Chiral aspects of the metabolism of ethosuximide

✍ Scribed by Jeffrey S. Millership; Paul S. Collier; John T. G. Hamilton; W. Colin McRoberts; Janet Mifsud

• Publisher: John Wiley and Sons
• Year: 1995
• Tongue: English
• Weight: 466 KB
• Volume: 7
• Category: Article
• ISSN: 0899-0042
• DOI: 10.1002/chir.530070312

✦ Synopsis

Ethosuximide is a chiral drug substance primarily indicated for the treatment of absence seizures. This drug is used clinically as the racemate. The urinary metabolites of ethosuximide (following i.p. administration of the racemate or individual enantiomers to rats) have been studied using chiral gas chromatography (GC) and gas chromatographymass spectroscopy (GCMS). The metabolites identified were unchanged ethosuximide enantiomers, all four stereoisomers of 2-(l-hydroxyethyl)-2-methylsuccinimide, and a single stereoisomer of 2-ethyl-3-hydroxy-2-methylsuccinimide [derived from (R)-ethosuximide]. Prehnary quantitative studies indicate a degree of stereoselectivity in the fate of ethosuximide since the ratio of (R)-to 6)-ethosuximide in the urine was found to be 0.77 1 (0-24 h sample), 0.64: 1 (24-48 h sample), and 0.83: 1 (48-72 h sample). This would suggest that the (R)-isomer is preferentially metabolised. Results obtained following the administration of individual enantiomers of ethosuximide indicate that the 2-(1-hydroxyethyl)-2-methylsuccinimide diastereoisomers derived from (R)-ethosuximide are produced in approximately equal proportions [ratio 1.051 (0-24 h sample), 1.101 (24-48 h sample)], whilst those from 6)-ethosuximide are produced in unequal proportions [ratio 1.65:l (0-24 h sample), 1.74:l (24-48 h sample)].