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However, bumetanide poorly penetrates into the brain and, in rodents, is rapidly eliminated because of extensive oxidation of its<jats:italic><jats:styled-content style=\"fixed-case\">N<\/jats:styled-content><\/jats:italic>\u2010butyl sidechain, reducing the translational value of rodent experiments. Inhibition of oxidation by piperonyl butoxide (<jats:styled-content style=\"fixed-case\">PBO<\/jats:styled-content>) has previously been reported to increase the half\u2010life and diuretic activity of bumetanide in rats. Here we studied whether inhibition of bumetanide metabolism by<jats:styled-content style=\"fixed-case\">PBO<\/jats:styled-content>also increases brain levels of bumetanide in rats, and whether this alters pharmacodynamic effects in the kindling model of epilepsy. Furthermore, we studied the effects of<jats:styled-content style=\"fixed-case\">PBO<\/jats:styled-content>in mice. Mice eliminated bumetanide less rapidly than rats (elimination half\u2010life 47\u00a0min vs. 13\u00a0min). Pretreatment with<jats:styled-content style=\"fixed-case\">PBO<\/jats:styled-content>increased the half\u2010life in mice to average values (70\u00a0min) previously determined in humans, and markedly elevated brain levels of bumetanide. In rats, the increase in plasma and brain levels of bumetanide by<jats:styled-content style=\"fixed-case\">PBO<\/jats:styled-content>was less marked than in mice.<jats:styled-content style=\"fixed-case\">PBO<\/jats:styled-content>significantly increased the diuretic activity of bumetanide in rats and, less effectively, in mice. In epileptic mice, bumetanide (with<jats:styled-content style=\"fixed-case\">PBO<\/jats:styled-content>) did not suppress spontaneous seizures. In the rat kindling model, bumetanide (with or without<jats:styled-content style=\"fixed-case\">PBO<\/jats:styled-content>) did not exert anticonvulsant effects on fully kindled seizures, but dose\u2010dependently altered kindling development. These data indicate that<jats:styled-content style=\"fixed-case\">PBO<\/jats:styled-content>offers a simple means to enhance the translational properties of rodent experiments with bumetanide, particularly when using mice.<\/jats:p>","DOI":"10.1111\/ejn.12424","type":"journal-article","created":{"date-parts":[[2013,11,20]],"date-time":"2013-11-20T04:06:39Z","timestamp":1384920399000},"page":"673-687","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":56,"title":["Consequences of inhibition of bumetanide metabolism in rodents on brain penetration and effects of bumetanide in chronic models of epilepsy"],"prefix":"10.1111","volume":"39","author":[{"given":"Manuel","family":"T\u00f6pfer","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Toxicology and Pharmacy University of Veterinary Medicine B\u00fcnteweg 17 Hannover D\u201030559 Germany"},{"name":"Center for Systems Neuroscience Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathrin","family":"T\u00f6llner","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology and Pharmacy University of Veterinary Medicine B\u00fcnteweg 17 Hannover D\u201030559 Germany"},{"name":"Center for Systems Neuroscience Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Brandt","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology and Pharmacy University of Veterinary Medicine B\u00fcnteweg 17 Hannover D\u201030559 Germany"},{"name":"Center for Systems Neuroscience Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Friederike","family":"Twele","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology and Pharmacy University of Veterinary Medicine B\u00fcnteweg 17 Hannover D\u201030559 Germany"},{"name":"Center for Systems Neuroscience Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonja","family":"Br\u00f6er","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology and Pharmacy University of Veterinary Medicine B\u00fcnteweg 17 Hannover D\u201030559 Germany"},{"name":"Center for Systems Neuroscience Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"L\u00f6scher","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology and Pharmacy University of Veterinary Medicine B\u00fcnteweg 17 Hannover D\u201030559 Germany"},{"name":"Center for Systems Neuroscience Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2013,11,19]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10571-004-1374-y"},{"key":"e_1_2_8_3_1","first-page":"221","volume-title":"Cell Physiology Sourcebook Essentials of Membrane Biophysics","author":"Alvarez\u2010Leefmans F.J.","year":"2012"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1157.1984.tb03460.x"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.106.102491"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2011.03247.x"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2011.03378.x"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2007.01068.x"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2009.03.003"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2009.06863.x"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0633-10.2010"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0057148"},{"key":"e_1_2_8_13_1","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/S0022-3565(25)30556-2","article-title":"A comparative diuretic and tissue distribution study of bumetanide and furosemide in the dog","volume":"197","author":"Cohen M.R.","year":"1976","journal-title":"J. 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