The pharmacokinetics of ethosuximide enantiomers in the rat

A chiral gas chromatographic assay previously developed for quantitative an alysis of ethosuximide and its major metabolites in rat urine has been adap ted for the analysis of the drug in plasma. Ethosuximide, both as a racemic mixture and as the individual enantiomers, was administered to conscious r ats by the intravenous (i.v.) and intraperitoneal (i.p.) routes. Pharmacoki netic parameters were estimated using standard non-compartmental methods. C omparison of the pharmacokinetic parameters of (S)-ethosuximide and (R)-eth osuximide showed that total body clearance of (R)-ethosuximide was signific antly larger than that of (S)-ethosuximide and that elimination half-life w as significantly shorter following administration of both 40 mg i.v. and i. p. doses, indicating that there is stereoselective elimination of ethosuxim ide. However, no significant differences were found between apparent volume s of distribution. In addition, no significant differences were found for e ither enantiomer between the estimates of the pharmacokinetic parameters ob tained following administration as the individual enantiomer and as a const ituent of the racemic mixture. This indicates that, at the doses studied, t he preferential faster elimination of (R)-ethosuximide is not dependent upo n the presence of the (S)-enantiomer. Also, for each enantiomer, the lack o f any significant difference between estimates of clearance when administer ed as part of a racemic mixture and when administered separately indicates that neither enantiomer affects the clearance of the other. Copyright (C) 2 001 John Wiley & Sons, Ltd.