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

摘要

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 and the early efficacy of CsA. The levels of blood glucose, creatinine, urea nitrogen and uric acid were not significantly different between CYP3A5 expression and non-expression groups. CONCLUSlON CYP3A5 non-expression recipients whose starting amount of Tac was 0.1 mg·kg-1 have drug overdoses. CYP3A5 genotype is one of the factors affecting the efficacy of Tac. CYP3A5 genotype has no association with the efficacy of CsA in renal transplantation recipients.%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( CsA)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CsA＋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ELlSA和化学发光法检测全血Tac和CsA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 CsA疗效无明显相关性,CsA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CsA的疗效无相关性。