ABCB1基因多态性对肝移植后他克莫司用量的影响

背景：钙神经素抑制剂他克莫司被广泛用于移植后预防排斥反应的发生,但其治疗窗狭窄,且药代动力学个体差异较大。目的：观察ABCB1基因多态性对肝移植患者移植后早期免疫抑制剂他克莫司的用量及C/D比值的影响。方法：选择2008-01/2010-09-31在昆明市第一人民医院暨昆明医学院附属甘美医院肝胆外科接受原位肝移植患者67例,通过检测67例肝移植受者移植后不同时间他克莫司的血药浓度及其用量,并利用DNA直接测序检测受体ABCB1的基因多态性,分析肝移植后免疫抑制剂他克莫司的用量及其血药浓度与ABCB1基因多态性的关系。结果与结论：肝移植后他克莫司的口服需药量在个体间存在很大差异,67例肝移植患者中,ABCB1不同位点的基因多态性分布不同,其中仅ABCB1 3435C〉T基因多态性与他克莫司用量有关。提示ABCB1的基因多态性可能是患者肝移植后他克莫司药代动力学显著个体差异的重要因素,ABCB1 3435C〉T野生型的患者需要更高剂量的他克莫司便可达到目标血药浓度水平,检测ABCB1的基因多态性可以优化肝移植后免疫抑制剂的个体化治疗方案。

Influence of ABCB1 polymorphisms on tacrolimus dosage requirements in patients following liver transplantation

BACKGROUND：The calcineurin inhibitor tacrolimus is widely used to prevent allograft rejection after liver transplantation. It has a narrow therapeutic index and shows considerable interindividual differences in its pharmacokinetics.OBJECTIVE：To evaluate retrospectively the effect of genetic polymorphisms of ABCB1 on tacrolimus dosage and dosage adjusted trough blood concentration during the early period after liver transplantation in patients. METHODS：Sixty-seven liver transplantation recipients were genotyped by DNA sequencing for ABCB1.Tacrolimus whole blood levels were measured by enzyme-linked immunospecific assay. Dose-adjusted trough blood concentrations （C） were determined and compared among different genotype groups. RESULTS AND CONCLUSION： The tacrolimus dosage had great variation between individuals. A synonymous single nucleotide polymorphism （SNP） of ABCB1 in various exons was different. Furthermore, ABCB1 3435CT polymorphisms was significantly correlated with tacrolimus dose-adjusted pre-dose concentrations at various time points. The present study shows that genetic polymorphisms in ABCB1 may be responsible, in part, for the large interindividual variability of tacrolimus pharmacokinetics during the early period after liver transplantation in patients. Patients in ABCB1 3435CT wild-type expressors require a high dose of tacrolimus to reach target levels compared with mutator expressors. Genotyping future transplant recipients for ABCB1 polymorphisms, therefore, could have the potential to individualize better tacrolimus immunosuppressive therapy and enhance drug safety.