28-Day Toxicity of 1-Methylethyl 2-Chloro-5-(((1-Methylethoxy)Thiomethyl)Amino)Benzoate (NSC-D629243) in Beagle Dogs.

摘要

The purpose of the study was to determine potential target organ toxicity and its reversibility in dogs that were treated orally, twice daily, for 28 consecutive days with NSC-D629243. Beagle dogs (2/sex) were treated by gavage with NSC-D629243 in sesame oil at doses of 0, 8.75, 43.8, 87.5, and 130 mg/kg/dose. Clinical signs were infrequent and were limited to soft feces, diarrhea, and emesis. Body weights and temperatures did not change significantly with treatment. Water consumption was normal for all dogs in all dose groups. Decreased food consumption was evident in all dose groups including controls and was not related to drug treatment. Mean plasma levels of NSC-D629243 for each dose group increased with dose through the 87.5 mg/kg/dose group despite a fair amount of variability among animals. Plasma drug levels were slightly higher in females than males. For most of the dose groups, peak plasma levels occurred 2 hours after the second dose administration (at the 10 hour timepoint). There were no drug-related changes in hematologic parameters. Slight increases in the level of serum alanine transaminase (ALT) activity were seen on Study Days 2 and 4 in the 130 mg/kg/dose female dogs. The ALT values of the 130 mg/kg/dose females returned to control levels by Day 8, and no morphological evidence of damage was seen when livers of treated dogs sacrificed at Days 29 and 60 were examined. Doses up to 130 mg/kg/dose of NSC-D629243 given orally twice daily for 28 days were non-toxic.