Pharmacokinetics of recombinant human erythropoietin in rabbits and 3/4 nephrectomized rats

The nonlinear pharmacokinetics (1000, 5000, and 10000 IU/kg) and tissue distribution (5000 IU/kg) of erythropoietin (EPO) after intravenous administration of recombinant human EPO (rhuEPO) to rabbits, extent of absolute bioavailability (F) of EPO after subcutaneous administration (5000 IU/kg) to rabbits, and pharmacokinetics of EPO after intravenous administration to 3/4 nephrectomized rats (1000 IU/kg) were investigated. After intravenous administration of rhuEPO, 1000 IU/kg to rabbits, the terminal half-life, t1/2 (296, 368, and 378 min) and mean residence time (255, 318, and 326 min) decreased significantly, however, the total body clearance, CL (0.233, 0.165, and 0.169 ml/min/kg) and nonrenal clearance, CLNR (0.196, 0.141, and 0.120 ml/min/kg) increased significantly when compared with those of 5000 and 10000 IU/kg. The above dose-dependent pharmacokinetic parameters of EPO could be due to saturable metabolism of EPO in rabbits. The affinity of EPO to rabbit tissues studied was very low as reflected to less-than-unity values of tissue to plasma ratios except in the bile. This was supported by a considerably low value of volume of distribution of EPO at steady state (Vss) after intravenous administration of rhuEPO, 1000-10000 IU/kg, to rabbits (0.0524-0.0591 l/kg). After subcutaneous administration of rhuEPO, 5000 IU/kg, to rabbits, the plasma concentration of EPO was reached its peak at 600-720 min and declined slowly with a mean t1/2 of 1040 min. The F value after subcutaneous administration to rabbits was 43.1%. After intravenous administration of rhuEPO, 1000 IU/kg, to control and 3/4 nephrectomized rats, the CL, CLNR, and Vss were not significantly different, however, the MRT and CLR were significantly different between two groups of rats.