Stereoselective pharmacokinetic analysis of valnoctamide, a CNS-active chiral amide analogue of valproic acid, in dogs, rats, and mice

The purpose of this study was to evaluate the stereoselective pharmacokinetics of valnoctamide (VCD) in dogs, rats, and mice; which are the most common animal models for pharmacokinetic, pharmacologic, and toxicologic evaluation; and to compare it with previously published human data. Racemic VCD (mixture of four stereoisomers) was administered intravenously to six mongrel dogs and to rats (five rats per time-point), and intraperitoneally to mice (five mice per time-point). Plasma concentrations of the individual stereoisomers were measured by a stereospecific gas chromatography assay. In dogs, (2S,3R)-VCD had a larger clearance (0.33 L/h · kg) and a larger volume of distribution (0.79 L/kg) than its two diastereomers (0.24-0.25 L/h · kg and 0.65 L/kg, respectively). A tendency toward slightly higher clearance and volume of distribution values for (2S,3R)-VCD was observed in rats and mice as well. Consequently, in all three animal species the half-life (t(1/2)) of (2S,3R)-VCD was not different from the t(1/2) of the other three VCD stereoisomers. The stereoselective pharmacokinetics of VCD as observed in dogs, rats, and mice is in line with the stereoselectivity previously observed in healthy subjects and epileptic patients.