CYP3A4、3A5基因多态性对肾移植患者术后他克莫司浓度/剂量比值的影响  

Effect of CYP3A4/5 Gene Polymorphism on Ratio of Tacrolimus Concentration and Dosage in Patients with Renal Transplantation

作　　者：欧阳萌[1,2] 辛华雯[1] 唐霞[1,3] 

机构地区：[1]广州军区武汉总医院,武汉430070 [2]湖北中医药大学 [3]南昌大学

出　　处：《中国药师》2014年第7期1069-1073,共5页China Pharmacist

基　　金：湖北省自然科学基金资助项目(编号:2011CDC074)

摘　　要：目的:探讨CYP3A4*18B(82266G>A,rs2242480)、CYP3A5*3(6986A>G,rs776746)位点的基因多态性对肾移植术后服用他克莫司(FK506)用药的指导作用。方法:采用PCR-RFLP(聚合酶链反应-限制性片段长度多态性)方法对280名肾移植患者进行CYP3A4*18B、CYP3A5*3基因型检测,利用化学发光微粒子免疫分析技术(CMIA)检测肾移植患者FK506血浓度,比较不同基因型患者之间FK506血药谷浓度/剂量*体质量(C0/D)比值。结果:280例肾移植患者中,CYP3A4*18B和CYP3A5*3基因型的突变频率分别为29.1%和69.3%。CYP3A4*18B/*18B基因型肾移植患者术后1个月,3个月FK506的C0及C0/D值显著低于CYP3A4*1/*1、CYP3A4*1/*18B基因型(P<0.05)。CYP3A5*3/*3基因型肾移植患者术后7日,1个月FK506的C0及C0/D值显著高于CYP3A5*1/*1、CYP3A5*1/*3基因型(P<0.05)。将CYP3A4*18B和CYP3A5*3进行单倍体基因型组合分析,用药后15 d、1个月,GG-GG基因型组的C0明显高于AA-GG基因型组(P<0.05);用药后6月,GG-GG、GA-GG、GA-AG基因型组的C0均明显高于AA-GG基因型组(P<0.05)。结论:CYP3A4*18B和CYP3A5*3基因多态性对肾移植患者的FK506血药浓度及其C0/D值有一定影响,患者在使用FK506前进行CYP3A4*18B和CYP3A5*3基因型检测,对预测FK506用药剂量有一定的指导作用。Objective：To evaluate the effect of CYP3A4/5 gene polymorphisms on tacrolimus application in the patients with renal transplantation.Methods：The CYP3A4 ＊ 18B and CYP3A5 ＊ 3 genotypes of 280 renal transplantation patients were determined by PCR followed by restriction fragment length polymorphism （RFLP） method.The whole blood FK506 levels of renal transplantation recipients were detected by chemilumunescence microparticle immunoassay.The differences in C0/D ratios were compared among all of the genotype groups treated with tacrolimus.Results：In the 280 renal transplantation recipients,the frequency of CYP3A4 ＊ 18B and CYP3A5 ＊ 3 mutation alleles was 29.1％ and 69.3％,respectively.After one and three months of the renal transplantation,the blood trough concentrations and the value of C0/D of FK506 in CYP3A4 ＊ 18B/＊ 18B group was significantly lower than that in ＊ 1/＊ 1 and ＊ 1/＊ 18B group（P ＜ 0.05）.After 7 days and one months of the transplantation,the blood trough concentrations and the value of C0/D of FK506 in CYP3A5 ＊ 3/＊ 3 group was significantly higher than that in ＊ 1/＊ 1 and ＊ 1/＊ 3 group（P ＜ 0.05）.Conclusion：Genetic polymorphism of CYP3A4 ＊ 18B and CYP3A5 ＊ 3 may be responsible in part for the large inter-individual variability of FK506 pharmacokinetics during the early period of renal transplantation in patients.

关 键 词：肾移植术后 他克莫司 CYP3A4 CYP3A5 基因多态性 

分 类 号：R968[医药卫生—药理学]