Changes in tacrolimus distribution in blood and plasma protein binding following liver transplantation.

Therapeutic drug monitoring of tacrolimus is complicated by the conflicting evidence of a relationship between trough blood tacrolimus concentration and clinical outcome. This prospective study investigated the blood distribution and protein binding of tacrolimus in liver transplant recipients over the first 60 days after transplantation with a view to identifying possible predictors of clinical outcome. Blood samples were collected from 10 liver transplant recipients on days 1, 7, and 60 after the initiation of tacrolimus therapy, and the distribution of tacrolimus in blood and the plasma protein binding were investigated. The unbound concentration of tacrolimus in plasma was estimated. Graft status was assessed using liver function tests and liver biopsies. The association of tacrolimus with erythrocytes varied significantly (74.4 +/- 5.0% vs 80.4 +/- 3.4%; P = 0.034) from day 1 to day 60. In plasma, tacrolimus mainly associated with lipoprotein-deficient plasma (60.1 +/- 6.5%), followed by high-density lipoproteins (27.2 +/- 6.6%), low-density lipoproteins (10.0 +/- 4.2%), and very low-density lipoproteins (2.8 +/- 1.8%). The percentage of tacrolimus associated with leukocytes (1.10 +/- 0.40% vs 0.40 +/- 0.09%; P = 0.0003) and the unbound concentration of tacrolimus (0.70 +/- 0.19 vs 0.28 +/- 0.04 ng/L; P < 0.0001) were observed to be significantly lower during episodes of rejection. In patients experiencing tacrolimus-related side effects, only the unbound concentration of tacrolimus was found to be significantly higher (0.84 +/- 0.19 vs 0.53 +/- 0.19 ng/L; P < 0.0001), and blood concentrations were not different (9.2 +/- 2.2 vs 8.1 +/- 1.8 ng/mL; P = 0.1). Blood distribution and protein binding of tacrolimus vary significantly over the posttransplantation period, leading to changes in its unbound concentration. A prospective study in a larger cohort of patients is required to establish the role of blood distribution and protein binding of tacrolimus in its therapeutic drug monitoring.