METABOLIC CHIRAL INVERSION OF STIRIPENTOL IN THE RAT .1. MECHANISTIC STUDIES

To study enantioselective aspects of the disposition of stiripentol (S TP), a chiral allylic alcohol undergoing development as an antiepilept ic drug, a stereoselective synthesis was developed and the configurati on of the two enantiomers determined to be (R)-(+) and (S)-(-). Follow ing a single oral dose (300 mg kg(-1)) of the individual enantiomers t o adult male Sprague-Dawley rats, it was found that (R)-STP was transf ormed extensively to its antipode, whereas little inversion was detect ed when (S)-STP was administered. Studies on the mechanism of this app arently unidirectional chiral inversion revealed that the phenomenon w as dependent on the presence of the side-chain C=C double bond, becaus e the enantiomers of the corresponding saturated alcohol (D2602) did n ot interconvert in vivo. Experiments with analogs of STP labeled with deuterium or oxygen-18 at the chiral center showed that, whereas the d euterium was retained in vivo, partial loss of the O-18 occurred from both enantiomers of the drug. Pretreatment of rats with pentachlorophe nol (40 mu mol kg(-1) ip), an inhibitor of sulfation (and possibly oth er conjugation reactions), led to a marked decrease in the rate of con version of (R)STP to its antipode, suggesting that the chiral inversio n phenomenon may be mediated, at least in part, by an enantioselective conjugation process.