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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 effect of polymorphisms of CYP3A5 and ABCB1 on the initiation of tacrolimus administration in individual recipients after cyclosporine A (CsA) conversion to tacrolimus (FK506). Methods The genotypes of exon12C1236T, exon21G (A) 2677T and exon26C3435T were detected by polymerase chain reaction (PCR) and restriction fragment length polymorphism (PCR-RFLP) Retrospective evaluation of CYP3A5 and ABCB1 three loci genotypes and haplotypes for the conversion of CsA to Tacrolimus in renal transplant recipients tacrolimus initial plasma concentration / dose ratio (concentration / dose, C0 / D )Impact. Results For renal transplant recipients converted from CsA to Tacrolimus, there was a statistically significant difference between C0 / D of CYP3A5AA, AG and GG groups on days 7, 14, 21 and 28 after conversion (P <0.05). The daily dose of tacrolimus in CYP3A5AA group and AG group reached 3.5 times [(0.14 ± 0.03) mg · kg-1 vs (0.04 ± 0.01) mg · (P <0.01), the difference was statistically significant (P> 0.05), and the difference was statistically significant (P> 0.05) To achieve the same target concentration. The ABCB1C1236T, G (A) 2677T and C3435T genotypes and their homozygous haplotype had no effect on the initial Tacrolimus C0 / D (P> 0.05) for CYP3A5GG recipients converted from CsA to Tacrolimus, . Conclusions For CsA recipients who need to be converted to tacrolimus in renal transplant recipients, the initial dose of tacrolimus should be chosen based on the CYP3A5 genotype in order to achieve an effective immunosuppressive effect quickly.