期刊
REGULATORY TOXICOLOGY AND PHARMACOLOGY
卷 123, 期 -, 页码 -出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.yrtph.2021.104939
关键词
Cyclocreatine; Creatine analog; Creatine transporter deficiency; Preclinical toxicity; Animal models of disease; Non-conventional toxicology
In toxicology studies involving cyclocreatine, a creatine analog, it was found that wild-type mice were more sensitive to cyclocreatine-induced toxicity compared to creatine transporter-deficient mice. The biodistribution study showed greater accumulation of cyclocreatine in the brains of wild-type mice, indicating its ability to be transported by the creatine transporter. Although the transporter-deficient mice appeared to be more sensitive, there were no functional correlates to this sensitivity in the strain.
In standard general toxicology studies in two species to support clinical development, cyclocreatine, a creatine analog for the treatment of creatine transporter deficiency, caused deaths, convulsions, and/or multi-organ pathology. The potential translatability of these findings to patients was evaluated by comparing toxicity of cyclocreatine in wild-type mice to creatine transporter-deficient mice, a model of the human disease. A biodistribution study indicated greater accumulation of cyclocreatine in the brains of wild-type mice, consistent with its ability to be transported by the creatine transporter. Subsequent toxicology studies confirmed greater sensitivity of wild-type mice to cyclocreatine-induced toxicity. Exposure at the no observed adverse effect level in creatine transporter-deficient (554 mu g*hr/ml) mice exceeded exposure at the maximum tolerated dose in wildtype (248 mu g*hr/ml) mice. When dosed at 300 mg/kg/day for 3 months, cyclocreatine-related mortality, convulsions, and multi-organ pathology were observed in wild-type mice whereas there were no adverse findings in creatine transporter-deficient mice. Brain vacuolation was common to both strains. Although transporterdeficient mice appeared to be more sensitive, the finding had no functional correlates in this strain. The results highlight the importance of considering models of disease for toxicology in cases where they may be relevant to assessing safety in the intended patient population.
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