关键词: 肝移植, 他克莫司, CYP3A5, SLCO1B1, 基因多态性

Abstract: AIM: To explore the relationship between SLCO1B1 rs2291075 polymorphism and tacrolimus (FK506) dose-corrected trough concentration (C/D, ng·mL-1·mg-1·kg-1) during early period of liver transplantation.  METHODS: CYP3A5 rs776746 and SLCO1B1 rs2291075 polymorphisms of 210 liver transplantation patients and their corresponding donor livers were assessed by PCR amplification and DNA sequencing. The influence of gene polymorphisms on C/D values of FK506 was analyzed. The early postoperative period after liver transplantation was divided into convalescence phase (1-14 days) and stationary phase (15-28 days) according to the change of liver function and FK506 C/D values. RESULTS: The combined analysis of donor and recipient CYP3A5 rs776746 could distinguish the metabolic phenotype of FK506 into three groups: extensive metabolism (EM), intermediate metabolism (IM) and poor metabolism (PM), which was entitled the E-I-P classification system. Tacrolimus C/D ratios of recipient SLCO1B1 rs2291075 CT and TT carriers were very close and were significantly lower than those of recipient SLCO1B1 rs2291075 CC genotype carriers in convalescence phase (P=0.019 5) and in stationary phase (P=0.015 2). There were no statistically significant differences between tacrolimus C/D ratios of patients carried with SLCO1B1 rs2291075 CT, TT genotype donors and those carried with SLCO1B1 rs2291075 CC genotype donors. A model consisting of FK506 daily dose, total bilirubin, E-I-P classification, and recipient SLCO1B1 rs2291075 could predict FK506 C/D ratios in convalescence phase by multivariate analysis. However, Recipient SLCO1B1 rs2291075 genotype failed to enter forecast model for C/D ratios in stationary phase. Recipient SLCO1B1 rs2291075 genotype had significant effect on FK506 C/D ratios in convalescence phase (P=0.030) and stationary phase (P=0.040) in PM subgroup, which excluded the interference come from donor and recipient CYP3A5 rs776746. CONCLUSION: SLCO1B1 rs2291075 can be a novel genetic locus associated with FK506 metabolism. The combined analysis of donor and recipient CYP3A5 rs776746, recipient SLCO1B1 rs2291075 genotypes helps to guide the personalized administration of FK506 in early period after liver transplantation.

Key words: live transplantation, tacrolimus, CYP3A5, SLCO1B1, polymorphism