Stereoselective pharmacokinetic analysis and antiepileptic activity of N-2-hydroxypropyl valpromide, a central nervous system--active chiral valproylamide.

Abstract

The purpose of this study was to evaluate the anticonvulsant activity and pharmacokinetics (PK) of a novel chiral CNS-active 2-hydroxypropyl valpromide (HP-VPD), a derivative of valproic acid (VPA). The individual enantiomers, R, S, and racemic (R,S)-HP-VPD were synthesized and evaluated for their pharmacokinetics and pharmacodynamics in a stereoselective manner. A stereoselective gas chromatography (GC) assay for simultaneous quantification of HP-VPD enantiomers in plasma and urine was developed and used to investigate the pharmacokinetics of HP-VPD in dogs. Pharmacodynamic analysis in rats showed that (S)-HP-VPD was 2.5 times more potent as an anticonvulsant in the maximal electroshock seizure (MES) test than its enantiomer and approximately 10 times more potent than VPA. No significant differences were observed in major PK parameters (clearance, volume of distribution, and half-life) between S and (R)-HP-VPD, and this suggested that pharmacodynamic differences could be attributed to the intrinsic pharmacodynamics of each enantiomer rather than to a preferable pharmacokinetic profile. The pharmacokinetic (metabolic) analysis showed that the fraction metabolized to HP-VPD-glucuronide ranged from 5% to 7% and no biotransformation of HP-VPD to VPA and 2-ketopropyl valpromide was observed. This is the first report of significant stereoselectivity in the anticonvulsant activity of a valproylamide with a chiral carbon situated on the alkyl chain of the amine moiety.