RESUMEN
The anticonvulsant compound oxcarbazepine and its principal 10-monohydroxy metabolite protected potently against electroshock-induced tonic hindlimb extension. Maximal plasma concentrations depended on dose and were reached < or = 1 h after an oral dose of oxcarbazepine and < 2 h after monohydroxy derivative. In mice, the ED50 was 14 mg/kg for oxcarbazepine and 20.5 mg/kg for the monohydroxy derivative, p.o. In rats, the ED50 was 13.5 mg/kg for oxcarbazepine and 17.0 mg/kg for monohydroxy derivative, p.o. This protective effect compared favorably with the efficacy of carbamazepine, phenytoin, phenobarbital and diazepam in the same test. As observed previously, valproate and ethosuximide were markedly less potent. The effect of oxcarbazepine and its monohydroxy derivative on sustained high frequency repetitive firing of sodium-dependent action potentials of mouse spinal cord neurons in cell culture was also examined using intracellular recording techniques. Both compounds reduced the percentage of neurons capable of sustained action potential firing in concentration-dependent manner. The EC50 for oxcarbazepine was 5 x 10(-8) M and that for monohydroxy derivative was 2 x 10(-8) M (P > 0.05 vs. oxcarbazepine). For comparison, the EC50 for carbamazepine was significantly higher (6 x 10(-7) M, P < 0.001 vs. oxcarbazepine and monohydroxy derivative). Limitation of firing by oxcarbazepine and the monohydroxy derivative depended on firing frequency and membrane potential and was enhanced by depolarization. Input resistance and resting membrane potential were not altered by either drug. The in vitro effect on action potential firing frequency occurred at concentrations below plasma levels of oxcarbazepine and monohydroxy derivative which protected animals against electroshock and were therapeutically effective in patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Anticonvulsivantes/farmacología , Carbamazepina/análogos & derivados , Convulsiones/prevención & control , Potenciales de Acción/efectos de los fármacos , Animales , Carbamazepina/farmacología , Células Cultivadas , Masculino , Ratones , Oxcarbazepina , Ratas , Sodio/metabolismo , Médula Espinal/efectos de los fármacos , Médula Espinal/fisiologíaRESUMEN
The antiepileptic drug (AED) oxcarbazepine (OCBZ) and its rapidly formed 10-monohydroxy metabolite (MHD) protect against electroshock-induced tonic hindlimb extension in rodents (ED50 14-21 mg/kg p.o.). Both stereoisomers of MHD also protect. As with carbamazepine (CBZ), these findings suggest clinical efficacy against generalized tonic-clonic and, to some extent, partial seizures. OCBZ (IC50 5 x 10(-8) M), MHD (IC50 2 x 10 (-8) M), and CBZ (IC50 6 x 10(-7) M) limit the frequency of firing of sodium-dependent action potentials by cultured mouse central neurons and reduce Vmax progressively in a use-dependent manner at concentrations below therapeutic plasma concentrations in OCBZ-treated patients. This suggests that blockade of voltage-sensitive sodium channels could contribute to the antiepileptic efficacy of OCBZ. Blockade of penicillin-induced epileptiform discharges in hippocampal slices by MHD and its stereoisomers was diminished when the potassium channel blocker 4-aminopyridine was added to the bath fluid. This indicates that additional mechanisms of action, e.g., an effect on potassium channels, might be clinically important. In addition, both stereoisomers are equally responsible for the antiepileptic activity of the racemate, i.e., MHD, and are therefore likely to play a therapeutic role. Such actions could confer broad clinical utility on OCBZ.
Asunto(s)
Anticonvulsivantes/farmacología , Carbamazepina/análogos & derivados , Potenciales de Acción/efectos de los fármacos , Animales , Anticonvulsivantes/uso terapéutico , Carbamazepina/farmacología , Carbamazepina/uso terapéutico , Células Cultivadas , Modelos Animales de Enfermedad , Electrochoque , Hipocampo/citología , Hipocampo/efectos de los fármacos , Humanos , Conducción Nerviosa/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/fisiología , Oxcarbazepina , Roedores , Convulsiones/prevención & control , Médula Espinal/citologíaRESUMEN
The disposition of the new anti-epileptic agent oxcarbazepine (10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide) has been studied in two healthy volunteers following an oral 400 mg dose of 14C-labelled drug. The dose was excreted almost completely in the urine (94.6 and 97.1%) within six days. Faecal excretion amounted to 4.3 and 1.9% of the dose in the two subjects. In the 0-6 days urine samples the biotransformation products have been isolated and identified. 10,11-Dihydro-10-hydroxycarbamazepine (GP 47,779) and its two diastereoisomeric O-glucuronides were found as main metabolites. Taken together, they accounted for 79% of urinary 14C. Unchanged oxcarbazepine, and its sulphate and glucuronide conjugates were isolated in smaller amounts only (13%). Other minor metabolites were the trans- and cis-isomers of 10,11-dihydro-10,11-dihydroxy-carbamazepine (approximately 4%), and a phenolic derivative of GP 47,779 (less than 1%). The biotransformation of oxcarbazepine proceeds mainly by reduction to GP 47,779, and subsequent conjugation with glucuronic acid. Reduction is stereospecific, favouring the S-configuration of GP 47,779. Direct conjugation of oxcarbazepine, in the enol form, is a minor pathway. Oxidative reactions are unimportant.
Asunto(s)
Carbamazepina/análogos & derivados , Biotransformación , Carbamazepina/metabolismo , Carbamazepina/orina , Cromatografía Líquida de Alta Presión , Heces/metabolismo , Humanos , Masculino , Oxcarbazepina , Estereoisomerismo , Factores de TiempoRESUMEN
The efficacy and safety of long-term therapy depends on the dose regimen. The early recognition of individual pharmacokinetic defects is a professional task of the clinical pharmacologist. The application of test compounds has been used to differentiate between slow and fast metabolizers. Modern techniques for identifying and quantitating drug metabolites facilitate the determination of the individual metabolic state without resorting to compounds foreign to the particular therapy. This paper exemplifies this principle by examining the metabolism and pharmacokinetics of carbamazepine, oxprenolol, hydralazine, maprotiline and diclofenac sodium. The systematic collection and analysis of representative samples of data is shown to be a prerequisite for the conclusive assessment and interpretation of the individual metabolic state.