Brain penetration and anticonvulsant efficacy of intranasal phenobarbital in rats.
OBJECTIVE
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.


CONCLUSIONS
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.
Czapp
Marion
M
Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilian-University, Munich, Germany.
Bankstahl
Jens P
JP
Zibell
Guido
G
Potschka
Heidrun
H
D000281:Administration, Intranasal; D000679:Amygdala / Q000166:cytology / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D004333:Drug Administration Routes; D005260:Female; D007275:Injections, Intravenous; D007696:Kindling, Neurologic / Q000187:drug effects; D017551:Microdialysis; D010634:Phenobarbital / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar
D000927:Anticonvulsants; D010634:Phenobarbital