrolimus administration after kidney transplantation,the Tacrolimus dose was reduced gradually,and Tacrolimus trough concentration (C0) was also declined gradually.Tacrolimus trough concemration (C0)/dose ratio was increased slowly,and it was stable one month later in group I.Tacrolimus trough concentration (Co)/dose ratio was increased gradually with time in groups Ⅱ and Ⅲ.At the first three months,there was no statistically significant difference in Tacmlimus trough concentration (C0)/dose ratio between group Ⅰ and group Ⅱ (P＞0.05),and 3 months later,there existed statistically significant difference between them (P＜ 0.05).During the first one year,Tacrolimus trough concemration (C0)/dose ratio showed statistically significant difference between group Ⅱ and group Ⅲ (P＜0.05).After one year,there was no significant difference in Tacrolimus trough concentration (C0)/dose ratio between them group Ⅱ and group]Ⅲ (P＞ 0.05).Conclusion * 1/* 1 recipients have a faster rate in the basic metabolism of Tacrolimus,so we should increase doses in the early stage properly after Kidney Transplantation to achieve the target trough concentration.* 1/* 3 recipients on Tacrolimus show slow-fast metabolism.So the initial doses should increase and the speed of dosage reducing should be controlled in late stage.Three months later,the speed of the dosage reducing can be accelerated appropriately.* 3/* 3 recipients have a slower metabolism of Tacrolimus,which tells us that we should decrease the initial doses and accelerate the speed of doses reducing properly in late stage.