Department of Pharmaceutical Analysis, School of Pharmacy, Second Military Medical University, No. 325 Guohe Road, Shanghai 200433, PR China; Shanghai Key Laboratory for Pharmaceutical Metabolite Research, No. 325 Guohe Road, Shanghai 200433, PR China; Shanghai Research Centre for Drug (Chinese Materia Medica) Metabolism, No. 325 Guohe Road, Shanghai 200433, PR China.
Environ Toxicol Pharmacol. 2009 Mar;27(2):237-46. doi: 10.1016/j.etap.2008.10.011. Epub 2008 Nov 8.
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 40mg/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 40mg/kg/day during administration, but the dogs recovered within 1h after oral administration. Significant increases in total bilirubin and alkaline phosphatase were observed in dogs receiving the 40mg/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 40mg/kg/day and the no-observed-adverse-effect level (NOAEL) was 20mg/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.
MCC-555 是一种用于 2 型糖尿病的治疗候选药物，是一种新型噻唑烷二酮类药物，具有较高的抗糖尿病疗效。本研究通过灌胃给药，在犬中评估其毒性和毒代动力学，剂量分别为 0、6.67、20 或 40mg/kg/天，为期 270 天。研究结束时包括 30 天恢复期，以评估毒性作用的可逆性。在治疗和恢复期内，检查了受试药物对死亡率、体重、食物消耗、血液学、血清生物化学、尿液分析、心电图（ECG）、器官重量、骨髓和组织病理学的影响。没有与治疗相关的死亡。在给予 40mg/kg/天剂量的犬中观察到呕吐，但在口服给药后 1 小时内恢复。在治疗期间，接受 40mg/kg/天剂量的犬总胆红素和碱性磷酸酶水平显著升高，但在 30 天恢复期内恢复正常。在治疗和恢复期结束时，肝脏也偶尔出现轻微的水肿或脂肪变性以及肝小叶或门脉区的炎性细胞浸润，但无剂量依赖性关系。犬最明显的毒性是在消化系统。然而，MCC-555 的这些毒性作用是短暂的且可逆的。在 40mg/kg/天的毒性剂量下，270 天口服给药后 MCC-555 的积累不明显，无观察到不良效应水平（NOAEL）为 20mg/kg/天。在雄性和雌性犬中，MCC-555 的毒代动力学无差异，在重复治疗 270 天后，组织中未观察到 MCC-555 的明显蓄积。MCC-555 分布到不同器官时，在肝脏、肾脏和睾丸中的穿透性较高，其次是卵巢和子宫。MCC-555 的代谢物和代谢方式有待批准。
