METABOLIC CHIRAL INVERSION OF STIRIPENTOL IN THE RAT .2. INFLUENCE OFROUTE OF ADMINISTRATION

As described in the accompanying study, it was found that when the S e nantiomer of stiripentol [(S)-STP] was given orally to rats, blood spe cimens contained only (S)-STP, whereas following administration of an equivalent dose of (R)-STP, both R and S forms of the drug were detect ed in the systemic circulation. In the present study, we investigated the influence of route of administration on this apparently unidirecti onal chiral inversion of (R)-STP in the rat. When (R)STP was given eit her intravenously (60 mg kg(-1)) or intraperitoneally (300 mg kg(-1)), the inversion phenomenon was not observed, indicating that the proces s must take place presystemically. Following oral administration of ei ther enantiomer of STP, it was found that the drug present at various points along the gastrointestinal tract became progressively enriched in molecules of R configuration, such that the free STP in cecum, larg e intestine, and feces consisted largely of the R enantiomer, regardle ss of the configuration of the administered drug. In a parallel in vit ro study, it was demonstrated that STP undergoes acid-catalyzed racemi zation, the rate of which is appreciable at the pH value of the rat st omach (pH similar to 4). On the basis of these observations, it is pro posed that the apparent metabolic chiral inversion of (R)-STP results from the combination of at least two factors: 1) partial acid-catalyze d racemization in gastric acid (that affects both enantiomers equally) , and 2) enantioselectivity in one or more of the processes involved i n the absorption, first pass metabolism or biliary excretion of STP, s uch that the S isomer appears selectively in the systemic circulation, whereas the R enantiomer is eliminated preferentially in the feces.