Toxicity of hydroxyurea in rats and dogs.
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 (+dP/dt), and decreased QT and PR intervals and maximum left ventricular systolic and end diastolic pressures with measures returning to control levels within 24 hr.
Pfizer Inc., Andover, Massachusetts, USA dan.g.morton@pfizer.com.
Daniel
D
Morton
Pfizer Inc., Andover, Massachusetts, USA.
Lori
L
Reed
Pfizer Inc., La Jolla, California, USA.
Wenhu
W
Huang
Pfizer Inc., Groton, Connecticut, USA.
John M
JM
Marcek
Pfizer Inc., Groton, Connecticut, USA.
Robert
R
Austin-LaFrance
Pfizer Inc., Groton, Connecticut, USA.
Carrie A
CA
Northcott
Pfizer Inc., Andover, Massachusetts, USA.
Scott H
SH
Schelling
Pfizer Inc., Groton, Connecticut, USA.
Bradley E
BE
Enerson
Pfizer Inc., Andover, Massachusetts, USA.
Lindsay
L
Tomlinson
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D004285:Dogs; D005260:Female; D006321:Heart / Q000187:drug effects; D006918:Hydroxyurea / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D009206:Myocardium / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018675:Toxicity Tests
D006918:Hydroxyurea
blood; bone marrow; dog; heart; hydroxyurea; rat