Stereoselective Pharmacokinetics and Pharmacodynamics of Propylisopropyl Acetamide,a CNS-Active Chiral Amide Analog of Valproic Acid

Purpose. The purpose of this study was to evaluate there existed stereoselective effects in the pharmacokinetics, anticonvulsant activity, microsomal epoxide hydrolase (mEH) inhibition, and teratogenicity of the two enantiomers of propylisopropyl acetamide (PID), a CNS-active chiral amide analogue of valproic acid. Methods. Racemic PID, as well as the individual enantiomers, were intravenously administered to six dogs in order to investigate the stereoselectivity in their pharmacokinetics. Anticonvulsant activity was evaluated in mice (ip) and rats (oral), mEH inhibition studies were performed in human liver microsomes, and teratogenicity was evaluated in an inbred susceptible mice strain. Results. Following intravenous administration to dogs of the individual enantiomers, (R)-PID had significantly lower clearance and longer half-life than (S)-PID, however, the volumes of distribution were similar. In contrast, following intravenous administration of racemic PID, both enantiomers had similar pharmacokinetic parameters. In rats (oral), (R)-PID had a significantly lower ED₅₀ in the maximal electroshock seizure test than (S)-PID; 16 and 25 mg/kg, respectively. PID enantiomers were non-teratogenic and did not demonstrate stereoselective mEH inhibition. Conclusions. (R)-PID demonstrated better anticonvulsant activity, lower clearance and a longer half-life compared to (S)-PID. When racemic PID was administered, the clearance of (S)-PID was significantly reduced, reflecting an enantiomer-enantiomer interaction.