Abstract
Purpose: To investigate the differences in pharmacokinetics of S-oxiracetam (S-ORT) and Roxiracetam (R-ORT) in rats.Methods: Sprague-Dawley rats (20) were randomly divided into two groups (ten rats per group), viz, SORT and R-ORT groups. Rats in S-ORT group received 200 mg S-ORT/kg while rats in R-ORT group were given 200 mg R-ORT/kg. Both treatments were given orally, and blood samples were collected at fixed time intervals for analysis. Ultra performance liquid chromatography-electrospray ionizationtandem mass spectrometry (UPLC–ESI-MS/MS) was used for pharmacokinetic analysis. Portions of the rat plasma were also subjected to configurational transformation analysis using normal phase-high performance liquid chromatographic (NP-HPLC) fitted with a Chiral OC column. Blank blood samples from five rats were used for plasma protein binding rate studying.Results: The two enantiomers did not transform into each other after oral administration, and the concentrations of S-ORT at 1, 1.5 and 2 h were significantly higher than those of R-ORT (p < 0.05). The area under the curve (AUC0-∞) and maximum concentration (Cmax) of S-ORT were also significantly larger than those of R-ORT (p < 0.05). There were no stereoselective differences between the two enantiomers.Conclusion: There are significant differences in absorption between two ORT enantiomers, and this may result in different pharmacological effects.Keywords: S-oxiracetam, R-oxiracetam, Configuration, Pharmacokinetics, Rats
Highlights
Chiral compounds constitute more than 50 % of pharmaceuticals in use currently, and biomolecules such as proteins, amino acids, fatty acids, nucleic acids, and monosaccharides exhibit chirality
Plasma samples at different time interval were used for pharmacokinetic studies, while portions of the plasma at 0, 1, 1.5, and 2 h were used for configurational transformation analysis
The Cmax and AUC0-∞ of SORT were larger than those of R-ORT. While these results are in agreement with those reported in beagle dogs [8], they are not consistent with results obtained in some previous studies [9,10]
Summary
Chiral compounds constitute more than 50 % of pharmaceuticals in use currently, and biomolecules such as proteins, amino acids, fatty acids, nucleic acids, and monosaccharides exhibit chirality. Enantiomers have the same physicochemical properties, but may exhibit differences in pharmacokinetics, pharmacodynamics, and toxicity [1]. Oxiracetam (ORT) belongs to the cyclic γaminobutyric acid class of drugs and as a nootropic agent, it is used to treat various cognitive disorders due to its ability to promote both learning and memory processes [2,3,4,5] In clinical practice, it is used as a racemic mixture of S-ORT) and R-ORT (Figure 1). Blood samples were centrifuged at 4000 rpm for 5 min and the plasma obtained stored at -80 °C until analysis. Plasma samples at different time interval were used for pharmacokinetic studies, while portions of the plasma at 0, 1, 1.5, and 2 h were used for configurational transformation analysis. Ethical clearance for the animal experiments was obtained from the Ethics Committee of the Yijishan Hospital (approval no. 20170116) and international guidelines for animal studies were followed [8]
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