Disposition of tacrolimus (FK 506) in rabbits. Role of red blood cell binding in hepatic clearance.

Tacrolimus is a macrolide immunosuppressive drug undergoing clinical trials for organ transplantation. Whole animal studies were undertaken to assess the rabbit as an animal model for tacrolimus pharmacokinetics. The disposition of tacrolimus in rabbits following 0.5 mg/kg iv and 2.0 mg/kg po doses is similar to man. The apparent plasma clearance 1.67 liters/hr/kg is more than 5-fold higher than blood clearance 0.31 liters/hr/kg. The steady-state volume of distribution is 30.7 liters/kg for plasma and 6.3 liters/kg for whole blood. The bioavailability after oral administration calculated from plasma and whole blood is low with a mean value of 9.7%. The in vitro studies and fitting using a nonlinear red blood cell (RBC)-plasma binding/diffusion model showed slow diffusion of drug from RBC to plasma (t1/2 = 7 min, CLD = 0.085 ml/min). In perfused liver studies, the extraction ratio of tacrolimus from blood with hematocrit of 0.1 is low (0.20). However, extraction of drug from plasma is moderate (0.42), and plasma concentrations are elevated by an average of 28% because of redistribution of tacrolimus from RBC. This creates a lower apparent plasma clearance (DO/AUC) for equilibrated (30 min at 37 degrees C) samples (15.4 ml/min) compared with samples centrifuged within 5 min (22.1 ml/min). RBC efflux was accounted for using a comprehensive perfusion/diffusion model. The intrinsic metabolic clearance averaged 29.2 ml/min. Simulations showed that the apparent plasma clearance of tacrolimus is closely correlated with RBC binding capacity (whole blood:plasma ratio). Higher ratios caused greater apparent plasma clearance (lower concentration of tacrolimus in reservoir plasma) because strong binding of drug by erythrocytes prevents tacrolimus from diffusion into plasma.(ABSTRACT TRUNCATED AT 250 WORDS)