Carcinogenicity study of CKD-501, a novel dual peroxisome proliferator-activated receptors α and γ agonist, following oral administration to Sprague Dawley rats for 94-101 weeks

• Published in: Regulatory toxicology and pharmacology Vol. 69; no. 2; p. 207
• Main Authors: Lee, Hee Su, Chang, Minsun, Lee, Ji-Eun, Kim, Woojin, Hwang, In-Chang, Kim, Dal-Hyun, Park, Hyun-Kyu, Choi, Hyun-Ji, Jo, Woori, Cha, Shin-Woo, Son, Woo-Chan
• Format: Journal Article
• Language: English
• Published: Netherlands 01.07.2014
• Subjects: Administration, Oral; Animals; Body Weight - drug effects; Carcinogenicity Tests; Carcinogens - administration & dosage; Carcinogens - toxicity; Dose-Response Relationship, Drug; Female; Lipoma - chemically induced; Lipoma - pathology; Liposarcoma - chemically induced; Liposarcoma - pathology; Male; Platelet Count; PPAR alpha - agonists; PPAR gamma - agonists; Pyrimidines - administration & dosage; Pyrimidines - toxicity; Rats; Rats, Sprague-Dawley; Thiazolidinediones - administration & dosage; Thiazolidinediones - toxicity; Time Factors; Carcinogenicity; CKD-501; Dual PPARα/γ agonist
• ISSN: 1096-0295
• DOI: 10.1016/j.yrtph.2014.04.003

CKD-501 is a peroxisome proliferator-activated receptor (PPAR) agonist. The current study was conducted in Sprague Dawley (SD) rats for 94-101 weeks to investigate the carcinogenic potential of CKD-501. 60 males received 0, 0.03, 0.12, or 1.0mg/kg/day, which was changed after 66 weeks to 0.24 mg/kg/day due to increased mortality, while 60 females received 0, 0.03, 0.06, or 0.12 mg/kg/day throughout the study period. After switching the dosage, no significant changes in the survival rates were observed. Non-neoplastic lesions such as bladder transitional cell hyperplasia and a diminished corpus luteum were observed in females administered 0.12 mg/kg/day and the right chamber dilation and left ventricular hypertrophy were increased dose dependently in both males and females. Non-neoplastic lesions such as bone marrow hypoplasia and fat cell proliferation and neoplastic lesions such as lipomas and liposarcomas observed in males and/or females were considered expected pharmacological effects for this compound. Compared to rosiglitazone, CKD-501 had a 4.4-fold higher margin of safety for tumor induction and did not cause bladder carcinoma as was observed with pioglitazone.