{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T22:03:43Z","timestamp":1773007423683,"version":"3.50.1"},"reference-count":39,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2009,1,29]],"date-time":"2009-01-29T00:00:00Z","timestamp":1233187200000},"content-version":"vor","delay-in-days":59,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2008,12]]},"abstract":"<jats:sec><jats:title>Background and purpose:<\/jats:title><jats:p>Accurate prediction of biophase pharmacokinetics (PK) is essential to optimize pharmacotherapy in epilepsy. Here, we characterized the PK of the active metabolite of oxcarbazepine, 10,11\u2010dihydro\u201010\u2010hydroxy\u2010carbamazepine (MHD) in plasma and in the hippocampus. Simultaneously, the impact of acute seizures and efflux transport mechanisms on brain distribution was quantified.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental approach:<\/jats:title><jats:p>Rats received subtherapeutic and anticonvulsant doses of MHD in non\u2010epileptic conditions and during focal pilocarpine\u2010induced limbic seizures. To evaluate the effect of efflux transport blockade, a separate group received subtherapeutic doses combined with intrahippocampal perfusion of verapamil. Free plasma and extracellular hippocampal MHD concentrations were determined using microdialysis and liquid chromatography techniques. An integrated PK model describing simultaneously the PK of MHD in plasma and brain was developed using nonlinear mixed effects modelling. A bootstrap procedure and a visual predictive check were performed to assess model performance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key results:<\/jats:title><jats:p>A compartmental model with combined zero\u2010 and first\u2010order absorption, including lag time and biophase distribution best described the PK of MHD. A distributional process appeared to underlie the increased brain MHD concentrations observed following seizure activity and efflux transport inhibition, as reflected by changes in the volume of distribution of the biophase compartment. In contrast, no changes were observed in plasma PK.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and implications:<\/jats:title><jats:p>Simultaneous PK modelling of plasma and brain concentrations has not been used previously in the evaluation of antiepileptic drugs (AEDs). Characterisation of biophase PK is critical to assess the impact of efflux transport mechanisms and acute seizures on brain disposition and, consequently, on AED effects.<\/jats:p><jats:p><jats:italic>British Journal of Pharmacology<\/jats:italic> (2008) <jats:bold>155<\/jats:bold>, 1127\u20131138; doi:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1038\/bjp.2008.366\">10.1038\/bjp.2008.366<\/jats:ext-link>; published online 6 October 2008<\/jats:p><\/jats:sec>","DOI":"10.1038\/bjp.2008.366","type":"journal-article","created":{"date-parts":[[2008,10,6]],"date-time":"2008-10-06T09:46:35Z","timestamp":1223286395000},"page":"1127-1138","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Impact of efflux transporters and of seizures on the pharmacokinetics of oxcarbazepine metabolite in the rat brain"],"prefix":"10.1111","volume":"155","author":[{"given":"R","family":"Clinckers","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"I","family":"Smolders","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Y","family":"Michotte","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G","family":"Ebinger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M","family":"Danhof","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R A","family":"Voskuyl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"O Della","family":"Pasqua","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2009,1,29]]},"reference":[{"key":"e_1_2_9_2_1","volume-title":"NONMEM Users Guide","author":"Beal SL","year":"1999"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1054\/bjoc.2001.2184"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/0301-0082(90)90027-E"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-0270(99)00064-3"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1020999114109"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.105.085514"},{"key":"e_1_2_9_8_1","first-page":"R303","article-title":"Distributed model for drug delivery to CSF and brain tissue","volume":"245","author":"Collins J","year":"1983","journal-title":"Am J Physiol"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2008.01.007"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-200241100-00001"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1177\/0091270003253624"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1007513812018"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-007-9390-5"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0707257"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1012080106490"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-007-9361-x"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2005.59204.x"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1088\/0031-9155\/44\/4\/021"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.0013-9580.2005.31904.x"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/0024-3205(91)90082-M"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.41.1.569"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-6147(00)01974-X"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1728"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2005.00265.x"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2006.00817.x"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.283.5400.401"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-200038030-00001"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-0270(91)90114-F"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.34.9.1252"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(00)02893-6"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01371005"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1345\/aph.1E068"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/0378-4347(95)00195-O"},{"key":"e_1_2_9_34_1","first-page":"442","article-title":"Analysis of drug\u2013receptor interactions in vivo: a new approach in pharmacokinetic\u2013pharmacodynamic modelling","volume":"35","author":"Van der Graaf P","year":"1997","journal-title":"Int J Clin Pharmacol Ther"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2006.00496.x"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.107.121178"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1011527125570"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1016092525901"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/0920-1211(93)90078-L"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1011555016423"}],"container-title":["British Journal of Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1038%2Fbjp.2008.366","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1038%2Fbjp.2008.366","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1038\/bjp.2008.366","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,11]],"date-time":"2025-04-11T02:03:49Z","timestamp":1744337029000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1038\/bjp.2008.366"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,12]]},"references-count":39,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2008,12]]}},"alternative-id":["10.1038\/bjp.2008.366"],"URL":"https:\/\/doi.org\/10.1038\/bjp.2008.366","archive":["Portico"],"relation":{},"ISSN":["0007-1188","1476-5381"],"issn-type":[{"value":"0007-1188","type":"print"},{"value":"1476-5381","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,12]]},"assertion":[{"value":"2009-01-29","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}