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Vol. 283, Issue 2, 520-527, 1997

Mechanism for the Nonlinear Pharmacokinetics of Erythropoietin in Rats

Motohiro Kato, Hiroshi Kamiyama, Akira Okazaki, Kenji Kumaki, Yukio Kato and Yuichi Sugiyama

Drug Metabolism and Pharmacokinetics Laboratory, Chugai Pharmaceutical Co., Ltd.(M.K., H.K., A.O., K.K.) and Faculty of Pharmaceutical Sciences, University of Tokyo (Y.K., Y.S), Tokyo, Japan

The contribution of erythropoietin- (EPO) receptors in target tissues, such as bone marrow and spleen, to the nonlinear pharmacokinetics of recombinant human EPO (rh-EPO) was evaluated in rats. The total body clearance after i.v. administration of rh-EPO (0.2-5 µg/kg) decreased as the dose of rh-EPO increased, approaching a plateau at high doses. The uptake clearance of 125I-rh-EPO by the target tissues, bone marrow and spleen, exhibited clear saturation. The Km values ranged from 240 to 450 pM, which are comparable with the reported value for the dissociation constant of EPO binding to EPO-receptors (180 pM) in rat bone marrow cells. A single s.c. administration of a large dose of rh-EPO (1 µg/kg) caused a reduction in tissue uptake clearance of 125I-rh-EPO by bone marrow and spleen (down-regulation). Furthermore, repeated intravenous injection of rh-EPO caused up-regulation of the tissue uptake clearance of 125I-rh-EPO, especially by the spleen, in a dose-dependent manner. Hematopoietic parameters such as hematocrit and hemoglobin concentration were also increased by repeated rh-EPO treatment and significantly correlated with the sum of the tissue uptake clearances in bone marrow and spleen. These findings suggest that the pharmacological receptor could be an important factor in defining the nonlinear pharmacokinetics of rh-EPO.

Copyright © by The American Society for Pharmacology and Experimental Therapeutics


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