Comparative toxicity and toxicokinetic studies of oxiracetam and (S)-oxiracetam in dogs

Abstract

1. Oxiracetam (ORT) is known as a derivative of piracetam in the family of nootropics for treating memory impairment and cognition disorders.

2. Given the chiral toxicological concerns surrounding ORT and the absence studies of (S)-ORT, the toxicity and toxicokinetics of (S)-ORT, and comparative toxicology of oxiracetam were systematically investigated in dogs following acute and 13-week repeated oral dosing.

3. The animal toxicity mainly manifested as loose stools in both the acute and the 13-week studies. The no-observed-adverse-effect level is proposed to be 100 mg/kg. The 13-week toxicokinetics study indicated that, in the (S)-ORT group, the time to peak concentration was delayed, elimination half-life extended, and apparent volume of distribution increased compared with the ORT group. The clearance rate increased at low- and mid-doses, but decreased in the high-dose group and was accompanied by drug accumulation. Compared with the same dose of ORT, (S)-ORT had a lower clearance rate and longer elimination half-life.

Keywords:

• Oxiracetam
• enantiomer
• chiral
• toxicity
• toxicokinetics

Acknowledgments

We are grateful for the provision of ORT and (S)-ORT by Dongze Pharmaceutical Science and Technology Co, Ltd., and to Beijing Union-Genius Pharmaceutical Technology Co., Ltd. for their scientific input in this study.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

Financial support for this research was received from the National Science and Technology Major Projects for “Major New Drugs Innovation and Development” and Chinese Academy of Medical Sciences-CAMS Innovation (CAMS-I2M) (grant numbers, 2018ZX09201017-005,2017- I2M-1-011).