CYP3A5和多重耐药基因1多态性对肾移植患者他克莫司药代动力学参数的影响

The Influence of CYP3A5 and MDR1(ABCB1) polymorphisms on the pharmacokinetics of tacrolimus in renal transplant recipients

目的探讨细胞色素P450,家族3,亚家族A,多肽5(CYP3A5)基因和多重耐药基因1(MDR1)C3435T多态性对肾移植患者他克莫司药代动力学参数的影响,在基因水平为临床合理用药提供参考。方法采用聚合酶链反应(PCR)和限制酶切片长多态性(RFIP)方法对63例肾移植术后患者进行CYP3A5和MDR1基因分型。移植手术1个月后进行血药浓度测定和药代动力学参数计算。结果携带CYP3A5*1基因型肾移植患者的剂量校正曲线下面积(AUC_(0-t))明显低于CYP3A5*3*3型患者,在随后对上述2组不同CYP3A5基因分型的患者进行MDR1的C3435T基因多态性分型研究表明,MDR1 C3435T基因多态性对他可莫司的药代动力学参数无明显影响。结论 CYP3A5基因多态性与他可莫司药代动力学参数相关,携带CYP3A5*1基因型肾移植患者比CYP3A5*3*3型患者需要较高的剂量才能达到目的浓度;而在影响他可莫司药代动力学参数的因素中MDR1 C3435T基因多态性不是重要因素。药代动力学参数的测定有利于器官移植患者剂量选择及个体化用药治疗。

Objective To investigate the influence of CYP3A5 and MDR1 genetic polymorphisms on tacrolimus pharmacokinetics in renal transplant recipients for the rational administration in clinical practice.Methods The blood concentration was measured and pharmacokinetic parameters of tacrolimus were calculated in steady-state on day 28 after transplantation.Polymerase chain reaction and restriction fragment length polymorphisms were used for CYP3A5 and MDR1 polymorphisms,respectively.Results The dose-adjusted area under the concentration-time curve（AUC0-12）was significantly lower among CYP3A5＊1 carriers than those bearing CYP3A5＊3/＊3.In the following study,a distinction was made between carriers of CYP3A5＊1/＊1＋ CYP3A5＊1/＊3 and CYP3A5＊3/＊3 to investigate the influence of the MDR1C3435T mutation on tacrolimus pharmacokinetics.The MDR1 C3435T polymorphisms did not affect any tacrolimus pharmacokinetic parameter in either group.Conclusion Renal transplant recipients who were CYP3A5＊1 carriers required a higher dose of tacrolimus than those with CYP3A5＊3/＊3.In contrast,MDR1 C3435T polymorphism was not an important factor in tacrolimus pharmacokinetics.Pharmacogenetic methods could be employed to help the dose selection and to individualize immunosuppressive therapy prospectively.