Nimodipine restores the altered hippocampal phenytoin phamacokinetic in a refractory epileptic model”

CH HÖCHT; A LAZAROWSKI; N N GONZALEZ; J AUZMENDI; JAW OPEZZO; G F BRAMUGLIA; C A TAIRA; E GIRARDI

NEUROSCIENCE LETTERS

Elsevier Headquarter

Lugar: The Netherlands; Año: 2007 vol. 413 p. 168 - 172

0304-3940

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, 2mg 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, Cmax: 2.7±0.3gml−1, p < 0.05 versus C rats) than in C animals (Cmax: 5.3±0.9gml−1). Control rats pre-treated with NIMO showed similar results (Cmax: 4.5±0.8gml−1) than those pre-treated with V. NIMO pre-treatment of MP rats showed higher PHT concentrations (Cmax: 6.8±1.0gml−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. © 2006 Elsevier Ireland Ltd. All rights reserved.−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, 2mg 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, Cmax: 2.7±0.3gml−1, p < 0.05 versus C rats) than in C animals (Cmax: 5.3±0.9gml−1). Control rats pre-treated with NIMO showed similar results (Cmax: 4.5±0.8gml−1) than those pre-treated with V. NIMO pre-treatment of MP rats showed higher PHT concentrations (Cmax: 6.8±1.0gml−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. © 2006 Elsevier Ireland Ltd. All rights reserved.−1, i.v.) 30 min after intraperitoneal administration of vehicle (V) or nimodipine (NIMO, 2mg 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, Cmax: 2.7±0.3gml−1, p < 0.05 versus C rats) than in C animals (Cmax: 5.3±0.9gml−1). Control rats pre-treated with NIMO showed similar results (Cmax: 4.5±0.8gml−1) than those pre-treated with V. NIMO pre-treatment of MP rats showed higher PHT concentrations (Cmax: 6.8±1.0gml−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. © 2006 Elsevier Ireland Ltd. All rights reserved.−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, Cmax: 2.7±0.3gml−1, p < 0.05 versus C rats) than in C animals (Cmax: 5.3±0.9gml−1). Control rats pre-treated with NIMO showed similar results (Cmax: 4.5±0.8gml−1) than those pre-treated with V. NIMO pre-treatment of MP rats showed higher PHT concentrations (Cmax: 6.8±1.0gml−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. © 2006 Elsevier Ireland Ltd. All rights reserved.Cmax: 2.7±0.3gml−1, p < 0.05 versus C rats) than in C animals (Cmax: 5.3±0.9gml−1). Control rats pre-treated with NIMO showed similar results (Cmax: 4.5±0.8gml−1) than those pre-treated with V. NIMO pre-treatment of MP rats showed higher PHT concentrations (Cmax: 6.8±1.0gml−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. © 2006 Elsevier Ireland Ltd. All rights reserved.±0.9gml−1). Control rats pre-treated with NIMO showed similar results (Cmax: 4.5±0.8gml−1) than those pre-treated with V. NIMO pre-treatment of MP rats showed higher PHT concentrations (Cmax: 6.8±1.0gml−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. © 2006 Elsevier Ireland Ltd. All rights reserved.Cmax: 6.8±1.0gml−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. © 2006 Elsevier Ireland Ltd. All rights reserved.