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 (45mgkg(-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 (30mgkg(-1), i.v.) 30min after intraperitoneal administration of vehicle (V) or nimodipine (NIMO, 2mgkg(-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+/-0.3mugml(-1), p<0.05 versus C rats) than in C animals (C(max): 5.3+/-0.9mugml(-1)). Control rats pre-treated with NIMO showed similar results (C(max): 4.5+/-0.8mugml(-1)) than those pre-treated with V. NIMO pre-treatment of MP rats showed higher PHT concentrations (C(max): 6.8+/-1.0mugml(-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.[1]References
- Nimodipine restores the altered hippocampal phenytoin pharmacokinetics in a refractory epileptic model. Höcht, C., Lazarowski, A., Gonzalez, N.N., Auzmendi, J., Opezzo, J.A., Bramuglia, G.F., Taira, C.A., Girardi, E. Neurosci. Lett. (2007) [Pubmed]
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