PHARMACOKINETICS OF RECOMBINANT-HUMAN-ERYTHROPOIETIN IN RABBITS AND 34 NEPHRECTOMIZED RATS/

The nonlinear pharmacokinetics (1000, 5000, and 10000 IU/kg) and tissu e 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 intravenou s administration to 3/4 nephrectomized rats (1000 IU/kg) were investig ated. After intravenous administration of rhuEPO, 1000 IU/kg to rabbit s, the terminal half-life, t(1/2) (296, 368, and 378 min) and mean res idence time (255, 318, and 326 min) decreased significantly, however, the total body clearance, CLNR (0.233, 0.165, and 0.169 ml/min/kg) and nonrenal clearance, CLNR (0.196, 0.141, and 0.120 ml/min/kg) increase d 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 o f tissue to plasma ratios except in the bile. This was supported by a considerably low value of volume of distribution of EPO at steady stat e (V-SS) 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 re ached its peak at 600-720 mm and declined slowly with a mean t(1/2) of 1040 min. The F value after subcutaneous administration to rabbits wa s 43.1%. After intravenous administration of rhuEPO, 1000 IU/kg, to co ntrol and 3/4 nephrectomized rats, the CL, CLNR, and V-SS were not sig nificantly different, however, the MRT and CLR were significantly diff erent between two groups of rats.