Development of tolerance to levetiracetam in rats with chronic epilepsy.
OBJECTIVE
Pharmacoresistance is a major problem in the treatment of epilepsy. We showed previously that pharmacoresistance, at least partially, is due to an up-regulation of the multidrug transporter (MDT) P-glycoprotein (P-gp): inhibition of P-gp improves seizure control in phenytoin-treated epileptic rats (poststatus epilepticus rat model for temporal lobe epilepsy). Since it has been suggested that levetiracetam (LEV) is no substrate for MDTs, we hypothesized that LEV would more adequately control seizures in this rat model.


METHODS
Chronic epileptic rats were treated repeatedly with LEV (2-week interval; different dosages) via continuous infusion using osmotic minipumps, 5-6 months after electrically induced status epilepticus. The anticonvulsive effects were determined by video-EEG monitoring and the concentration of LEV was measured in plasma and brain homogenates using gas chromatography.


RESULTS
LEV adequately entered the epileptic brain and dose-dependently suppressed spontaneous seizures in chronic epileptic rats for 3-4 days. Hereafter, seizure frequency increased, while LEV plasma levels did not change. Seizure behavior was less severe throughout the whole treatment. LEV did not affect seizure duration. After a withdrawal period of 2 weeks all rats initially responded again to LEV.


CONCLUSIONS
The initial seizure control by LEV supports the observation that LEV is not impeded by MDTs. However, the failure to control seizures for a longer period of time indicates the development of tolerance to this drug. This poses another problem in the treatment of this kind of epilepsy. Whether tolerance may be prevented by intermittent administration of LEV should be further investigated.
van Vliet
Erwin A
EA
Epilepsy Institute of The Netherlands (SEIN), Heemstede, The Netherlands.
van Schaik
Rosalinda
R
Edelbroek
Peter M
PM
da Silva
Fernando H Lopes
FH
Wadman
Wytse J
WJ
Gorter
Jan A
JA
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002849:Chromatography, Gas; D002908:Chronic Disease; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D004567:Electrodes, Implanted; D004569:Electroencephalography; D004833:Epilepsy, Temporal Lobe / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D007260:Infusion Pumps; D000077287:Levetiracetam; D008297:Male; D010672:Phenytoin / Q000627:therapeutic use; D010889:Piracetam / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013702:Temporal Lobe / Q000378:metabolism; D014743:Videotape Recording
D000927:Anticonvulsants; D000077287:Levetiracetam; D010672:Phenytoin; D010889:Piracetam