Acute, subchronic oral toxicity, toxicokinetics, and genotoxicity studies of DFC-2, an antitubercular drug candidate

• Published in: Regulatory toxicology and pharmacology Vol. 95; pp. 91 - 101
• Main Authors: Seo, Hoonhee, Al mahmud, Hafij, Kim, Sukyung, Islam, Md Imtiazul, Lee, Kee-In, Gil, Young Sig, Song, Ho-Yeon
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01-06-2018
• Subjects: Chromosomal aberrations; DFC-2; Genotoxicity; M. tuberculosis; Micronucleus formation test; Preclinical toxicology; Reverse mutation test; Subchronic oral toxicity; Subchronic oral toxicity; Chromosomal aberrations; Genotoxicity; DFC-2; M. tuberculosis; Preclinical toxicology; Reverse mutation test; Micronucleus formation test
• ISSN: 0273-2300; 1096-0295
• DOI: 10.1016/j.yrtph.2018.02.011

The infectious disease tuberculosis remains a serious global health issue and is responsible for nearly 1.8 million deaths every year. In our previous study, DFC-2 was confirmed to show anti-tubercular activity against drug-susceptible and drug-resistant strains of Mycobacterium tuberculosis. To support the safety-in-use of DFC-2 as an anti-tubercular drug, DFC-2 was tested via single- and 28-day repeated-dose oral toxicity study and mutagenicity assays. In the oral toxicity study, a single oral dose of DFC-2 at 2000 mg/kg did not produce deaths or abnormal lesions in the internal organs of rats. The results of a 28-day orally repeated dose of DFC-2 did not show treatment-related deaths or obvious toxicity symptoms in the animals treated with a dose of 300 mg/kg/day during the experimental period. Therefore, the no-observed-adverse-effect level (NOAEL) of DFC-2 was determined as 300 mg/kg/day for both male and female rats. In addition, DFC-2 showed no genetic toxicity in in vitro bacterial reverse mutation test, in vitro chromosomal aberration test, and in vivo mouse bone marrow micronucleus formation test. These results indicate that DFC-2 is a promising anti-tubercular drug candidate with a favorable safety profile.
•Oral toxicity (acute, subchronic) and genotoxicity of a new antitubercular drug candidate, DFC-2, was investigated in rats.•No acute oral toxicity or adverse effects were observed at dosages up to 2000 mg/kg body weight.•NOAEL (No observed adverse effect level) for subchronic toxicity (28 days) in rats is 300 mg/kg/day.•Negative outcomes obtained in the genotoxicity tests.