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

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