Single and Four-week Intravenous Toxicity Studies of DA-3585, a Recombinant Human Erythropoietin, in Rats

재조합 사람 적혈구 조혈인자 DA-3585의 랫드에 대한 단회 및 4주반복 정맥투여 독성시험

DA-3585 is a recombinant human erythropoietin produced by Dong-A pharmaceutical Co. Ltd. using recombinant DNA technique. Recently, recombinant human erythropoietin (rHu-EPO) has been used to treat various types of anemia. In this study, we examined acute and subacute toxicity of DA-3585 in rats. DA-3585 was intravenously administered to rats at dose levels of 0, 6,250, 12,500 and 25,000 lU/kg for single dose toxicity study and at dose levels of 0,100,500 and 2,500IU/kg daily for 4 week-repeated dose toxicity study. In the single dose toxicity study, there were no death, clinical signs and changes in body weight gain related to the treatment. Necropsy revealed no evidence of toxicity related to DA-3585, In the repeated dose toxicity study, all the rats survived throughout the study. There were no treatment-related changes in clinical signs, food and water intake, and body weight. Hematological examination showed increases in the number of erythrocytes, hemoglobin concentration, hematocrit value and mean corpuscular volume, and decrease in the number of platelet in 500 and 2,500 lU/kg dosed groups. Extramedullary hematopoiesis in the spleen and erythroid hyperplasia in the bone marrow were noted as treatment-related histological changes. Toxicologically significant changes were not observed in blood biochemistry, urinalysis, organ weights and in any other examinations. The treatment-related changes observed in this study were hematological or histological changes associated with pharmacological effects of DA-3585. On the basis of the results of this study, LD5n value of DA-3585 was above 25,000 lU/kg and the no-observed-adverse-effect-level was estimated to be 100 lU/kg.