Toxicity of high-dose chlorambucil in Wistar rats

Abstract

The aim of this study was to determine the maximum tolerated dose and the haematological and non-haematological toxicity of chlorambucil in male Wistar rats. Chlorambucil (pulverized pills or pure substance) was dissolved in ethanol and administered orally at a dose ranging from 0.15 to 50 mg/kg/day for 5 days. Evaluations of experimental rats included general clinical state of health, body weight, haematological indicators (red blood cell count, white blood cell count, platelet count, differential leukocyte count, packed cell volume and haemoglobin concentration), biochemical plasma indicators (urea, creatinine, ALP, ALT, AST, Na, K, Cl), immunophenotype of leukocytes (CD3, CD8 and CD4 markers), as well as histopathology. Doses of chlorambucil from 0.15 to 0.75 mg/kg/day had no effect on the general clinical state of health as well as on other laboratory variables. Doses of 2-12 mg/kg/day were well tolerated, but mild myelotoxicity (leukopaenia) and elevated activities of liver transaminases were found. Doses of 20 to 50 mg/kg/day were myelotoxic (p < 0.01) with prevailing lymphopaenia but only minimum effects on red blood cells and platelets. Histology revealed pneumotoxicity, nephrotoxicity and damage to the gastrointestinal tract. Doses of 40 and 50 mg/kg/day resulted in acute lethal effects in 50% and 75% of individuals, respectively. Results of this study are intended for use in the testing of chlorambucil in combination with other drugs as a conditioning for bone marrow transplantation.