CYP3A5和ABCB1多态性对肾移植受者由环孢素转换为他克莫司个体化给药的影响

Impact of CYP3A5 and ABCB1 polymorphisms on drug switching from cyclosporine to tacrolimus for individualized treatment of renal transplant recipients

目的探讨CYP3A5和ABCB1基因多态性对肾移植受者将环孢素(cyclosporine A,CsA)转换为他克莫司(tacrolimus,FK506)后的初始他克莫司个体化给药的影响。方法利用聚合酶链反应(PCR)和限制性内切片段长度多态性(PCR-RFLP)方法检测CYP3A5*3(A6989G)和ABCB1 3个位点exon12C1236T、exon21G(A)2677T和exon26C3435T基因型;回顾性评价CYP3A5和ABCB1 3个位点基因型及单倍体型对由CsA转换为他克莫司的肾移植受者他克莫司初始血药谷浓度/剂量比(concentration/dose,C0/D)的影响。结果对于由CsA转换为他克莫司的肾移植受者,在转换后的第7、14、21和28天,CYP3A5AA、AG与GG组的他克莫司C0/D之间差异有统计学意义(P<0.05);当第28天CYP3A5AA组和AG组的他克莫司日剂量D分别达到GG组的3.5倍[(0.14±0.03)mg·kg-1 vs(0.04±0.01)mg·kg-1,P=0.00]和1.75倍[(0.07±0.03)mg·kg-1 vs(0.04±0.01)mg·kg-1,P=0.00]时,CYP3A5不同基因型的他克莫司C0才达到同一靶浓度。对于由CsA转换为他克莫司的CYP3A5GG肾移植受者,ABCB1C1236T、G(A)2677T和C3435T基因型及其纯合子单倍体型对初始他克莫司C0/D无影响(P>0.05)。结论对于需将CsA转换为他克莫司肾移植受者,应根据CYP3A5基因型选择他克莫司的初始给药日剂量,以期迅速达到有效免疫抑制效果。

Objective To investigate the impact of CYP3A5 and ABCB1 polymorphisms on the initial individualized treatment with taerolimus （FK506） in renal transplant recipients during switching from cyclosporine （CsA） to FK506. Methods Polymerase chain reaction and restriction fragment length polymorphism method （PCR-RFLP） was employed to investigate CYP3A5 （A6989G） and ABCB1 （exon12[C1236T],exon21G[A]2677T and exon26 [C3435T]） genotype data. The initial trough concentration/dose （C0/D） values were compared among different CYP3A5 genotypes in renal transplant recipients switching from CsA to FK506 using one-way ANOVA. In addition, the initial Co/D values were also compared among different ABCB1 （exon12[C1236T] ,exon21G[A]2677T and exon26[C3435T]） genotypes and their haplotypes using one-way ANOVA. Results The FKSGG C0/D values were significantly different hetween different CYP3A5 genotypes （AA, AG and GG） at the 7th , 14th , 21th and 28th day of conversion from CsA to FK506 in renal transplant recipients （P（0.05）. Only on the 28th day ofconversion, when the FK506 D in CYP3A5AA group was 3.5-fold that of CYP3A5GG group[0. 14±0.03] mg·kg^-1·d^-1 vs [0.04±0.01] mg·kg^-1·d^-1, P=0.00） and the FK506 D in CYP3A5AG group was 1.75-fold that of CYP3A5GG group （E0. 07±0. 03] mg·kg^-1·d^-1 vs E0. 04±0. 01] mg·kg^-1·d^-1, P=0.00）, the FK506 Co in different CYP3A5 genotypes reached the same target concentration. The initial FKS06 C0/D was not associated with different ABCB1 （exon12 [C1236T], exon21 G[A] 2677T and exon26 [C3435T]） genotypes or their haplotypes in renal transplant recipients. Conclusion Appropriate initial daily dose of FKS06 should be selected according to CYP3A5 genotype in order to quickly achieve the target immunosuppression in renal transplant recipients who are switching immunosuppressive regimen from CsA to FK506.