Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5850450 | Food and Chemical Toxicology | 2013 | 12 Pages |
Abstract
GRD081, a newly developed dual PI3K/mTOR inhibitor, is now being considered for evaluation in phase I clinical trial. In this work, the subchronic toxicity of GRD081 in Sprague-Dawley (SD) rats and beagle dogs has been characterized. Rats and dogs received GRD081 orally (2, 5, 10 and 1, 2, 4Â mg/kg/day, respectively) on a consecutive daily dosing schedule for 28Â days following a 14Â days of recovery period. The treatment resulted in unscheduled mortality in rats receiving 5Â mg/kg/day and 10Â mg/kg/day. The adverse effects of GRD081 on rats and dogs mainly included myelosuppression, immunosuppression, hematological toxicity, and moderate liver, pancreas and kidney toxicity. These observations are consistent with pharmacologic perturbations of physiologic processes associated with the intended molecular targets for this class of PI3K/mTOR signaling inhibitors. Most of the treatment-induced effects were reversible upon discontinuation of treatment. The no-observed-adverse-effect level (NOAEL) of GRD081 was 1Â mg/kg/day for beagle dogs and less than 2Â mg/kg/day for SD rats.
Keywords
Related Topics
Life Sciences
Agricultural and Biological Sciences
Food Science
Authors
Zhenna Xia, Tingting Gao, Ying Zong, Xiaofang Zhang, Yu Mao, Bojun Yuan, Guocai Lu,