Factors affecting variability in distribution of tacrolimus in liver transplant recipients

Br J Clin Pharmacol. 2004 Mar;57(3):298-309. doi: 10.1046/j.1365-2125.2003.02008.x.


Aims: Therapeutic drug monitoring (TDM) of tacrolimus is complicated by conflicting data on the correlation between tacrolimus trough blood concentrations and the incidence of rejection. The aim of this cross-sectional study was to investigate the blood distribution and protein binding of tacrolimus in liver transplant recipients to explore better predictors of clinical outcome.

Methods: Blood and plasma distribution of 3H-dihydro-tacrolimus was investigated in 40 liver transplant recipients using Ficoll Paque and density gradient ultracentrifugation, respectively, and equilibrium dialysis to investigate plasma protein binding.

Results: In blood tacrolimus was mainly associated with the erythrocyte fraction (83.2%, range 74.6-94.9%), followed by diluted plasma (16.1%, range 4.5-24.9%), and lymphocyte fraction (0.61%, range: 0.11-1.53%). In plasma, lipoprotein deficient serum fraction (54.2%, range 38.5-68.2%) was the main reservoir of tacrolimus. The unbound fraction of tacrolimus was found to be 0.47 +/- 0.18% (range 0.07-0.89%). The percentage of tacrolimus associated with the lymphocytes (0.8 +/- 0.4 vs 0.3 +/- 0.1%, P = 0.012) and estimated unbound concentration (0.42 +/- 0.21 ng l-1vs 0.24 +/- 0.08 ng l-1, P < 0.001) of tacrolimus were significantly different in stable transplant recipients and those experiencing rejection. Haematocrit and red blood cell count significantly influenced the percentage of tacrolimus associated with erythrocytes. The fraction unbound of tacrolimus was correlated with alpha1-acid glycoprotein and high density lipoprotein cholesterol concentrations.

Conclusions: Tacrolimus unbound concentration was observed to be lower in liver transplant recipients experiencing rejection and further study is required to evaluate its utility in the TDM of tacrolimus.

MeSH terms

  • Adult
  • Aged
  • Analysis of Variance
  • Erythrocytes / metabolism
  • Female
  • Hematocrit
  • Humans
  • Immunosuppressive Agents / blood
  • Immunosuppressive Agents / pharmacokinetics*
  • Liver Transplantation
  • Male
  • Middle Aged
  • Plasma
  • Tacrolimus / blood
  • Tacrolimus / pharmacokinetics*


  • Immunosuppressive Agents
  • Tacrolimus