{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T09:32:12Z","timestamp":1791192732256,"version":"4.1.0"},"reference-count":71,"publisher":"Wiley","issue":"s5","license":[{"start":{"date-parts":[[2007,10,1]],"date-time":"2007-10-01T00:00:00Z","timestamp":1191196800000},"content-version":"vor","delay-in-days":30,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2007,9]]},"abstract":"<jats:p><jats:bold>Summary:\u2002<\/jats:bold> It is estimated 20\u201325% of the epileptic patients fails to achieve good control with the different antiepileptic drugs (AEDs) treatments, developing refractory epilepsy (RE). Discovered first in cancer, the activity of P\u2010glycoprotein (P\u2010gp) and others ABC transporters as multidrug\u2010resistance\u2010associated proteins (MRPs) and breast cancer resistant protein (BCRP) are directly related with the refractoriness. We have observed the overexpression of these all transporters in the brain of patients with RE, and according with other authors, all these data suggests an active drug efflux from brain. Both constitutive and seizure induced brain P\u2010gp overexpression was also suggested. As confirmation of these clinical evidences, different models of experimental epilepsy have demonstrated P\u2010gp overexpression on blood brain barrier (BBB) and brain parenchyma cells, as astrocytes and neurons. In our model, early P\u2010pg detection in vessel\u2010related cells and later additional P\u2010gp detection in neurons, correlated with the gradual loss of protective effect of phenytoin. The progressive neuronal P\u2010gp expression, depending on intensity and time\u2010constancy of seizure\u2010injury, was in agreement with the development of \u201cP\u2010gp\u2010positive seizure\u2010axis\u201d proposed by Kwan &amp; Brodie, who also showed that the development of RE directly correlated with the number and frequency of seizures before initiation of drug therapy. P\u2010gp expression in excretory organs suggests that P\u2010gp have a central role in drug elimination. Persistent low levels of AEDs in plasma and P\u2010gp brain overexpression in several RE pediatric patients were reported. We also observed in adult RE patients, an increased liver clearance of <jats:sup>99m<\/jats:sup>Tc\u2010hexakis\u20102\u2010methoxyisobutylisonitrile (<jats:sup>99m<\/jats:sup>Tc\u2010MIBI) (a P\u2010gp substrate), and the surgically treated cases showed P\u2010gp brain overexpression. These results suggest the systemic hyperactivity of P\u2010gp in RE patients, including brain P\u2010gp over\u2010expression should be suspected when persistent subtherapeutic levels of AEDs in plasma are detected. P\u2010gp neuronal expression described in both clinical and experimental reports indicates that additional mechanisms could be operative from seizure\u2010affected P\u2010gp\u2010positive neurons, due to AEDs targets are expressed at membrane level. An alternative mechanism was demonstrated in P\u2010gp\u2010expressed cells that exhibit lower membrane potential (<jats:italic>\u0394\u03c8<jats:sub>0<\/jats:sub><\/jats:italic>=\u221210 to \u201320) compared to normal physiological <jats:italic>\u0394\u03c8<jats:sub>0<\/jats:sub><\/jats:italic> of \u201360 mV. Under this situation and irrespective to the P\u2010gp pharmacoresistant property or type of drug treatment selected, P\u2010gp\u2010expressed neurons could increase their sensitivity to new seizures perhaps as an epileptogenic mechanism. The understanding of properties of these ABC transporters can offer new tools for better selection of more effective preventive or therapeutic strategies and avoid the invasive surgical treatments for RE.<\/jats:p>","DOI":"10.1111\/j.1528-1167.2007.01302.x","type":"journal-article","created":{"date-parts":[[2007,10,3]],"date-time":"2007-10-03T07:27:23Z","timestamp":1191396443000},"page":"140-149","source":"Crossref","is-referenced-by-count":188,"title":["ABC Transporters during Epilepsy and Mechanisms Underlying Multidrug Resistance in Refractory Epilepsy"],"prefix":"10.1111","volume":"48","author":[{"given":"Alberto","family":"Lazarowski","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liliana","family":"Czornyj","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabiana","family":"Lubienieki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Girardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Vazquez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"D'Giano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2007,10]]},"reference":[{"key":"e_1_2_11_2_1","first-page":"3352","article-title":"Rapid activation of MDR1 gene expression in human metastatic sarcoma following in vivo exposure to doxorubicin","volume":"5","author":"Abolhoa A","year":"1999","journal-title":"Clinical Cancer Research"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4522(02)00992-2"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.0013-9580.2004.57703.x"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj3260539"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9149(80)90057-0"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1157.1992.tb02281.x"},{"key":"e_1_2_11_8_1","doi-asserted-by":"crossref","first-page":"29715","DOI":"10.1016\/S0021-9258(18)43939-7","article-title":"NF\u2010IL6, a