Pharmacogenetics

European Journal of Clinical Pharmacology

, Volume 70, Issue 8, pp 925-931

First online:

Influence of TLR4 rs1927907 locus polymorphisms on tacrolimus pharmacokinetics in the early stage after liver transplantation

  • Zhaowen WangAffiliated withDepartment of General Surgery, Shanghai First People’s Hospital, School of Medicine, Shanghai Jiao Tong University
  • , Shaohan WuAffiliated withDepartment of General Surgery, Shanghai First People’s Hospital, School of Medicine, Shanghai Jiao Tong University
  • , Dawei ChenAffiliated withDepartment of General Surgery, Shanghai First People’s Hospital, School of Medicine, Shanghai Jiao Tong University
  • , Feng GuoAffiliated withDepartment of General Surgery, Shanghai First People’s Hospital, School of Medicine, Shanghai Jiao Tong University
  • , Lin ZhongAffiliated withDepartment of General Surgery, Shanghai First People’s Hospital, School of Medicine, Shanghai Jiao Tong University
  • , Junwei FanAffiliated withDepartment of General Surgery, Shanghai First People’s Hospital, School of Medicine, Shanghai Jiao Tong University Email author 
  • , Zhihai PengAffiliated withDepartment of General Surgery, Shanghai First People’s Hospital, School of Medicine, Shanghai Jiao Tong University Email author 

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Abstract

Purpose

The aim of this study was to assess the potential influence of single nucleotide polymorphisms (SNPs) in the TLR4 gene on tacrolimus pharmacokinetics in the early stage after liver transplantation.

Methods

A total of 96 liver transplant patients receiving tacrolimus-based immunosuppressive regimens were enrolled in this study. The SNPs of CYP3A5 rs776746 and TLR4 rs1927907 were genotyped in both donors and recipients. Trough tacrolimus concentration (ng/mL) and tacrolimus daily doses (mg/day) were recorded for the first 4 weeks post-transplantation. The tacrolimus dose-adjusted trough concentrations (C/D ratio) required to achieve target concentrations were compared among patients according to allele status for CYP3A5 rs776746 and TLR4 rs1927907 during the first 4 weeks post-transplantation.

Results

Both donor and recipient CYP3A5 rs776746 allele A and donor TLR4 rs1927907 allele A were associated with a lower C/D ratio during the early stage after transplantation. The difference was even more striking in patients with both the CYP3A5 and TLR4 genotypes. With increasing numbers of genotype AA/AG, patients were found to have increasingly lower tacrolimus C/D ratios at all time points between post-transplantation weeks 1 and 4.

Conclusions

Collectively, donor TLR4 rs1927907 SNPs were closely associated with tacrolimus elimination in our Chinese Han patient population. The combination of the donor TLR4 rs1927907 SNP and both donor and recipient CYP3A5 rs776746 SNP might have a greater effect on tacrolimus elimination than each SNP separately. Screening for these SNPs prior to liver transplantation might be useful for determining adequate initial daily doses of immunosuppressive agents and achieving the desired immunosuppressive effect.

Keywords

CYP3A5 Toll-like receptor 4 Single nucleotide polymorphism Tacrolimus elimination Liver transplantation