Safety assessment of aditoprim acute, subchronic toxicity and mutagenicity studies.

Abstract

Aditoprim (ADP), a new developed dihydrofolate reductase (DHFR) inhibitor, has great potential in clinical veterinary medicine because of its greater pharmacokinetic properties than structural analogs. Preclinical toxicology studies were performed to assess the safety of ADP including an acute oral toxicity test, a subchronic toxicity test and five mutagenicity tests. In the acute oral toxicity test, ADP was administered singly by oral gavage to Wistar rats and Kunming mice. The LD50 calculated was 1400 mg kg(-1) body weight (BW) day(-1) in rats and 1130 mg kg(-1) BW day(-1) in mice. In a subchronic study, Wistar rats were administered ADP at dose levels of 0, 20, 100 and 1000 mg kg(-1) diet for 90 days. Significant decreases were observed on body weight and food efficiency in the high-dose group. Treatment-related changes in clinical serum biochemistry were found in the medium- and high-dose groups. Significant increases in the relative weights of livers and kidneys in females and testis in males in the 1000 mg kg(-1) diet, and significant decrease in relative weights of livers in males in the 100 mg kg(-1) diet were noted. Histopathological observations revealed that the 1000 mg kg(-1) ADP diet could induce lymphocytic infiltration and hepatocytic necrosis near the hepatic portal area. The genotoxicity of ADP was negative in tests, such as the bacterial reverse mutation assay, mice bone marrow erythrocyte micronucleus assay, in vitro chromosomal aberration test, in vitro cho/hgprt mammalian cell mutagenesis assay and mice testicle cells chromosome aberration. Based on the subchronic study, the no-observed-adverse-effect level for ADP was a 20 mg kg(-1) diet, which is about 1.44-1.53 mg kg(-1) BW day(-1) in rats.

• Authors: Xu Wang, Ziqiang Tan, Yuanhu Pan, Awais Ihsan, Qianying Liu, Lingli Huang, Guyue Cheng, Dongmei Chen, Yanfei Tao, Zhenli Liu, Zonghui Yuan
• Journal: Journal of applied toxicology : JAT (J Appl Toxicol) Vol. 35 Issue 11 Pg. 1415-26 (Nov 2015) ISSN: 1099-1263 [Electronic] England
• PMID: 25663419 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 John Wiley & Sons, Ltd.

Chemical References

• aditoprim
• Trimethoprim

Topics

• Animals
• Body Weight
• CHO Cells
• Cricetulus
• Diet
• Dose-Response Relationship, Drug
• Female
• Kidney (drug effects)
• Liver (drug effects)
• Male
• Mice
• Micronucleus Tests
• Mutagenicity Tests
• No-Observed-Adverse-Effect Level
• Organ Size (drug effects)
• Rats
• Rats, Wistar
• Risk Assessment
• Toxicity Tests, Acute (methods)
• Toxicity Tests, Subchronic (methods)
• Trimethoprim (analogs & derivatives, toxicity)