title: Pharmacokinetics of recombinant human erythropoietin in rabbits and 3/4 nephrectomized rats.
abstract: 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.
authors.affiliation: College of Pharmacy, Seoul National University, Korea.
authors.forename: W H
authors.initials: WH
authors.lastname: Yoon
authors.forename: S J
authors.initials: SJ
authors.lastname: Park
authors.forename: I C
authors.initials: IC
authors.lastname: Kim
authors.forename: M G
authors.initials: MG
authors.lastname: Lee
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004921:Erythropoietin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D009392:Nephrectomy; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D011994:Recombinant Proteins; D004921:Erythropoietin