title: Comparative pharmacokinetic studies of racemic oxiracetam and its pure enantiomers after oral administration in rats by a stereoselective HPLC method.
abstract: 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 2h 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 200mg/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.
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Jiangsu, China.
authors.forename: Qiuyang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Jiangsu, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Jiangsu, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Jiangsu, China.
authors.forename: Han
authors.initials: H
authors.lastname: Xing
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Jiangsu, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Jiangsu, China.
authors.forename: Junxiu
authors.initials: J
authors.lastname: Li
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Jiangsu, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Jiangsu, China.
authors.forename: Jiake
authors.initials: J
authors.lastname: He
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Jiangsu, China.
authors.forename: Shuoye
authors.initials: S
authors.lastname: Yang
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Jiangsu, China.
authors.forename: Di
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Jiangsu, China. Electronic address: chenxj-lab@hotmail.com.
authors.forename: Xijing
authors.initials: X
authors.lastname: Chen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D011759:Pyrrolidines / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
chemical_list: D011759:Pyrrolidines; C040619:oxiracetam
keywords: Enantiomer; Oxiracetam; Pharmacokinetics; Racemate; Stereoselective HPLC