肾移植受者CYP3A5基因多态性对术后他克莫司药物代谢的影响

Effects of CYP3A5＊ 3 polymorphisms on tacrolimus pharmacokinetic in renal transplantation recipients by PyrosequencingTM

目的研究肾移植受者细胞色素P4503A（CYP3A）酶系中的CYP3A5基因多态性对术后他克莫司（Tac）药物代谢的影响，并探讨测定CYP3A5基因型的方法。方法选取97例肾移植术后常规使用Tac＋吗替麦考酚酯＋泼尼松三联免疫抑制方案的受者。用焦磷酸测序法测定受者CYP3A5基因型；用均相酶扩大免疫分析法（EMIT）测定受者全血Tac浓度谷值（G0）；比较不同基因型的受者肾移植术后第7天、第14天、1个月、3个月和6个月时的TacG与Tac校正剂量的比值（TacG0／Tac校正剂量）。结果焦磷酸测序法能够快速准确的测定肾移植受者CYP3A5基因型；97例肾移植受者CYP3A5基因型分别为：CYP3A5＊1／＊1型17例（17．5％），CYP3A5＋1／＋3型35例（36．1％），CYP3A5＋3／＋3型45例（46．4％）。CYP3A5＋1／＋1型和CYP3A5＋5／＋3型受者肾移植术后TacC0／Tac校正剂量均显著低于CYP3A5＋3／＋3型受者。结论肾移植受者CYP3A5基因型对Tac药物代谢具有显著的影响。采用焦磷酸法测定肾移植受者CYP3A5基因多态性，有助于确定不同个体移植术后理想的Tac起始剂量，实现Tac个体化用药。

Objective To study the influence of CYP3A5 genetic polymorphism on tacrolimus metabolism in renal transplantation recipients and evaluate the methods of detecting CYP3A5＋ 3 polymorphism. Methods Ninety-seven renal recipients receiving the triple immunosuppressive （tacrolimus ＋ mycophenolate mofetil ＋ prednison） were genotyped for CYP3A5 ＋ 3 polymorphisms by the PyrosequencingTM assays. Tacrolimus trough concentration of the patients was measured by enzyme multiplied immunoassay technique, and concentration/adjusted dose ratio （C/D） was investigated at the 7th day, 14th day, 1st month, 3rd month and 6th month after renal transplantation. Results The PyrosequencingTM assays allowed for quick and accurate detection of CYP3A5＋ 3 genotypes. There were CYP3A5＋ 1/＋1 genotype in 17 cases （17. 5 % ）, ＋ 1/＋3 in 35 cases （36. 1 %） and ＋3/＋3 in 45 cases （46.4 %） identified in 97 renal recipients. The C/D of CYP3A5 ＋ 1/＋1 and ＋ 1/＋ 3 patients was significantly lower than that of ＋ 3/＋ 3 patients （P〈0. 01） after renal transplantation. Conclusion The CYP3A5＋ 3 polymorphisms are significantly correlated with tacrolimus pharmacokinetic in renal transplant recipients. Detecting the CYP3A5 ＋ 3 genotype of the recipient before the transplantation by the PyrosequencingTM assays can be used to help determine the optimal initial dosage after transplantation, resulting in individualized drug therapy.