member of the C\/EBP family of transcription factors, binds and trans\u2010activates the human MDR1 gene promoter","volume":"269","author":"Combates NJ","year":"1994","journal-title":"Journal of Biological Chemistry"},{"key":"e_1_2_11_9_1","first-page":"3387","article-title":"Hypoxia\u2010inducible factor\u20101\u2010dependent regulation of the multidrug resistance (MDR1) gene","volume":"62","author":"Comerford K","year":"2002","journal-title":"Cancer Research"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1157.1981.tb06159.x"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1097\/00001756-200211150-00014"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1177\/38.9.1974900"},{"key":"e_1_2_11_13_1","doi-asserted-by":"crossref","first-page":"15347","DOI":"10.1016\/S0021-9258(18)82262-1","article-title":"A signal transduction pathway for activation of the mdr1 promoter involves the proto\u2010oncogene c\u2010raf kinase","volume":"268","author":"Cornwell MM","year":"1993","journal-title":"Journal of Biological Chemistry"},{"issue":"73","key":"e_1_2_11_14_1","first-page":"229","article-title":"Unusual transmantle focal\u2010cortical dysplasia (TD) and Refractory Epilepsy (RE) with brain expression of Breast Cancer Resistant Protein (BCRP)","volume":"5","author":"Czornyj L","year":"2004","journal-title":"Rev Mex de Neurociencias"},{"issue":"1","key":"e_1_2_11_15_1","first-page":"326","article-title":"Breast cancer resistant protein (BCRP) in cortical dysplasia with refractory epilepsy and failure to produce pharmacological coma","volume":"46","author":"Czornyj L","year":"2005","journal-title":"Epilepsia"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s002590050403"},{"issue":"7","key":"e_1_2_11_17_1","first-page":"41","article-title":"Expression of P\u2010glycoprotein and related proteins in brain of patients with refractory temporal lobe epilepsy","volume":"38","author":"D'Giano C","year":"1997","journal-title":"Epilepsia"},{"issue":"8","key":"e_1_2_11_18_1","first-page":"223","article-title":"Calcium antagonist effect on 99mTc\u2010SESTAMIBI liver clearance in drug\u2010resistance epilepsy","volume":"46","author":"D'Giano C","year":"2005","journal-title":"Epilepsia"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1528-1157.2001.12301.x"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.2174\/1389203023380521"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(03)02401-6"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2400827"},{"issue":"6","key":"e_1_2_11_23_1","first-page":"606","article-title":"Refractory phenotype reversion by nimodipine administration in a model of epilepsy resistant to phenytoin (PHT) treatment","volume":"46","author":"Girardi E","year":"2005","journal-title":"Epilepsia"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.4.1894"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.bi.62.070193.002125"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3835(98)00096-2"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.1998.57"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2006.11.075"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2005.59204.x"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200002033420503"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1528-1157.2002.156702.x"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1369\/jhc.6A7026.2006"},{"key":"e_1_2_11_33_1","doi-asserted-by":"crossref","first-page":"S28\u00b7#1\u201017\u201022","DOI":"10.1016\/S0022-510X(97)84963-5","article-title":"High expression of multidrug resistance gene (MDR\u20101) and persistent low levels of phenytoin (PHT) on a patient with refractory epilepsy due to tuberous sclerosis (TS)","volume":"150","author":"Lazarowski A","year":"1997","journal-title":"Journal of Neurological Science"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0887-8994(99)00074-0"},{"issue":"1","key":"e_1_2_11_35_1","first-page":"367","article-title":"99mTc\u2010SESTAMIBI scintigraphy in non\u2010Hodgkin Lymphoma as a predictive indicator for chemotherapy sensitivity","volume":"84","author":"Lazarowski A","year":"1999","journal-title":"Blood"},{"issue":"7","key":"e_1_2_11_36_1","first-page":"11","article-title":"Neuronal MDR\u20101 gene encoded P\u2010Glycoprotein (P\u2010170) Expression in 3\u2010Mercaptopropionic Acid\u2010induced Seizures in Rats","volume":"43","author":"Lazarowski A","year":"2002","journal-title":"Epilepsia"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1097\/00007691-200402000-00010"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1023\/B:CEMN.0000012726.43842.d2"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0887-8994(03)00407-7"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1369\/jhc.4A6542.2005"},{"key":"e_1_2_11_41_1","unstructured":"LazarowskiA CamareroS LubieniekiF. (2005b)Expression of multidrug resistance proteins \u201cMDR\u20101\u201d and \u201cBCRP\u201d in Subependimal Giant Astrocytoma (SEGA) and Refractory Epilepsy (RE) Tuberous Sclerosis Complex (TSC) & Lymphangioleiomyomatosis (LAM) International Research Symposium. April 8\u201310 2005 in Cincinnati Ohio . USA ."