供体CYP3A5基因多态性影响肝移植术后FK506的个体化用药

Influence of Genetic Polymorphism of Donor CYP3A5 on FK506 Individual Dosage Regimen in Liver Transplantation Recipients

目的探讨肝移植术后口服免疫抑制剂FK506的剂量及其全血谷浓度的个体差异与供体的肝药酶P450 3A5(CYP3A5)基因多态性的关系。方法观察44例接受肝移植的受体在术后1,2周及1月的FK506服药剂量和全血药物谷浓度,并利用PCR-限制性片断长度多态性(PCR-RFLP)方法和DNA直接测序法检测对应供体CYP3A5基因内含子3第6 986位A/G单核苷酸多态性(CYP3A5*3),分析基因多态性与FK506服用剂量及全血谷浓度/剂量比值(C/D)的相关性。结果肝移植术后FK506的口服需药量在个体间存在极大差异,在术后2周及1月,CYP3A5*3/*3基因型患者需要的剂量最小,分别为(0.074±0.042)和(0.084±0.045)mg.kg-1.d-1,而C/D比值明显高于*1/*1基因型患者。结论肝移植术后受体FK506服用剂量的个体化差异与供体CYP3A5*1/*3基因多态性密切相关,分析供体CYP3A5*1/*3基因多态性可以为肝移植术后FK506的个体化用药提供可靠的参考指标。

OBJECTIVE Tacrolimus （FK506） is worldwide used as an immunosuppressive drug in organ transplantation,but it is characterized by narrow therapeutic index and great interindividual variation in its pharmacokinetics. Tacrolimus is mainly metabolized and excluded by CYP3A in liver. It has been proven that the polymorphism 6 986 A/G of CYP3A5 in intron 3 （CYP3A5 ＊ 3 ） is correlated with gene expression and enzyme activity. The present study was aimed to evaluate whether the intefindividual variation of tacrolimus dosages and trough blood concentrations in liver transplantation were associated with donor CYP3A5 6 986 A/G polymorphism in liver transplantation. METHODS Forty-four liver transplantation recipients treated with FK506 were enrolled in this study. FK506 dosage and blood trough concentration were investigated at 1 week,2 weeks and 1 month after transplantation. Polymerase chain reaction-restriction fragment length polymorphism （PCR-RFLP） analysis and DNA sequencing were applied to determine the genotype of donor CYP3AS. RESULTS The oral FK506 dosage had great variation between individuals. According to donor CYP3A5 genotype,the recipients with CYP3A5 ＊ 3/＊ 3 homozygote required the least FK506 dosage,at （0.074 ±0. 042） and （0. 084 ±0. 045） mg· kg^-1· d^-1 at 2 weeks and 1 month, respectively. The concentration/dose ratio （C/D） was significantly higher in recipients with CYP3A5 ＊ 3/＊ 3 homozygote than that in recipients with ＊ 1/＊ 1 homozygote CONCLUSION In liver transplantation,the FK506 dose and trough blood concentration are associated with the polymorphism of donor CYP3A5. The determination of donor CYP3A5 genotype can offer individualized FK506 dosage regimen for liver transplant patients.