Toxicity of Hydroxyurea in Rats and Dogs. (June 2015)

• Record Type: Journal Article
• Authors: Morton, Daniel; Reed, Lori; Huang, Wenhu; Marcek, John M.; Austin-LaFrance, Robert; Northcott, Carrie A.; Schelling, Scott H.; Enerson, Bradley E.; Tomlinson, Lindsay
• Is Part Of: Toxicologic pathology. Volume 43:Number 4(2015)
• Page Start: 498
• Page End: 512
• Publication Date: 2015-06
• Subjects: bone marrow -- blood -- dog -- heart -- hydroxyurea -- rat; Pathology -- Periodicals; Toxicology -- Periodicals; Pathology; Toxicology; 615.9
• DOI: 10.1177/0192623314559103
• Languages: English
• ISSNs: 0192-6233

Abstract

The toxicity of hydroxyurea, a treatment for specific neoplasms, sickle-cell disease, polycythemia, and thrombocytosis that kills cells in mitosis, was assessed in repeat-dose, oral gavage studies in rats and dogs and a cardiovascular study in telemetered dogs. Hydroxyurea produced hematopoietic, lymphoid, cardiovascular, and gastrointestinal toxicity with steep dose response curves. In rats dosed for 10 days, 50 mg/kg/day was tolerated; 500 mg/kg/day produced decreased body weight gain; decreased circulating leukocytes, erythrocytes, and platelets; decreased cellularity of thymus, lymph nodes, and bone marrow; and epithelial degeneration and/or dysplasia of the stomach and small intestine; 1, 500 mg/kg/day resulted in deaths on day 5. In dogs, a single dose at ≥250 mg/kg caused prostration leading to unscheduled euthanasia. Dogs administered 50 mg/kg/day for 1 month had decreased circulating leukocytes, erythrocytes, and platelets; increased bone marrow cellularity with decreased maturing granulocytes; increased creatinine kinase activity; and increased iron pigment in bone marrow and hepatic sinusoidal cells. In telemetered dogs, doses ≥15 mg/kg decreased systolic blood pressure (BP); 50 mg/kg increased diastolic BP, heart rate, and change in blood pressure over time (+d P /d t ), and decreased QT and PR intervals and maximum left ventricular systolic and end diastolic pressures with measures returning to control levels within 24 hr.