Metabolic chiral inversion of stiripentol in the rat. I. Mechanistic studies.
To study enantioselective aspects of the disposition of stiripentol (STP), a chiral allylic alcohol undergoing development as an antiepileptic drug, a stereoselective synthesis was developed and the configuration of the two enantiomers determined to be (R)-(+) and (S)-(-). Following a single oral dose (300 mg kg-1) of the individual enantiomers to adult male Sprague-Dawley rats, it was found that (R)-STP was transformed extensively to its antipode, whereas little inversion was detected when (S)-STP was administered. Studies on the mechanism of this apparently unidirectional chiral inversion revealed that the phenomenon was dependent on the presence of the side-chain C==C double bond, because the enantiomers of the corresponding saturated alcohol (D2602) did not interconvert in vivo. Experiments with analogs of STP labeled with deuterium or oxygen-18 at the chiral center showed that, whereas the deuterium was retained in vivo, partial loss of the 18O occurred from both enantiomers of the drug. Pretreatment of rats with pentachlorophenol (40 mumol kg-1 i.p.), an inhibitor of sulfation (and possibly other conjugation reactions), led to a marked decrease in the rate of conversion of (R)-STP to its antipode, suggesting that the chiral inversion phenomenon may be mediated, at least in part, by an enantioselective conjugation process.
Zhang
K
K
Department of Medicinal Chemistry, University of Washington, Seattle 98195.
Tang
C
C
Rashed
M
M
Cui
D
D
Tombret
F
F
Botte
H
H
Lepage
F
F
Levy
R H
RH
Baillie
T A
TA
D000284:Administration, Oral; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000378:metabolism* / Q000493:pharmacokinetics*; D004148:Dioxolanes / Q000138:chemical synthesis / Q000378:metabolism* / Q000493:pharmacokinetics*; D004149:Dioxoles / Q000493:pharmacokinetics; D004347:Drug Interactions; D007408:Intestinal Absorption; D008297:Male; D013058:Mass Spectrometry; D010084:Oxidation-Reduction; D010104:Oxygen Radioisotopes; D010416:Pentachlorophenol / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013431:Sulfates / Q000378:metabolism; D014316:Tritium
D000927:Anticonvulsants; D004148:Dioxolanes; D004149:Dioxoles; D010104:Oxygen Radioisotopes; D013431:Sulfates; D014316:Tritium; C090345:alpha-1,1-dimethylethyl-1,3-benzodioxole-5-propanol; D010416:Pentachlorophenol; C021092:stiripentol