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Quantification of urinary excretion of ethosuximide enantiomers and their major metabolites in the rat
Author(s) -
Mifsud J.,
Millership J.S.,
Collier P.S.,
Morrow R.,
Hamilton J.T.G.,
McRoberts W.C.
Publication year - 2001
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.265
Subject(s) - ethosuximide , enantiomer , urine , diastereomer , chemistry , chromatography , excretion , stereoselectivity , metabolite , detection limit , pharmacology , anticonvulsant , stereochemistry , biochemistry , medicine , psychiatry , epilepsy , catalysis
Abstract A chiral gas chromatographic assay has been developed for quantitative analysis of ethosuximide and its major metabolites in rat urine. The extraction procedure was found to be precise and reproducible. Recovery was in the range of 94–98%, intraday CV(%) was 0.92% for ( S )‐ethosuximide (50 μg/ml) and 0.51% for ( R )‐ethosuximide (50 μg/ml). Interday CV(%) was 1.12% for ( S )‐ethosuximide and 0.72% for ( R )‐ethosuximide. The limit of detection was determined to be around 0.01 μg/ml for each enantiomer. Following administration of rac ‐ethosuximide by i.v., i.p. and oral routes, unchanged ethosuximide was detected in urine up to 72 h after drug administration. The appearance of all detected metabolites occurred within 24 h of drug administration. Significantly more ( S )‐ethosuximide was excreted unchanged than ( R )‐ethosuximide with all three routes studied. A substantial amount of the drug was eliminated as the 2‐(1‐hydroxyethyl)‐2‐methylsuccinimide (2 pairs of diastereoisomers). Much less drug was eliminated as the 2‐ethyl‐3‐hydroxy‐2‐methylsuccinimide with only one diastereoisomer observed. Examination of the one pair of diastereoisomers of 2‐(1‐hydroxyethyl)‐2‐methylsuccinimide that was resolved showed preferential excretion of one isomer. Comparison of both pairs of diastereoisomers showed that one pair was formed in preference to the other with a ratio of approximately 0.8:1. It is concluded that stereoselective metabolism of ethosuximide occurs. Copyright © 2001 John Wiley & Sons, Ltd.