title: Stereoselective anticonvulsant and pharmacokinetic analysis of valnoctamide, a CNS-active derivative of valproic acid with low teratogenic potential.
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.
  
  
  CONCLUSIONS
  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.
authors: Faculty of Medicine, School of Pharmacy, Institute for Drug Research, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors: Tawfeeq
authors: T
authors: Shekh-Ahmad
authors: Naama
authors: N
authors: Hen
authors: Boris
authors: B
authors: Yagen
authors: John H
authors: JH
authors: McDonough
authors: Richard H
authors: RH
authors: Finnell
authors: Bogdan J
authors: BJ
authors: Wlodarczyk
authors: Meir
authors: M
authors: Bialer
mesh_terms: D000577:Amides / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity; D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity; D000697:Central Nervous System Stimulants / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity; D008297:Male; D051379:Mice; D009436:Neural Tube Defects / Q000139:chemically induced; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013226:Status Epilepticus / Q000139:chemically induced / Q000517:prevention & control; D013237:Stereoisomerism; D013723:Teratogens / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity; D014635:Valproic Acid / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity
chemical_list: D000577:Amides; D000927:Anticonvulsants; D000697:Central Nervous System Stimulants; D013723:Teratogens; C045179:valnoctamide; D014635:Valproic Acid
keywords: CNS drugs; Chiral switch; New antiepileptic drugs; Strereoselective pharmacokinetic and pharmacodynamics analysis