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Chiral aspects of the metabolism of ethosuximide
Author(s) -
Millership Jeffrey S.,
Collier Paul S.,
Hamilton John T. G.,
McRoberts W. Colin,
Mifsud Janet
Publication year - 1995
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.530070312
Subject(s) - ethosuximide , chemistry , enantiomer , chromatography , urine , metabolite , stereoselectivity , stereochemistry , organic chemistry , anticonvulsant , biochemistry , psychology , neuroscience , epilepsy , catalysis
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 chromatography‐mass spectroscopy (GCMS). The metabolites identified were unchanged ethosuximide enantiomers, all four stereoisomers of 2‐(1‐hydroxyethyl)‐2‐methylsuccinimide, and a single stereoisomer of 2‐ethyl‐3‐hydroxy‐2‐methylsuccinimide [derived from (R)‐ethosuximide]. Preliminary quantitative studies indicate a degree of stereoselectivity in the fate of ethosuximide since the ratio of (R)‐ to (S)‐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 1.05:1 (0–24 h sample), 1.10:1 (24–48 h sample)], whilst those from (S)‐ethosuximide are produced in unequal proportions [ratio 1.65:1 (0–24 h sample), 1.74:1 (24–48 h sample)]. © 1995 Wiley‐Liss, Inc.