Comparative anticonvulsant potency and pharmacokinetics of (+)-and (-)-enantiomers of stiripentol.
The anticonvulsant potency and pharmacokinetics of the enantiomers of stiripentol were compared using the intravenous pentylenetetrazol infusion seizure model in the rat. Enantioselectivity was observed with respect to both the anticonvulsant activity and elimination kinetics of this compound. (+)-Stiripentol was 2.4 times more potent than its antipode against pentylenetetrazol-induced clonic seizure (brain EC50 of 15.2 micrograms/ml versus 36.1 micrograms/ml). The (+)-enantiomer was eliminated more rapidly than the (-)-enantiomer, as reflected in a higher plasma clearance (1.64 l/h/kg versus 0.557 l/h/kg) and a shorter half-life (2.83 h versus 6.50 h). Parallel studies with the racemate of stiripentol indicated that the anticonvulsant potency of the racemate was between the potency of the two enantiomers, suggesting that the combined activity reflects the additive action of (+)- and (-)-stiripentol. However, a marked metabolic interaction between enantiomers was evident after racemate administration. These results point to the need for information on the differential pharmacokinetics of stiripentol enantiomers following racemic drug administration.
Shen
D D
DD
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle 98195.
Levy
R H
RH
Savitch
J L
JL
Boddy
A V
AV
Tombret
F
F
Lepage
F
F
D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004148:Dioxolanes / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D010433:Pentylenetetrazole; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology; D013237:Stereoisomerism
D000927:Anticonvulsants; D004148:Dioxolanes; C021092:stiripentol; D010433:Pentylenetetrazole