异基因造血干细胞移植受者CYP3A4及CYP3A5基因多态性对他克莫司血药浓度及疗效的影响

Effect of CYP3A4 & CYP3A5 genetic polymorphism on concentration and efficacy of tacrolimus in patients with allogeneic hematopoietic stem cell transplantation

目的研究P450 3A4*18B(CYP3A4*18B)及3A5*3(CYP3A5*3)突变频率,探讨基因多态性与异基因造血干细胞移植受者他克莫司(Tac)血药浓度的关系。方法采用原位杂交荧光染色脱氧核糖核酸测序技术检测CYP3A4、CYP3A5基因型,酶联免疫吸附技术测定受者Tac浓度。比较术后7、15、30d不同基因型受者间Tac浓度/剂量(C_0/D)的差异。结果 16例中,CYP3A4*18B、CYP3A5*3突变等位基因发生的频率分别是25%和75%。CYP3A5纯合突变型受者中,CYP3A4野生纯合型者的浓度剂量比高于CYP3A4突变型。结论异基因造血干细胞移植受者CYP3A4*18B和CYP3A5*3基因多态性对TAC药代动力学的影响显著,可以考虑应用临床。

Objective To investigate the incidence rate of the mutation of gene CYP3 A4 and CYP3 A5 and study the relationship between their polymorphism and the concentration of tacrolimus(TAC) in blood of allogeneic hematopoietic stem cell transplant recipients. Methods Concentration of TAC/dosage on the day 7,15 and 30 after transplantation among recipients with different genotypes were compared after the administration of TAC. Genotypes of CYP3 A4 and CYP3 A5 of patients were detected by DNA direct sequencing,and concentration of TAC in blood was determined by ELISA method. Results The mutation rates of gene CYP3 A4 * 18 B and CYP3 A5 * 3 were 25% and 75% respectively in 16 cases. Overall, higher concentration of TAC was detected in those with wild-type of CYP3 A5 than the counterpart. In the recipients with homozygous mutant-type of CYP3 A5,wild homozygote of CYP3 A4 resulted in higher concentration of TAC in blood. Conclusion Polymorphism of CYP3 A4 and CYP3 A5 affected the pharmacokinetics of TAC significantly, which should be take into consideration of clinical application.