},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pediatrneurol.2005.06.008"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1089\/lrb.2006.4.23"},{"issue":"4","key":"e_1_2_11_44_1","first-page":"306","article-title":"Alterations in Central Pharmacokinetics of Phenytoin in an Experimental Model of Epilepsy","volume":"47","author":"Lazarowski A","year":"2006","journal-title":"Epilepsia"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2007.03.004"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/81.2.84"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1602\/neurorx.2.1.86"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4522(03)00515-3"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1097\/00002826-199710000-00008"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1023\/B:CEMN.0000012728.19117.73"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.7.3900"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.22-14-05833.2002"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.2174\/1381612003401163"},{"issue":"1","key":"e_1_2_11_54_1","first-page":"23","article-title":"Multidrug resistance Gene (MDR\u20101) expression in intestinal mucosa of patient with refractory ulcerative colitis \u201c(UC).\u201d","volume":"36","author":"Sambuelli A","year":"2006","journal-title":"Acta Gastroenterologica Latinoamericana"},{"key":"e_1_2_11_55_1","first-page":"69","volume-title":"Epilepsy. A comprehensive textbook","author":"Sander JW","year":"1998"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1528-1157.2002.33101.x"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.1097\/00001756-199911080-00032"},{"key":"e_1_2_11_58_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awf002"},{"key":"e_1_2_11_59_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1528-1157.2003.21803.x"},{"key":"e_1_2_11_60_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1528-1157.2003.42802.x"},{"key":"e_1_2_11_61_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2990.2005.00699.x"},{"key":"e_1_2_11_62_1","doi-asserted-by":"crossref","first-page":"235","DOI":"10.33549\/physiolres.930432","article-title":"ATP\u2010Binding Cassette (ABC) transporters in human metabolism and diseases","volume":"53","author":"\u0160tefakov\u00e1 J","year":"2004","journal-title":"Physiology Research"},{"key":"e_1_2_11_63_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1528-1157.2001.28900.x"},{"key":"e_1_2_11_64_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1157.1995.tb01657.x"},{"key":"e_1_2_11_65_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.0013-9580.2004.23504.x"},{"key":"e_1_2_11_66_1","first-page":"120","article-title":"Increase 99mTc\u2010SESTAMIBI (MIBI) liver clearance could identified epileptic pharmacoresistant patients. A preliminary study","volume":"45","author":"Vazquez SE","year":"2004","journal-title":"Epilepsia s7"},{"key":"e_1_2_11_67_1","unstructured":"VazquezSE SambuelliA LazarowskiA. (2005)Acelerated hepatobiliary clearance of 99mTc\u2010MIBI a marker of MDR\u20101 gene hyperactivity in IBD. (Submission ID: 44318; Update Code: 245e57) AGA; Digestive Disease Week McCormick Place in Chicago Illinois May 14\u201319 2005 USA ."},{"key":"e_1_2_11_68_1","first-page":"223","article-title":"Expression of multidrug transporters in dysembryoplastic neuroepithelial tumors causing intractable epilepsy","volume":"23","author":"Vogelgesang S","year":"2004","journal-title":"Clinical Neuropathology"},{"key":"e_1_2_11_69_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2003.10.012"},{"key":"e_1_2_11_70_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0074-7696(08)62587-5"},{"key":"e_1_2_11_71_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1528-1157.2003.32502.x"},{"key":"e_1_2_11_72_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.02-1131fje"}],"container-title":["Epilepsia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fj.1528-1167.2007.01302.x","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/j.1528-1167.2007.01302.x","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,26]],"date-time":"2023-09-26T22:41:09Z","timestamp":1695768069000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/j.1528-1167.2007.01302.x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,9]]},"references-count":71,"journal-issue":{"issue":"s5","published-print":{"date-parts":[[2007,9]]}},"alternative-id":["10.1111\/j.1528-1167.2007.01302.x"],"URL":"https:\/\/doi.org\/10.1111\/j.1528-1167.2007.01302.x","archive":["Portico"],"relation":{},"ISSN":["0013-9580","1528-1167"],"issn-type":[{"value":"0013-9580","type":"print"},{"value":"1528-1167","type":"electronic"}],"subject":[],"published":{"date-parts":[[2007,9]]}}}