Comparative pharmacokinetic studies of racemic oxiracetam and its pure enantiomers after oral administration in rats by a stereoselective HPLC method

• An enantioselective HPLC method was developed for oxiracetam (ORC) enantiomers.
• The pharmacokinetic profiles of (S)- and (R)-ORC were characterized and compared.
• Individual enantiomer and racemate of ORC have different pharmacokinetic profiles.
• The disposition of (S)-ORC in rats was influenced by the existence of (R)-antipode.
• (S)-ORC enanpure was better absorbed than the racemate.

Oxiracetam (ORC), a nootropic drug used for improving the cognition and memory, has an asymmetric carbon in its structure and exists as (S)- and (R)-ORC. The pharmacokinetic profiles of racemic oxiracetam and its pure enantiomers in rats were evaluated and compared by enantioselective high-performance liquid chromatography, which was performed on a Chiralpak ID column with a mobile phase of hexane–ethanol–trifluoroacetic acid (78:22:0.1, v/v/v). The method was validated with respect to selectivity, linearity, accuracy and precision, stability and the limit of quantification. The validation acceptance criteria were met in all cases. A saturating phenomenon of (S)-ORC was observed when the dosage ranged from 200 mg/kg to 800 mg/kg. The two enantiomers showed similar profiles in the absorb phase, and reached the maximum concentration at 2 h after oral administration. However, compared with the racemate group, the AUC/dose and Cmax/dose ratios of (S)-ORC were higher and Cl/f was lower in enanpure (S)-ORC group. The Cmax of (S)-ORC decreased from 21.3 ± 5.0 μg/ml to 13.2 ± 4.2 when (R)-ORC was co-administrated at the dose of 200 mg/kg. AUC0–t values of (S)-ORC were different after oral administration of 200 mg/kg (S)-ORC and 400 mg/kg racemic ORC (96.7 ± 15.5 and 50.1 ± 16.3 μg h/ml). The higher absorption and slower elimination suggest that enantiopure (S)-ORC could be a promising drug that efficiently reduces clinical dosage, improves therapeutic indices, decreases toxicology risks, and results in increased therapeutic ration.

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