Relation of Plasma and Brain Concentrations of the Anticonvulsant Ameltolide to Its Pharmacologic Effects

Abstract

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.

Nonlinear mixed effects pharmacokinetic/pharmacodynamic analysis of the anticonvulsant ameltolide (LY201116) in a canine seizure model

“…In radioligand binding assays in synaptosomes, the affinity of ameltolide (Kd) for the 3 H‐batrachotoxinin‐A‐20α (scorpion venom) binding site on voltage‐dependent sodium channels was 970 nM (Vamecq et al. , 1998), which correlates well with brain and plasma concentrations measured in rodents post oral administration (Leander et al. , 1992).…”

“…The plasma sample analysis was modified from a rodent plasma bioanalytical assay for ameltolide (Leander et al. , 1992).…”

“…To account for an observed shift in the empirical plasma concentration‐response (i.e. proportion of dogs with a CS ≤ 2) relationship at 3 and 24 h postdosing, and an observed delay between plasma and brain concentrations in rats following oral ameltolide dosing (Leander et al. , 1992), a biophase or effect‐site ameltolide concentration, , was modeled as the convolution of the plasma ameltolide concentration with an effect site distribution function (Gabrielson & Weiner, 2000), given by: with: where keo is the first order rate constant of input and output of the effect‐site distribution function and ‘*‘ denotes the convolution operator .…”

“…, 1998), and have similar high nanomolar (nM) affinity in vitro (Vamecq et al. , 1998) and in vivo (Leander et al. , 1992) in rodents.…”

“…, 1992). Moreover, extensive in vivo anticonvulsant activity (Clark, 1988; Leander et al. , 1988, 1992; Clark et al.…”