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Relationship of anticonvulsant activity to brain concentrations of the chiral anticonvulsant U‐54494A
Author(s) -
Von Voigtlander Philip F.,
Althaus John S.,
Lewis Richard A.,
Green Donnella S.
Publication year - 1989
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.430180304
Subject(s) - anticonvulsant , enantiomer , pharmacology , chemistry , epilepsy , oral administration , medicine , stereochemistry , psychiatry
U‐54494A and its enantiomers were administered to mice orally, intravenously, and intracerebroventricularly, and the anticonvulsant time anticonvuslant time courses were assessed by determination of electroshock seizure thresholds. The time courses of brain concentrations of the administered compounds were also assessed by an HPLC‐electrochemical detection assay. The recemate (U‐54494A) and both enantiomers were found to be long‐acting anticonvulsants with high oral apparent bioavailabilities. However, this was not reflected by the brain concentrations of administered compound; during the protracted anticonvulsant time courses, the drugs were present at only very low levels in the brain. This suggests the possibility of active metabolites contribting to the antoconvulsant effects of U‐54494A. However, both the enantiomers and the racemate are intrinsically active as indicated by anticonvulsant effects elicited via intracerebroventricular administration. Thus, both of the enantiomers and metabolites thereof contribute to the anticonvulsant effects of U‐54494A.