RESUMEN
PURPOSE: The use of alternate methods for antiepileptic drug delivery has been proposed as a putative strategy to enhance efficacy and tolerability of chronic pharmacotherapy. Intranasal administration is of specific interest based on its general potential for targeted central nervous system delivery. Therefore we analyzed whether intranasal administration of phenobarbital may render a valuable therapeutic approach. METHODS: Brain penetration of phenobarbital following its intranasal administration in rats was studied by microdialysis and by analysis of brain homogenates. The anticonvulsant efficacy of intranasal phenobarbital was determined in the amygdala kindling model. RESULTS: Phenobarbital was efficiently delivered to the rat brain following intranasal administration. A mucoadhesive preparation of phenobarbital thereby resulted in brain concentrations that were superior to those obtained with intranasal administration of an aqueous solution. In comparison with concentrations reached following intravenous administration of 5.4 mg/kg phenobarbital, intranasal administration of the same dosage resulted in 2.4-fold higher C(max) values in cortical dialysates. Ten minutes following intranasal administration, PB concentrations in the olfactory bulb exceeded that in more caudal parts of the brain, thus, indicating that phenobarbital has at least been partially targeted to the brain via local pathways. Testing in the amygdala kindling model demonstrated that effective brain concentrations were reached with intranasal phenobarbital delivery. DISCUSSION: In conclusion, intranasal administration of phenobarbital in rats is associated with efficient brain penetration rates allowing to achieve therapeutic concentrations. Based on these data, intranasal phenobarbital administration seems to render a suitable alternate delivery route for this antiepileptic drug, which should be further evaluated.
Asunto(s)
Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/farmacocinética , Encéfalo/metabolismo , Fenobarbital/administración & dosificación , Fenobarbital/farmacocinética , Administración Intranasal , Amígdala del Cerebelo/citología , Amígdala del Cerebelo/metabolismo , Animales , Anticonvulsivantes/uso terapéutico , Encéfalo/citología , Vías de Administración de Medicamentos , Femenino , Inyecciones Intravenosas , Excitación Neurológica/efectos de los fármacos , Microdiálisis , Fenobarbital/uso terapéutico , Ratas , Ratas WistarRESUMEN
Epileptic seizures drive expression of the blood-brain barrier efflux transporter P-glycoprotein via a glutamate/cyclooxygenase-2 mediated signalling pathway. Targeting this pathway may represent an innovative approach to control P-glycoprotein expression in the epileptic brain and to enhance brain delivery of antiepileptic drugs. Therefore, we tested the effect of specific cyclooxygenase-2 inhibition on P-glycoprotein expression in two different status epilepticus models. Moreover, the impact of a cyclooxygenase-2 inhibitor on expression of the efflux transporter and on brain delivery of an antiepileptic drug was evaluated in rats with recurrent spontaneous seizures. The highly selective cyclooxygenase-2 inhibitors SC-58236 and NS-398 both counteracted the status epilepticus-associated increase in P-glycoprotein expression in the parahippocampal cortex and the ventral hippocampus. In line with our working hypothesis, a sub-chronic 2-week treatment with SC-58236 in the chronic epileptic state kept P-glycoprotein expression at control levels. As described previously, enhanced P-glycoprotein expression in chronic epileptic rats was associated with a significant reduction in the brain penetration of the antiepileptic drug phenytoin. Importantly, the brain delivery of phenytoin was significantly enhanced by sub-chronic cyclooxygenase-2 inhibition in rats with recurrent seizures. In conclusion, the data substantiate targeting of cyclooxygenase-2 in the chronic epileptic brain as a promising strategy to control the expression levels of P-glycoprotein despite recurrent seizure activity. Cyclooxygenase-2 inhibition may therefore help to increase concentrations of antiepileptic drugs at the target sites in the epileptic brain. It needs to be further evaluated whether the approach also enhances efficacy.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Anticonvulsivantes/farmacocinética , Encéfalo/efectos de los fármacos , Inhibidores de la Ciclooxigenasa 2/farmacología , Fenitoína/farmacocinética , Estado Epiléptico/tratamiento farmacológico , Animales , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Enfermedad Crónica , Ciclooxigenasa 2/metabolismo , Modelos Animales de Enfermedad , Epilepsia/tratamiento farmacológico , Epilepsia/metabolismo , Femenino , Masculino , Nitrobencenos/farmacología , Pirazoles/farmacología , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Convulsiones/tratamiento farmacológico , Convulsiones/metabolismo , Transducción de Señal/efectos de los fármacos , Estado Epiléptico/metabolismo , Sulfonamidas/farmacologíaRESUMEN
In the epileptic brain, seizure activity induces expression of the blood-brain barrier efflux transporter, P-glycoprotein, thereby limiting brain penetration and therapeutic efficacy of antiepileptic drugs. We recently provided the first evidence that seizures drive P-glycoprotein induction through a pathway that involves glutamate-signaling through the NMDA receptor and cyclooxygenase-2 (COX-2). Based on these data, we hypothesized that selective inhibition of COX-2 could prevent seizure-induced P-glycoprotein up-regulation. In the present study, we found that the highly selective COX-2 inhibitors, NS-398 and indomethacin heptyl ester, blocked the glutamate-induced increase in P-glycoprotein expression and transport function in isolated rat brain capillaries. Importantly, consistent with this, the COX-2 inhibitor, celecoxib, blocked seizure-induced up-regulation of P-glycoprotein expression in brain capillaries of rats in vivo. To explore further the role of COX-2 in signaling P-glycoprotein induction, we analyzed COX-2 protein expression in capillary endothelial cells in brain sections from rats that had undergone pilocarpine-induced seizures and in isolated capillaries exposed to glutamate and found no change from control levels. However, in isolated rat brain capillaries, the COX-2 substrate, arachidonic acid, significantly increased P-glycoprotein transport activity and expression indicating that enhanced substrate flux to COX-2 rather than increased COX-2 expression drives P-glycoprotein up-regulation. Together, these results provide the first in vivo proof-of-principle that specific COX-2 inhibition may be used as a new therapeutic strategy to prevent seizure-induced P-glycoprotein up-regulation at the blood-brain barrier for improving pharmacotherapy of drug-resistant epilepsy.