Subchronic toxicity and toxicokinetics of MCC-555, a novel thiazolidinedione, after 270-day repeated oral administration in dogs

Abstract

MCC-555, a treatment candidate for type 2 diabetes, is a novel thiazolidinedione which has comparatively high anti-diabetic efficacy. The present study was conducted to evaluate its toxicity and toxicokinetics in beagle dogs by oral administration at doses of 0, 6.67, 20 or 40 mg/kg/day for 270 days. A 30-day recovery period was included at the end of the study to evaluate the reversibility of the toxic effects. During the treatment and recovery periods, the effects of the test agent on mortality, body weight, food consumption, hematology, serum biochemistry, urinalysis, electrocardiogram (ECG), organ weights, bone marrow and histopathology were examined. There were no treatment-related mortalities. Vomiting was observed in dogs receiving 40 mg/kg/day during administration, but the dogs recovered within 1 h after oral administration. Significant increases in total bilirubin and alkaline phosphatase were observed in dogs receiving the 40 mg/kg/day dose during the treatment period, but the levels returned toward normal during the 30-day recovery period. Mild hydropic or fatty degeneration in the liver and inflammatory cell infiltration in the hepatic lobule or portal area was also observed sporadically without a dose-dependent relationship at the end of treatment and recovery periods. The most apparent toxicity in dogs was in the digestive system. However, these toxic effects of MCC-555 were transient and reversible. The accumulation of MCC-555 after 270-day oral administration was not notable at the toxic dose of 40 mg/kg/day and the no-observed-adverse-effect level (NOAEL) was 20 mg/kg/day. No differences in toxicokinetics of MCC-555 were observed between male and female dogs and no significant accumulation of MCC-555 was observed in tissues after 270 days of repeated treatments. MCC-555 distribution into different organs showed a higher penetration in the liver, kidneys and testes, followed by the ovaries and uterus. Metabolites and the metabolic style of MCC-555 are to be approved.