Please cite this article in press as: C. Höcht, et al., Differential hippocampal pharmacokinetics of phenobarbital and carbamazepine in repetitive seizures induced by 3-mercaptopropionic acid, Neurosci. Lett. (2009), doi:10.1016/j.neulet.2009.01.079 ARTICLE IN PRESS G Model NSL-25819; No. of Pages 4 Neuroscience Letters xxx (2009) xxx–xxx Contents lists available at ScienceDirect Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet Differential hippocampal pharmacokinetics of phenobarbital and carbamazepine in repetitive seizures induced by 3-mercaptopropionic acid Christian Höcht a,b,∗ , Alberto Lazarowski b,c,d , Nélida N. Gonzalez c , Marcos A. Mayer a,b , Javier A.W. Opezzo a,b , Carlos A. Taira a,b , Elena Girardi c a Cátedra de Farmacología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, (C1113AAD) Buenos Aires, Argentina b Instituto de Fisiopatología y Bioquímica Clínica (INFIBIOC), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, (C1113AAD) Buenos Aires, Argentina c Instituto de Biología Celular y Neurociencia “Prof. Eduardo De Robertis”, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina d Departamento de Bioquímica Clínica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina article info Article history: Received 12 December 2008 Received in revised form 26 January 2009 Accepted 30 January 2009 Keywords: 3-Mercaptopropionic acid Chronic epilepsy Phenobarbital Carbamazepine Microdialysis Hippocampus P-glycoprotein abstract Previous evidence has shown that chronic 3-mercaptopropionic acid (MP) administration induced brain P- glycoprotein (P-gp) overexpression altering target site accumulation of phenytoin. The aim of the present work was to assess the involvement of P-glycoprotein in carbamazepine and phenobarbital hippocam- pal pharmacokinetics in an experimental model of epilepsy, induced by repetitive MP administration. Seizures were induced in Wistar rats by injection of MP (45 mg kg -1 , i.p.) during 10 days. Control rats (C) were injected with saline solution. In order to monitor extracellular brain antiepileptic levels, a concentric probe was inserted into the hippocampus. Animals were administered with carbamazepine (10 mg kg -1 , i.v.) or phenobarbital (20 mg kg -1 , i.v.) 30 min after intraperitoneal administration of vehicle or nimodipine (2 mg kg -1 ), a well known P-glycoprotein inhibitor. No differences were found in hippocam- pal concentrations of carbamazepine comparing all groups. In vehicle pre-treated rats, hippocampal phenobarbital concentrations were lower in MP (maximal concentration, C max : 6.0 ± 0.6 g ml -1 , p < 0.05) than in C animals (C max : 9.4 ± 0.9 g ml -1 ). Control rats pre-treated with nimodipine showed similar results (C max : 10.7 ± 0.6 g ml -1 ) than those pre-treated with vehicle. Nimodipine pre-treatment in MP rats enhanced hippocampal phenobarbital concentrations (C max : 10.2 ± 1.0 g ml -1 , p < 0.05) as compared with vehicle pre-treatment. Results of our work suggest that P-glycoprotein (P-gp) overexpression by repetitive seizures induced by MP administration does not modify brain bioavailability of carbamazepine. Conversely, hippocampal levels of phenobarbital are reduced in MP rats with regard to non-epileptic rats, suggesting a potential role of P-gp overexpression in pharmacoresistance to phenobarbital. © 2009 Elsevier Ireland Ltd. All rights reserved. Epilepsy is one of the most common neurological disorders [4]. 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 explains the pharmacoresistance because of an altered sensitivity of drug targets [28]. However, the fact that patients resistant to one AED are often resistant to other drugs with different mechanism of action supports the transporter hypothesis [13,16,28]. This hypothesis contends that expression or function of multidrug transporters is augmented in the epileptic brain [13,16,28]. P-glycoprotein, normally located on luminal cell membrane of endothelial cells of the blood-brain barrier (BBB), reduces brain accumulation of xenobiotics [6] and is thought to limit drug distri- ∗ Corresponding author. Tel.: +54 11 4964 8265; fax: +54 11 4508 3645. E-mail address: chocht@ffyb.uba.ar (C. Höcht). bution within brain parenchyma. P-gp reduces brain distribution of certain AEDs in experimental models [24,25,30,32]. This trans- porter was found to be overexpressed in endothelial cells, and present in neurons and glial cells from human drug-resistance epileptic brain tissue, as well as in experimental refractory epilepsy [13,16], leading to enhanced extrusion of drugs from brain to blood- stream. In this regard, Cucullo et al. [5] by using a humanized dynamic in-vitro BBB model have established that BBB permeabil- ity to phenytoin was 10-fold less in drug-resistant BBB models than in controls. However, in-vivo clinical study of this hypoth- esis is restricted by the limitation in obtaining suitable control tissue to compare with epileptogenic brain of patients [26]. High interindividual variability in AEDs extracellular levels was found in cortical regions of patients with intractable epilepsy [26]. Even- though lower extracellular concentrations of several antiepileptic drugs were found in cerebrospinal fluid of patients with intractable epilepsy, in the absence of data from non-epileptic tissues; it was not possible to determine if their findings were related to 0304-3940/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2009.01.079