Pharmacokinetic comparisons of S-oxiracetam and R-oxiracetam in beagle dogs

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Abstract

A pharmacokinetic comparison and conformational stability study of S-oxiracetam (S-ORT) and R-oxiracetam (R-ORT) in beagle dogs was used to investigate the possible mechanism of different effects of two oxiracetam enantiomers through a random crossover design. After drug administration to beagle dogs, blood samples were collected at different time points for pharmacokinetic analysis using the UPLC-ESI-MS/MS method. Parts of plasma samples were used for conformation transformation studies using a normal phase high performance liquid chromatographic (NP HPLC) method. The study showed that oxiracetam enantiomers maintained their original conformation when administered orally to beagle dogs. Concentrations of S-ORT were significantly higher than R-ORT 1.5 and 2 h after administration; the AUC0-∞ of S-ORT after oral administration tended to be higher than that of R-ORT, which showed that the different effects between S-ORT and R-ORT may be partly associated with their distinctive absorption at least.

1. Z. Hlinak, J. Vinsova and E. Kasafirek, Effect of alaptide, its analogues and oxiracetam on memory for an elevated plus-maze in mice, Eur. J. Pharmacol. 314 (1996) 1–7.

2. Z. Hlinak and I. Krejci, Oxiracetam pre-but not post-treatment prevented social recognition deficits produced with trimethyltin in rats, Behav. Brain Res. 161 (2005) 213–219; DOI: 10.1016/j.bbr.2005.02.030.

3. C. Mondadori, B. Hengerer, T. Ducret and J. Borkowski, Delayed emergence of effects of memoryenhancing drugs: implications for the dynamics of long-term memory, Proc. Natl. Acad. Sci. USA 91 (1994) 2041–2045.

4. C. Mondadori, H. J. Möbius and J. Borkowski, The GABAB receptor antagonist CGP 36,742 and the nootropic oxiracetam facilitate the formation of long-term memory, Behav. Brain Res. 77 (1996) 223–225.

5. W. H. Brooks, W. C. Guida and K. G. Daniel, The significance of chirality in drug design and development, Curr. Top. Med. Chem. 11 (2011) 760–770; DOI: 10.2174/156802611795165098.

6. A. J. Hutt, Chirality and pharmacokinetics: an area of neglected dimensionality, Drug Metabol. Drug Interact. 22 (2007) 79–112; DOI: 10.1515/DMDI.2007.22.2-3.79.

7. T. Kolev, M. Spiteller and B. Koleva, Spectroscopic and structural elucidation of amino acid derivatives and small peptides: experimental and theoretical tools, Amino Acids 38 (2010) 45–50; DOI: 10.1007/s00726-008-0220-9.

8. H. Lu, Stereoselectivity in drug metabolism, Expert Opin. Drug Metab. Toxicol. 3 (2007) 149–158; DOI: 10.1517/17425255.3.2.149.

9. Q. Shen, L. Wang, H. Zhou, L. S. Yu and S. Zeng, Stereoselective binding of chiral drugs to plasma proteins, Acta Pharmacol. Sinica 34 (2013) 998–1006; DOI: 10.1038/aps.2013.78.

10. N. Inotsume and M. Nakano, Stereoselective determination and pharmaco-kinetics of dihydropyridines: an updated review, J. Biochem. Biophys. Methods 54 (2002) 255–274; DOI: 10.1016/S0165-022X(02)00120-3.

11. R. Mehvar and D. R. Brocks, Stereospecific pharmacokinetics and pharmacodynamics of betaadrenergic blockers in humans, J. Pharm. Pharm. Sci. 4 (2001) 185–200.

12. L.A. Nguyen, H. He and C. Pham-Huy, Chiral drugs: an overview, Int. J. Biomed. Sci. 2 (2006) 85–100.

13. L. Chiodini, G. Pepeu, Composition Comprising S-oxiracetame for Use as Nootropic, EP. WO 1,993,006,826 A1, 15 April 1993; ref. Chem. Abstr. 119 (1993) 139083.

14. W. S. Wang, H. Ji, H. T. Xie, M. Dai, Y. W. Jia, D. H. Liang, L. Ye and Z. Y. Rong, A sensitive and specific UPLC–MS/MS analysis and preliminary pharmacokinetic characterization of S-oxiracetam in beagle dogs, Chin. J. Clin. Pharmacol Ther. 17 (2012) 988–994.

15. J. B. Lecaillon, J. P. Dubois, H. Coppens, T. Darragon, W. Theobald, G. Reumond and H. Beck, Pharmacokinetics of oxiracetam in elderly patients after 800 mg oral doses, comparison with nongeriatric healthy subjects, Eur. J. Drug Metab. Pharmacokinet. 15 (1990) 223–237.

16. E. Perucca, A. Albrici, G. Gatti, R. Spalluto, M. Visconti and A. Crema, Pharmacokinetics of oxiracetam following intravenous and oral administration in healthy volunteers, Eur. J. Drug Metab. Pharmacokinet. 9 (1984) 267–274.

17. E. Perucca, J. Parini, A. Albrici, M. Visconti and E. Ferrero, Oxiracetam pharmacokinetics following single and multiple dose administration in the elderly, Eur. J. Drug Metab. Pharmacokinet. 12 (1987) 145148.

18. X. Wan, H. Wang, P. Ma, L. Xi, J. Sun, Z. He, X. Zhang and X. Liu, Simultaneous determination of oxiracetam and its degraded substance in rat plasma by HPLC–MS/MS and its application to pharmacokinetic study after a single high-dose intravenous administration, J. Chromatogr. B. 969 (2014) 95–100; DOI: 10.1016/j.jchromb.2014.07.041.

Acta Pharmaceutica

The Journal of Croatian Pharmaceutical Society

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