Stereoselective pharmacokinetic analysis and antiepileptic activity of N-2-hydroxypropyl valpromide, a central nervous system-active chiral valproylamide
M. Wasserman et al., Stereoselective pharmacokinetic analysis and antiepileptic activity of N-2-hydroxypropyl valpromide, a central nervous system-active chiral valproylamide, THER DRUG M, 23(4), 2001, pp. 414-420
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.