Relation of plasma and brain concentrations of the anticonvulsant ameltolide to its pharmacologic effects.
Ameltolide, a newly described anticonvulsant, was studied to determine the relation between dose administered, plasma and brain concentrations, and pharmacologic effects. The relation of the N-acetyl metabolite and the OH-N-acetyl metabolite to the dose administered and to the pharmacologic effects was also determined. Ameltolide plasma concentrations in both mice and rats were linearly related to dose administered over the entire dose range from low doses, at which the anticonvulsant effects were noted, to high doses, at which neurologic impairment occurred. The plasma concentrations of the metabolites were not as consistently linearly dose-related in the two species. In rats, the brain concentrations of ameltolide were highly correlated with plasma concentrations and the doses administered. Ameltolide was shown to have a phenytoin (PHT)-like anticonvulsant profile in vitro in the cortical slice preparation. These data confirm the potent anticonvulsant profile of ameltolide and the lack of significant activity of the metabolites.
Leander
J D
JD
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
Parli
C J
CJ
Potts
B
B
Lodge
D
D
D000818:Animals; D000927:Anticonvulsants / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology*; D001549:Benzamides / Q000032:analysis / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D001923:Brain Chemistry / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D004597:Electroshock; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D011919:Rats, Inbred Strains; D012640:Seizures / Q000209:etiology / Q000517:prevention & control
D000927:Anticonvulsants; D001549:Benzamides; C055323:ameltolide