Neuroscience Letters 413 (2007) 168–172 Nimodipine restores the altered hippocampal phenytoin pharmacokinetics in a refractory epileptic model Christian H ¨ ocht a,∗ , Alberto Lazarowski b,c , N´ elida N. Gonzalez b , Jer ´ onimo Auzmendi b , Javier A.W. Opezzo a , Guillermo F. Bramuglia a , Carlos A. Taira a , Elena Girardi b a C´ atedra de Farmacolog´ ıa, Facultad de Farmacia y Bioqu´ ımica, Universidad de Buenos Aires, Jun´ ın 956, (C1113AAD) Buenos Aires, Argentina b Instituto de Biolog´ ıa Celular y Neurociencia “Prof. Eduardo De Robertis”, Facultad de Medicina, Universidad de Buenos Aires, Argentina c Departamento de Bioqu´ ımica Cl´ ınica, Facultad de Farmacia y Bioqu´ ımica, Universidad de Buenos Aires, Argentina Received 21 August 2006; received in revised form 16 October 2006; accepted 24 November 2006 Abstract 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, hippocam- pal PHT concentrations were lower in MP (maximal concentration, C max : 2.7 ± 0.3 g ml -1 , p < 0.05 versus C rats) than in C animals (C max : 5.3 ± 0.9 g ml -1 ). Control rats pre-treated with NIMO showed similar results (C max : 4.5 ± 0.8 g ml -1 ) than those pre-treated with V. NIMO pre-treatment of MP rats showed higher PHT concentrations (C max : 6.8 ± 1.0 g 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. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Refractory epilepsy; P-glycoprotein; Nimodipine; Phenytoin; Microdialysis Epilepsy is one of the most common neurological disorders [3]. Despite the existence of a large variety of antiepileptic drugs (AED), almost 30% of epileptic patients are resistant to treatment [27]. Two hypotheses have been put forward to explain pharmacoresistance to AED [27]. The target hypothesis explained the pharmacoresistance because of an altered sen- sitivity of drug targets [28]. However, the fact that a patient resistant to one AED is often resistant to other drugs with dif- ferent mechanism of action supports the transporter hypothesis [15,17,28]. This hypothesis contends that expression or func- tion of multidrug transporters is augmented in the epileptic brain [15,17,28]. P-glycoprotein (P-gp) is a defense mechanism located on luminal cell membrane of endothelial cells of the blood–brain ∗ Corresponding author. Tel.: +54 11 4964 8265; fax: +54 11 4508 3645. E-mail address: chocht@ffyb.uba.ar (C. H ¨ ocht). barrier (BBB), that reduces brain accumulation of naturally occurring toxins and xenobiotics [5,32] and is thought to limit drug distribution within brain parenchyma. P-gp reduces distri- bution of certain AED into the brain of experimental models [21,22,29,31]. Rizzi et al. using the Kainate model of epilepsy showed that overexpression of P-gp in the hippocampus is asso- ciated with reduced brain concentrations of phenytoin (PHT) when compared with control animals [29]. However, Potschka and L ¨ oscher did not find altered levels of PHT in the hippocam- pus and amygdala of kindled compared to non-kindled rats [25]. Recently, van Vliet et al. [35] reported that administration of tariquidar, a P-gp inhibitor, improves the anticonvulsivant action of PHT, suggesting that co-administration of P-gp inhibitors with AED might be a promising therapeutic strategy to avoid pharmacoresistance in epileptic patients [35]. In a previous report, we found an overexpression of P-gp in the BBB, as well as immunoreative astrocytes and neurons, in 3-mercaptopropionic acid (MP) induced epileptic rats [16]. 0304-3940/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2006.11.075