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

The purpose of this study was to evaluate the anticonvulsant activity and p harmacokinetics (PK) of a novel chiral CNS-active 2-hydroxypropyl valpromid e (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 p harmacokinetics and pharmacodynamics in a stereoselective manner. A stereos elective gas chromatography (GC) assay for simultaneous quantification of H P-VPD enantiomers in plasma and urine was developed and used to investigate the pharmacokinetics of HP-VPD in dogs. Pharmacodynamic analysis in rats s howed that (S)-HP-VPD was 2.5 times more potent as an anticonvulsant in the maximal electroshock seizure (MES) test than its enantiomer and approximat ely 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 differenc es 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-glucuron ide ranged from 5% to 7% and no biotransformation of HP-VPD to VPA and 2-ke topropyl valpromide was observed. This is the first report of significant s tereoselectivity in the anticonvulsant activity of a valproylamide with a c hiral carbon situated on the alkyl chain of the amine moiety.