普乐可复血药浓度与肝药酶P450 3AP1和多药耐药基因多态性的关系  

Gene polymorphisms of CYP 3AP1 and MDR1 associated with the interindividual variability of tacrolimus concentration

作　　者：张鑫[1] 刘志红[2] 郑敬民[2] 陈朝红[2] 陈强[2] 牛建英[2] 黎磊石[2] 

机构地区：[1]南京大学医学院临床学院 [2]南京军区南京总医院解放军肾脏病研究所,南京210002

出　　处：《肾脏病与透析肾移植杂志》2003年第5期445-449,共5页Chinese Journal of Nephrology,Dialysis & Transplantation

摘　　要：目的 :探讨普乐可复血药浓度的个体间差异与其在体内吸收、代谢相关基因肝药酶P4 5 0 3AP1(CYP3AP1)和多药耐药基因 1(MDR1)多态性的关系。　 方法 :观察 4 1例口服普乐可复治疗的狼疮或膜性肾病患者的体重、普乐可复剂量、普乐可复全血谷浓度 ,并利用PCR 限制性片断长度多态性的方法检测患者CYP 3AP1基因— 4 4位A/G和MDR1基因 3435位C/T多态性 ,分析浓度 /剂量比与基因型的关系。　 结果 :CYP 3AP1基因为AA型患者的血药浓度明显高于AG或GG型 (15 1 3± 93 4 ,n =2 1vs6 9 2± 39 4 ,n =2 0 ,P <0 0 0 1) ,MDR1基因为CC型患者的血药浓度明显低于CT或TT型 (73 7± 38 2 ,n =12vs 12 6 8± 91 3,n =2 9,P <0 0 5 )。　 结论 :CYP 3AP1和MDR1基因多态性与普乐可复的血药浓度显著相关。根据上述基因不同基因型药物代谢的特点 ,有针对性地进行剂量调整 ,或在用药前通过检测基因型更合理地选择患者 ,有助于提高普乐可复的疗效 。Objective: Tacrolimus is an immunosuppressive drug with narrow therapeutic range and wide interindividual variation in its pharmacokinetics. P-glycoprotein(P-gp) and CYP3A play an important role in the absorption or metabolism of tacrolimus. The polymorphism 3435CT of MDR1, the gene encoding P-gp, could influence the expression and activity of P-gp, while it was proved that the activity of CYP3A5 was correlated with the CYP 3AP1 A-44G polymorphism. The aim of this study was to evaluate whether the MDR1 polymorphism or the CYP 3AP1 polymorphism were associated with tacrolimus concentration/dose ratio. Methodology: Forty one lupus nephritis or membranous nephropathy patients treated with tacrolimus were enrolled in this study. Their body weight, dosage and concentration of tacrolimus were observed. CYP 3AP1 and MDR1 genotypes were determined by polymerase chain reaction followed by restriction fragment length polymorphism analysis. Results: According to CYP 3AP1 genotype, the concentration/dose ratio was higher in AA homozygotes than that in the patients with at least one G allele (151.3±93.4, n =21 vs 69.2±39.4, n =20, p <0.001). The difference between MDR1 CC and CT/TT subjects was also statistically significant (73.7±38.2, n =12 vs 126.8±91.3, n =29, p <0.05). Conclusion: CYP 3AP1 A-44G polymorphism and MDR1 C3435T polymorphism are associated with tacrolimus pharmacokinetics and dose requirements. Pharmacogenetic methods could be employed prospectively to help the dose selection and to individualize immunosuppressive therapy according to this information.

关 键 词：普乐可复 血药浓度 免疫抑制剂 多药耐药基因1 肝药酶P450 多态性 

分 类 号：R969[医药卫生—药理学]