An overview of the preclinical aspects of topiramate: pharmacology, pharmacokinetics, and mechanism of action.
In this overview, we discuss the discovery and development of topiramate (TPM) as an anticonvulsant, including notable aspects of its chemical, biologic, and pharmacokinetic properties. In particular, we highlight its anticonvulsant profile in traditional seizure tests and animal models of epilepsy and the results of recent electrophysiological and biochemical studies using cultured neurons that have revealed a unique combination of pharmacologic properties of TPM. Finally, we present a hypothesis for the mechanistic basis of the anticonvulsant activity of TPM, which proposes that TPM binds to certain membrane ion channel proteins at phosphorylation sites and thereby allosterically modulates channel conductance and secondarily inhibits protein phosphorylation.
Shank
R P
RP
The R. W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania 19477, USA.
Gardocki
J F
JF
Streeter
A J
AJ
Maryanoff
B E
BE
D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D015220:Calcium Channels / Q000187:drug effects; D004195:Disease Models, Animal; D004827:Epilepsy / Q000188:drug therapy / Q000517:prevention & control; D005071:Evoked Potentials / Q000187:drug effects; D005632:Fructose / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D006624:Hippocampus / Q000187:drug effects; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D018408:Patch-Clamp Techniques; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000187:drug effects; D018079:Receptors, GABA / Q000187:drug effects; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors / Q000187:drug effects; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000187:drug effects; D000077236:Topiramate
D000927:Anticonvulsants; D015220:Calcium Channels; D005632:Fructose; D018091:Receptors, AMPA; D018079:Receptors, GABA; D018092:Kainic Acid Receptors; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D000077236:Topiramate