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  

Association between CYP3A5 genotypes and early efficacy of tacrolimus and cyclosporin A in kidney transplantation recipients

作　　者：潘晓东[1] 陈文伟[1] 倪晓洁[1] 王瑾珺[1] 吴存造[1] 蔡勇[1] 夏鹏[1] 郑少玲[1] 陈必成[1] 

机构地区：[1]温州医科大学附属第一医院移植中心,浙江温州325000

出　　处：《中国药理学与毒理学杂志》2014年第6期892-897,共6页Chinese Journal of Pharmacology and Toxicology

基　　金：温州市科技计划项目(H20100070);浙江省自然科学基金(Y2110944);浙江省自然科学基金(LY12H10004)~~

摘　　要：目的研究细胞色素P-450酶(CYP)家族中CYP3A5基因多态性与肾移植术后他克莫司(Tac)和环孢素A(Cs A)早期临床疗效的相关性,为其个体化治疗提供依据。方法选取2012.08-2013.04期间肾移植受者74例,其中术后口服给予Tac+吗替麦考酚酯胶囊(MMF)+甲泼尼松龙三联用药的43例,给予Cs A+MMF+甲基强的松龙三联用药的31例。术前应用序列特异性引物-PCR(SSP-PCR)检测受者CYP3A5基因型;分别采用ELISA和化学发光法检测全血Tac和Cs A浓度,监测术后2周及1,2,3和6个月血药浓度/剂量比(c/D);同时用己糖激酶法检测血糖、肌酐酶法检测肌酐、尿素酶法检测尿素氮和尿酸酶法检测尿酸水平。结果 74例肾移植受者中,CYP3A5*1/*1型占9.5%,CYP3A5*1/*3型占48.6%,CYP3A5*3/*3型占41.9%。按其表型可分为CYP3A5表达型(包括CYP3A5*1/*1型和CYP3A5*1/*3型)和不表达型(CYP3A5*3/*3型),分别占58.1%和41.9%。Tac受者中CYP3A5表达型在术后2周及1,2,3和6个月时c/D中位值分别为25.49,49.64,53.72,51.93和44.5;CYP3A5不表达型受者则分别为65.48,100.84,99.54,123.01和133.21;前者均明显低于后者(P<0.05)。对于CYP3A5不表达型受者,Tac的起始剂量(0.1 mg·kg-1)偏大,术后早期肾功能恢复较表达型慢,存在一定的肾毒性损伤。而CYP3A5基因型与Cs A疗效无明显相关性,Cs A受者上述各时间点血药浓度、血糖、肌酐、尿素氮和尿酸等CYP3A5表达型和CYP3A5不表达型均无显著性差异。结论 CYP3A5不表达型受者使用常规Tac 0.1 mg·kg-1的起始剂量存在一定程度的药物过量,CYP3A5表型是影响Tac肾移植术后受者早期疗效的因素之一。而CYP3A5基因型与术后早期Cs A的疗效无相关性。OBJECTlVE To investigate the association between CYP3A5 genotypes and the early efficacy of tacrolimus （ Tac） and cyclosporin A （ CsA） in renal transplantation recipients, and provide a basis for individualized treatment. METHODS Seventy-four kidney transplantation recipients were en-rolled in this study between August 2012 and April 2013. Thirty-one patients were treated with the combi-nation of CsA, MMF and methylprednisolone while the rest were treated with Tac, MMF and methylpred-nisolone. The genotype CYP3A5 was detected by sequence specific primer-polymerase chain reaction （ SSP-PCR） before transplantation. The levels of Tac and CsA were detected by ELlSA and chemilumi-nescence, respectively, to monitor the blood concentration/dose of drugs （ c/D） at 2 weeks, 1 month, 2 months, 3 months and 6 months after transplantation. Simultaneously, the concentrations of blood glu-cose, creatinine, urea nitrogen and uric acid were determined with hexokinase method, creatininase method, urease method and uricolase method, respectively. RESULTS Among the 74 recipients, 9.5%carried CYP3A5＊1/＊1, 48.6%carried CYP3A5＊1/＊3 and 41.9%carried CYP3A5＊3/＊3. According to the phenotype of CYP3A5, the patients were divided into CYP3A5 expression group （ including CYP3A5＊1/＊1 and CYP3A5＊1/＊3） and non-expression group （ including CYP3A5＊3/＊3） , which accounted for 58.1%and 41.9%of the cases, respectively. Among the patients taking Tac, the median value of c/D at 2 weeks, 1 month, 2 months, 3 months and 6 months was 25.49, 49.64, 53.72, 51.9 and 44.5 in CYP3A5 expression group, and 65.48,100.84,99.54,123.01 and 133.21 in non-expression group. The c/D ratio of CYP3A5 non-expressers was higher than among CYP3A5 expressers at each time point （ P〈0.05） . The initial dose of Tac 0.1 mg·kg^-1 was high for CYP3A5 non-expressers, and the kidney function recovered more slowly than among CYP3A5 expressers and kidney damage occurred. However, there was no association between CYP3A5 genotype an

关 键 词：肾移植 细胞色素P450 CYP3A5 他克莫司 环孢素A 

分 类 号：R969[医药卫生—药理学]