{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:36:49Z","timestamp":1785411409728,"version":"3.56.0"},"reference-count":40,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T00:00:00Z","timestamp":1776297600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfeicoamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","award":["001"],"award-info":[{"award-number":["001"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]},{"award":["001"],"award-info":[{"award-number":["001"]}],"id":[{"id":"https:\/\/ror.org\/00x0ma614","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004901","name":"Minas Gerais State Research Foundation","doi-asserted-by":"publisher","award":["APQ-00544-23"],"award-info":[{"award-number":["APQ-00544-23"]}],"id":[{"id":"10.13039\/501100004901","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004901","name":"Minas Gerais State Research Foundation","doi-asserted-by":"publisher","award":["APQ-05218-23"],"award-info":[{"award-number":["APQ-05218-23"]}],"id":[{"id":"10.13039\/501100004901","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Drug resistance remains a major challenge in epilepsy, and overexpression of ATP-binding cassette transporters, particularly P-glycoprotein (P-gp), at the blood\u2013brain barrier (BBB) has been consistently implicated in limiting central nervous system drug exposure. Genetic experimental models suitable for investigating molecular regulation and functional alterations of P-gp in epilepsy remain scarce. This study evaluated P-gp expression and functional alterations in the Wistar Audiogenic Rat (WAR), a genetic model of epilepsy exhibiting phenotypic heterogeneity. WAR animals were classified into refractory epilepsy (WAR-RE) or temporal lobe epilepsy (WAR-TLE) phenotypes and compared with non-epileptic Wistar controls. Fexofenadine, a well-established in vivo P-gp probe substrate, was administered orally, and plasma pharmacokinetic parameters were determined. P-gp expression at the BBB was assessed by immunohistochemistry in hippocampal regions. WAR-RE animals exhibited significantly increased systemic exposure to fexofenadine, characterized by higher area under the curve and prolonged half-life, alongside reduced apparent clearance, compared with control animals (p &lt; 0.05). In contrast, WAR-TLE animals showed greater interindividual variability without statistically significant differences. Immunohistochemical analysis revealed increased P-gp expression in hippocampal microvessels in both WAR phenotypes. These findings demonstrate that the WAR model displays molecular upregulation of P-gp at the BBB, accompanied by functional alterations in the disposition of a prototypical P-gp substrate. Although direct brain drug concentrations were not assessed, the integration of systemic pharmacokinetics with transporter expression supports the use of WAR as a genetic proof-of-concept model for studying P-gp regulation and transporter-mediated drug disposition in epilepsy. This model provides a valuable molecular framework for future investigations addressing transporter modulation and mechanisms underlying pharmacoresistance.<\/jats:p>","DOI":"10.3390\/ijms27083544","type":"journal-article","created":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T09:04:42Z","timestamp":1776330282000},"page":"3544","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Molecular and Functional Alterations of P-Glycoprotein in a Genetic Model of Epilepsy: Insights from the Wistar Audiogenic Rat"],"prefix":"10.3390","volume":"27","author":[{"given":"Rodrigo V.","family":"Placido","sequence":"first","affiliation":[{"name":"Pharmaceutical Sciences Faculty, Federal University of Alfenas, Alfenas 37130-001, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafaela F.","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Pharmaceutical Sciences Faculty, Federal University of Alfenas, Alfenas 37130-001, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lellis H.","family":"Costa","sequence":"additional","affiliation":[{"name":"Pharmaceutical Sciences Faculty, Federal University of Alfenas, Alfenas 37130-001, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taila","family":"Kawano","sequence":"additional","affiliation":[{"name":"Pharmaceutical Sciences Faculty, Federal University of Alfenas, Alfenas 37130-001, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"J\u00fanior","given":"Milton K.","family":"Aquino","sequence":"additional","affiliation":[{"name":"Pharmaceutical Sciences Faculty, Federal University of Alfenas, Alfenas 37130-001, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriella B.","family":"Martinez","sequence":"additional","affiliation":[{"name":"Pharmaceutical Sciences Faculty, Federal University of Alfenas, Alfenas 37130-001, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana T. R.","family":"Hummel","sequence":"additional","affiliation":[{"name":"Pharmaceutical Sciences Faculty, Federal University of Alfenas, Alfenas 37130-001, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Eduarda T.","family":"de Lima","sequence":"additional","affiliation":[{"name":"Pharmaceutical Sciences Faculty, Federal University of Alfenas, Alfenas 37130-001, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"J\u00fanior","given":"Rui M. P.","family":"da Silva","sequence":"additional","affiliation":[{"name":"Neurophysiology and Experimental Neuroethology Laboratory, Department of Physiology, University of S\u00e3o Paulo, Ribeir\u00e3o Preto 05508-220, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8857-3775","authenticated-orcid":false,"given":"Norberto","family":"Garcia-Cairasco","sequence":"additional","affiliation":[{"name":"Neurophysiology and Experimental Neuroethology Laboratory, Department of Physiology, University of S\u00e3o Paulo, Ribeir\u00e3o Preto 05508-220, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0534-0077","authenticated-orcid":false,"given":"Silvia G.","family":"Ruginsk","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences, Federal University of Alfenas, Alfenas 37130-001, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0894-954X","authenticated-orcid":false,"given":"Mar\u00edlia G. A. G.","family":"Pereira","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences, Federal University of Alfenas, Alfenas 37130-001, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7033-0350","authenticated-orcid":false,"given":"Vanessa B.","family":"Boralli","sequence":"additional","affiliation":[{"name":"Pharmaceutical Sciences Faculty, Federal University of Alfenas, Alfenas 37130-001, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,16]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2025, August 19). Epilepsy. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/epilepsy."},{"key":"ref_2","first-page":"591","article-title":"Drug resistance in brain diseases and the role of drug efflux transporters","volume":"6","author":"Potschka","year":"2015","journal-title":"Nat. Rev. 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