Nimodipine restores the altered hippocampal phenytoin pharmacokinetics in a refractory epileptic model.
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 microg ml(-1), p<0.05 versus C rats) than in C animals (C(max): 5.3+/-0.9 microg ml(-1)). Control rats pre-treated with NIMO showed similar results (C(max): 4.5+/-0.8 microg ml(-1)) than those pre-treated with V. NIMO pre-treatment of MP rats showed higher PHT concentrations (C(max): 6.8+/-1.0 microg 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.
Höcht
Christian
C
Cátedra de Farmacología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, (C1113AAD) Buenos Aires, Argentina. chocht@ffyb.uba.ar
Lazarowski
Alberto
A
Gonzalez
Nélida N
NN
Auzmendi
Jerónimo
J
Opezzo
Javier A W
JA
Bramuglia
Guillermo F
GF
Taira
Carlos A
CA
Girardi
Elena
E
D015097:3-Mercaptopropionic Acid; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000819:agonists / Q000493:pharmacokinetics; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use; D003292:Convulsants; D004195:Disease Models, Animal; D004351:Drug Resistance / Q000187:drug effects* / Q000502:physiology; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D017551:Microdialysis; D009553:Nimodipine / Q000494:pharmacology* / Q000627:therapeutic use; D010672:Phenytoin / Q000819:agonists* / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants; D002121:Calcium Channel Blockers; D003292:Convulsants; D009553:Nimodipine; D010672:Phenytoin; D015097:3-Mercaptopropionic Acid