Individual and combined antiepileptic and neurotoxic activity of carbamazepine and carbamazepine-10,11-epoxide in mice.
Anticonvulsant effect and neurological toxicity were investigated in mice for carbamazepine (CBZ) and its main metabolites, carbamazepine-10,11-epoxide (CBZ-E) and 10,11-dihydro-10,11-trans-dihydroxy-CBZ. The compounds were first tested separately and the results were expressed in terms of brain concentrations. Brain penetration was very poor for 10,11-dihydro-10,11-trans-dihydroxy-CBZ, which had neither anticonvulsant nor neurotoxic activity. Against maximal electroshock, CBZ was slightly more potent than CBZ-E and both were ineffective against pentylenetetrazole and bicuculline. CBZ and CBZ-E displayed similar neurotoxicity. Combined administration of CBZ and CBZ-E revealed a slightly synergistic interaction with regard to both anticonvulsant and neurotoxic action, the therapeutic index of the mixture being similar to that of CBZ. These results suggest that antiepileptic activity and neurological toxicity of CBZ are proportional to the sum of the concentrations of CBZ and its metabolite CBZ-E. Furthermore, variable levels of CBZ-E in relation to CBZ do not affect the overall therapeutic index. Finally, the results do not indicate that CBZ-E alone has any advantage over CBZ with regard to neurotoxic side-effects and therapeutic index.
D000818:Animals; D001921:Brain / Q000378:metabolism; D002220:Carbamazepine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D004357:Drug Synergism; D005260:Female; D051379:Mice; D008813:Mice, Inbred ICR; D009420:Nervous System / Q000187:drug effects*; D011335:Proadifen / Q000494:pharmacology; D012640:Seizures / Q000188:drug therapy
D002220:Carbamazepine; D011335:Proadifen; C012227:carbamazepine epoxide