肾移植患者他克莫司的血药浓度与CYP3A5*3基因多态性的关系

Relationship between CYP3A5*3 gene polymorphism and blood concentration of tacrolimus in renal transplant patients

目的研究CYP3A5*3基因突变对他克莫司全血谷浓度(经体表面积剂量校正)、不良反应和急性排斥反应的影响。方法采用聚合酶链反应(PCR)和限制性内切片段长度多态性(RFLP)方法检测227例肾移植患者CYP3A5*3基因型,比较不同基因型患者之间他克莫司的全血谷浓度、不良反应和急性排斥反应发生率的差异。结果 CYP3A5*3基因多态性中,*1/*1型18例(7.9%),*1/*3型81例(35.7%),*3/*3型128例(56.4%)。肾移植术后3个月内,*1/*1型、*1/*3型和*3/*3型患者的他克莫司全血谷浓度经体表面积剂量校正后分别为1.84±0.71、2.06±0.83和4.11±2.13,*1/*1型和*1/*3型之间差异未见统计学意义(P>0.05),但与*3/*3型之间差异均有高度统计学意义(P<0.01)。组间不良反应和急性排斥反应发生率之间差异无统计学意义(P>0.05)。结论肾移植患者的CYP3A5*3基因多态性与他克莫司的服用剂量密切相关,对含CYP3A5*3等位基因的患者在应用他克莫司时应较常规减少用药剂量并注意不良反应的发生,而对CYP3A5野生型的肾移植患者应适当增加服药次数以降低排异反应。

AIM To investigate the effect of CYP3A5 ＊ 3 gene mutation on concentration （by body surface area of dose calibration）, adverse reactions and acute rejection of tacrolimus in renal transplant patients. METHODS The CYP3A5 ＊ 3 genotypes of 277 renal transplant patients were determined by PCR-RFLP method. The differences of cor- rected concentration, adverse reactions and acute rejection were compared among all of the genotype groups treated with tacrolimus. RESULTS There were ＊ 1/＊ 1 genotype in 18 cases （7.9%）, ＊ 1/＊ 3 in 81 cases （35.7%） and s 3 / s 3 in 128 cases （56.4%） identified in the process of CYP3A5 s 3 genetic polymorphism. Within 3 months after trans- plantation, the corrected concentration ratio of tacrolimus in patients with s 3/＊ 3 genotype group was 4.11 _＋ 2.13, which was higher than 1.84 ± 0.71 and 2.06± 0.83 of ＊ 1/＊ 1 and ＊ 1/＊ 3 genotype groups （P 〈 0.01）. There was the relationship between CYF3A5 ＊ 1/＊ 1 homozygotes and ＊ 1/＊ 3 heterozygotes , but not statistically significant（ P 〉 0.05）. No significant difference in adverse effects and acute rejection among different genotypes was found. CONCLU- SION CYP3A5 ＊ 3 polymorphism is associated with tacrolimus dose requirements. For the renal transplant recipients, an individualized dosage regimen design wiU help to increase clinical efficacy of tacrolimus in CYP3A5 ＊ 3 allelie patients while reducing adverse drug reactions in wild type patients.