Format

Send to

Choose Destination
See comment in PubMed Commons below
Epilepsia. 2014 Feb;55(2):353-61. doi: 10.1111/epi.12480. Epub 2013 Dec 6.

Stereoselective anticonvulsant and pharmacokinetic analysis of valnoctamide, a CNS-active derivative of valproic acid with low teratogenic potential.

Author information

1
Faculty of Medicine, School of Pharmacy, Institute for Drug Research, The Hebrew University of Jerusalem, Jerusalem, Israel.

Abstract

OBJECTIVE:

Valnoctamide (VCD), a central nervous system (CNS)-active chiral constitutional isomer of valpromide, the corresponding amide of valproic acid (VPA), is currently undergoing phase IIb clinical trials in acute mania. VCD exhibits stereoselective pharmacokinetics (PK) in animals and humans. The current study comparatively evaluated the pharmacodynamics (PD; anticonvulsant activity and teratogenicity) and PK of the four individual stereoisomers of VCD.

METHODS:

The anticonvulsant activity of VCD individual stereoisomers was evaluated in several rodent anticonvulsant models including maximal electroshock, 6 Hz psychomotor, subcutaneous metrazol, and the pilocarpine-induced and soman-induced status epilepticus (SE). The PK-PD (anticonvulsant activity) relationship of VCD stereoisomers was evaluated following intraperitoneal administration (70 mg/kg) to rats. Induction of neural tube defects (NTDs) by VCD stereoisomers was evaluated in a mouse strain that was highly susceptible to teratogen-induced NTDs.

RESULTS:

VCD had a stereoselective PK, with (2S,3S)-VCD exhibiting the lowest clearance, and consequently a twice-higher plasma exposure than all other stereoisomers. Nervertheless, there was less stereoselectivity in VCD anticonvulsant activity and each stereoisomer had similar median effective dose (ED)50 values in most models. VCD stereoisomers (258 or 389 mg/kg) did not cause NTDs. These doses are 3-12 times higher than VCD anticonvulsant ED50 values.

SIGNIFICANCE:

VCD displayed stereoselective PK that did not lead to significant stereoselective activity in various anticonvulsant rodent models. If VCD exerted its broad-spectrum anticonvulsant activity using a single mechanism of action (MOA), it is likely that it would exhibit a stereoselective PD. The fact that there was no significant difference between racemic VCD and its individual stereoisomers suggests that VCD's anticonvulsant activity is due to multiple MOAs.

KEYWORDS:

CNS drugs; Chiral switch; New antiepileptic drugs; Strereoselective pharmacokinetic and pharmacodynamics analysis

PMID:
24313671
PMCID:
PMC4963464
DOI:
10.1111/epi.12480
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Wiley Icon for PubMed Central
    Loading ...
    Support Center