Nimodipine restores the altered hippocampal phenytoin pharmacokinetics in a refractory epileptic model

• Published in: Neuroscience letters Vol. 413; no. 2; pp. 168 - 172
• Main Authors: Höcht, Christian, Lazarowski, Alberto, Gonzalez, Nélida N., Auzmendi, Jerónimo, Opezzo, Javier A.W., Bramuglia, Guillermo F., Taira, Carlos A., Girardi, Elena
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier Ireland Ltd 14-02-2007; Elsevier
• Subjects: 3-Mercaptopropionic Acid; Animals; Anticonvulsants - agonists; Anticonvulsants - pharmacokinetics; ATP-Binding Cassette, Sub-Family B, Member 1 - drug effects; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Biological and medical sciences; Calcium Channel Blockers - pharmacology; Calcium Channel Blockers - therapeutic use; Convulsants; Disease Models, Animal; Drug Resistance - drug effects; Drug Resistance - physiology; Epilepsy - chemically induced; Epilepsy - drug therapy; Epilepsy - metabolism; Extracellular Fluid - drug effects; Extracellular Fluid - metabolism; Fundamental and applied biological sciences. Psychology; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Hippocampus - drug effects; Hippocampus - metabolism; Hippocampus - physiopathology; Male; Medical sciences; Microdialysis; Nervous system (semeiology, syndromes); Neurology; Nimodipine; Nimodipine - pharmacology; Nimodipine - therapeutic use; P-glycoprotein; Phenytoin; Phenytoin - agonists; Phenytoin - pharmacokinetics; Rats; Rats, Wistar; Refractory epilepsy; Vertebrates: nervous system and sense organs; P-glycoprotein; Refractory epilepsy; Microdialysis; Nimodipine; Phenytoin; Nervous system diseases; Epilepsy; Central nervous system; Glycoprotein; Anticonvulsant; Cerebral disorder; Central nervous system disease; Models; Hippocampus
• ISSN: 0304-3940; 1872-7972
• DOI: 10.1016/j.neulet.2006.11.075

The present work was undertaken to examine the central pharmacokinetics of phenytoin (PHT) in an experimental model of epilepsy, induced by administration of 3-mercaptopropionic acid (MP), and possible participation of P-glycoprotein in this model of epilepsy. Repeated seizures were induced in male Wistar rats by injection of 3-MP (45
mg
kg
−1, i.p.) during 10 days. Control rats (C) were injected with saline solution. In order to monitor extracellular PHT levels, either a shunt microdialysis probe or a concentric probe was inserted into carotid artery or hippocampus, respectively. All animals were administered with PHT (30
mg
kg
−1, i.v.) 30
min after intraperitoneal administration of vehicle (V) or nimodipine (NIMO, 2
mg
kg
−1). No differences were found in PHT plasma levels comparing all experimental groups. In pre-treated rats with V, hippocampal PHT concentrations were lower in MP (maximal concentration,
C
max: 2.7
±
0.3
μg
ml
−1,
p
<
0.05 versus C rats) than in C animals (
C
max: 5.3
±
0.9
μg
ml
−1). Control rats pre-treated with NIMO showed similar results (
C
max: 4.5
±
0.8
μg
ml
−1) than those pre-treated with V. NIMO pre-treatment of MP rats showed higher PHT concentrations (
C
max: 6.8
±
1.0
μg
ml
−1,
p
<
0.05) when compared with V pre-treated MP group. Our results indicate that central pharmacokinetics of PHT is altered in MP epileptic rats. The effect of NIMO on hippocampal concentrations of PHT suggests that P-glycoprotein has a role in reduced central bioavailability of PHT in our epileptic refractory model.