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

摘要

The study was conducted to determine potential target organ toxicity and its reversibility in hamsters following twice daily oral doses of NSC-D629243 for 28 consecutive days. Male and female hamsters were administered NSC-D629243 dissolved in sesame oil at doses of 0, 8.75, 43.8, 87.5, or 130 mg/kg/dose. Clinical pathology determinations were conducted in selected animals of each group on Study Days 15, 22, 29 and 61. Plasma drug measurements were made on Study Days 14 and 28. Necropsy and histopathological evaluations were conducted on Study Days 29 and 61. Dose-dependent increases in mean plasma drug levels occurred in both sexes of hamsters on Study Days 14 and on 28, indicating that the drug was systemically available when orally administered. No drug-related clinical toxic signs were observed in the hamsters and all animals survived to scheduled termination. Drug treatment produced dose-dependent decreases in the growth rate of female hamsters in the 87.5 and 130 mg/kg/dose groups during the dosing period. The depression in body weight effect persisted after dosing was completed in the males in the 130 mg/kg/dose group. No effects on body weight were evident in animals in the 8.75 or 43.8 mg/kg dose groups. Drug-related alterations in clinical pathology determinations included mild elevations in serum bile salts, cholesterol, and triglyceride mean values of male hamsters from the 43.8, 87.5 and 130 mg/kg/dose groups. Mild increases in serum cholesterol mean values also occurred in female hamsters in the 87.5 and the 130 mg/kg/dose groups. These effects were not observed in animals after dosing was completed. No drug-induced gross lesions or histopathologic changes were observed in animals necropsied on Study Days 29 or 61. Thus, there was no apparent target organ toxicity in hamsters administered NSC-D629243 orally twice daily for 28 consecutive days at doses up to 130 mg/kg/dose.