Effect of Dose and Duration of Exposure on the Toxicity to Dogs of Intravenously or Orally Administered 5-Fluorouracil

摘要

5-Fluorouracil was administered to beagle dogs by intravenous infusion or orally, in divided doses, over periods of 24 to 72 hours in total doses of 12.5 to 100 mg/kg. Some dogs received a single dose and some received several doses separated by intervals of 12 to 24 days. All dogs died following a single infusion of 50 mg/kg over 24 or 48 hours. Longer infusion periods or lesser doses were not lethal. Death occurred either during dosing or within 24 hours after completion of dosing. Intravenous infusion over 48 hours appeared to be slightly more toxic than oral administration in divided doses over 48 hours. Signs of toxicity appeared to be CNS related and included clonic and tonic convulsions. Pretreatment with Dilantin or phenobarbital had no effect on the toxicity of 5-fluorouracil. Decreased numbers of platelets and leukocytes were frequently found postdose and occasional low values of hematocrit, hemoglobin and RBC count. Alkaline phosphatase and serum transaminase values were frequently elevated immediately postdose. At histopathological examination the major organs were found to be too inconsistently affected to allow cytological changes to be related to dose, duration of exposure, or mode of administration. (Author)