Abstract
PurposeTo explore the relationship between rs2291075 polymorphism in SLCO1B1 gene, which encodes an influx transmembrane protein transporter, and tacrolimus dose–corrected trough concentration (C/D, ng ml−1 mg−1 kg−1) in the early period after liver transplantation.MethodsCYP3A5 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 tacrolimus was analyzed. The early postoperative period after liver transplantation was divided into the convalescence phase (1–14 days) and stationary phase (15–28 days) according to the change of liver function and tacrolimus C/D values.ResultsThe combined analysis of donor and recipient CYP3A5 rs776746 could distinguish the metabolic phenotype of tacrolimus into three groups: fast elimination (FE), intermediate elimination (IE), and slow elimination (SE), which was entitled the FIS 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 = 0.0195) and in stationary phase (p = 0.0152). 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 tacrolimus daily dose, total bilirubin, FIS classification, and recipient SLCO1B1 rs2291075 could predict tacrolimus C/D ratios in the 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 tacrolimus C/D ratios in convalescence phase (p = 0.0300) and stationary phase (p = 0.0400) in subgroup, which excluded the interference come from donor and recipient CYP3A5 rs776746.ConclusionSLCO1B1 rs2291075 could be a novel genetic locus associated with tacrolimus metabolism. The combined analysis of donor and recipient CYP3A5 rs776746, recipient SLCO1B1 rs2291075 genotypes, could be helpful to guide the personalized administration of tacrolimus in early period after liver transplantation.
Highlights
Liver transplantation is the method of choice in the treatment of patients with end-stage liver failure and selected group of patients with hepatocellular carcinoma (HCC) [1, 2]
No statistically significant differences in genotype and allele frequencies were observed between recipients and donors for any of CYP3A5 rs776746 and SLCO1B1 rs2291075 polymorphisms
We demonstrated the influence of recipient SLCO1B1 rs2291075 polymorphisms on tacrolimus C/D ratios based on pieces of evidence from the three levels of analysis: Firstly, recipient SLCO1B1 rs2291075 polymorphisms were associated with tacrolimus C/D ratios by univariate correlation analysis
Summary
Liver transplantation is the method of choice in the treatment of patients with end-stage liver failure and selected group of patients with hepatocellular carcinoma (HCC) [1, 2]. Tacrolimus is a calcineurin inhibitor and the main immunosuppressant drug used after liver transplantation. The dosage of tacrolimus was adjusted continuously guided by monitoring trough blood concentrations in the early period after liver transplantation, and the individualized dosage was found. After this period, the clinical value of pharmacogenomics decreased, and the frequency of detection of trough blood concentrations of tacrolimus was reduced. The clinical value of pharmacogenomics decreased, and the frequency of detection of trough blood concentrations of tacrolimus was reduced This “trial and error” process was prone to result in rejection or adverse drug reactions. Predicting the tacrolimus clearance rate and providing a prospective dosage within an accurate reference range to achieve immune balance in a short time was crucial in immunosuppressive therapy
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