Differential hippocampal pharmacokinetics of phenobarbital and carbamazepine in repetitive seizures induced by 3-mercaptopropionic acid.

C HÖCHT; A LAZAROWSKI; N N GONZALEZ; M. A. MAYER; J.A. OPEZZO; C.A. TAIRA; E. GIRARDI

NEUROSCIENCE LETTERS

Año: 2009 vol. 453 p. 54 - 57

0304-3940

&lt;!-- /* Font Definitions */ @font-face {font-family:"Cambria Math"; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:roman; mso-font-pitch:variable; mso-font-signature:-1610611985 1107304683 0 0 159 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin:0cm; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Times New Roman","serif"; mso-fareast-font-family:"Times New Roman"; mso-ansi-language:ES-AR; mso-fareast-language:ES-AR;} .MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-size:10.0pt; mso-ansi-font-size:10.0pt; mso-bidi-font-size:10.0pt; mso-ascii-font-family:Calibri; mso-fareast-font-family:Calibri; mso-hansi-font-family:Calibri;} @page Section1 {size:612.0pt 792.0pt; margin:70.85pt 3.0cm 70.85pt 3.0cm; mso-header-margin:36.0pt; mso-footer-margin:36.0pt; mso-paper-source:0;} div.Section1 {page:Section1;} --&gt; Previous evidencehas shownthat chronic 3-mercaptopropionic acid(MP) administrationinducedbrainP-glycoprotein (P-gp) overexpression altering target site accumulation of phenytoin. The aimof the presentwork 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 (45mg kg−1, i.p.) during 10 days. Control rats(C) were injected with saline solution. In order to monitor extracellular brain antiepileptic levels, aconcentric probe was inserted into the hippocampus. Animals were administered with carbamazepine(10mgkg−1, i.v.) or phenobarbital (20mg kg−1, i.v.) 30min after intraperitoneal administration of vehicleornimodipine (2mg kg−1), awell knownP-glycoproteininhibitor.No differenceswere found inhippocam-pal concentrations of carbamazepine comparing all groups. In vehicle pre-treated rats, hippocampalphenobarbital concentrationswere lower inMP (maximal concentration, Cmax: 6.0±0.6gml−1, p < 0.05)than in C animals (Cmax: 9.4±0.9gml−1). Control rats pre-treated with nimodipine showed similarresults (Cmax: 10.7±0.6gml−1) than those pre-treated with vehicle. Nimodipine pre-treatment in MPrats enhanced hippocampal phenobarbital concentrations (Cmax: 10.2±1.0gml−1, p < 0.05) as comparedwith vehicle pre-treatment.Results of our work suggest that P-glycoprotein (P-gp) overexpression by repetitive seizures inducedby MP administration does not modify brain bioavailability of carbamazepine. Conversely, hippocampallevels of phenobarbital are reduced in MP rats with regard to non-epileptic rats, suggesting a potentialrole of P-gp overexpression in pharmacoresistance to phenobarbital.