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However, following systemic administration, bumetanide only poorly penetrates into the brain parenchyma and does not reach levels sufficient to inhibit NKCC1. The low brain penetration is a consequence of both the high ionization rate and plasma protein binding, which restrict brain entry by passive diffusion, and of brain efflux transport. In previous studies, bumetanide was determined in the whole brain or a few brain regions, such as the hippocampus. However, the blood\u2013brain barrier and its efflux transporters are heterogeneous across brain regions, so it cannot be excluded that bumetanide reaches sufficiently high brain levels for NKCC1 inhibition in some discrete brain areas. Here, bumetanide was determined in 14 brain regions following i.v. administration of 10\u00a0mg\/kg in rats. Because bumetanide is much more rapidly eliminated by rats than humans, its metabolism was reduced by pretreatment with piperonyl butoxide. Significant, up to 5\u2010fold differences in regional bumetanide levels were determined with the highest levels in the midbrain and olfactory bulb and the lowest levels in the striatum and amygdala. Brain:plasma ratios ranged between 0.004 (amygdala) and 0.022 (olfactory bulb). Regional brain levels were significantly correlated with local cerebral blood flow. However, regional bumetanide levels were far below the IC<jats:sub>50<\/jats:sub> (2.4\u00a0\u03bcM) determined previously for rat NKCC1. Thus, these data further substantiate that the reported effects of bumetanide in rodent models of brain disorders are not related to NKCC1 inhibition in the brain.<\/jats:p>","DOI":"10.1002\/bdd.2390","type":"journal-article","created":{"date-parts":[[2024,6,1]],"date-time":"2024-06-01T18:23:57Z","timestamp":1717266237000},"page":"138-148","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Heterogeneous brain distribution of bumetanide following systemic administration in rats"],"prefix":"10.1002","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9648-8973","authenticated-orcid":false,"given":"Wolfgang","family":"L\u00f6scher","sequence":"first","affiliation":[{"name":"Translational Neuropharmacology Laboratory NIFE Department of Experimental Otology of the ENT Clinics Hannover Medical School  Hannover Germany"},{"name":"Department of Pharmacology, Toxicology, and Pharmacy University of Veterinary Medicine Hannover  Hannover Germany"},{"name":"Center for Systems Neuroscience Hannover  Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Gramer","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology, and Pharmacy University of Veterinary Medicine Hannover  Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerstin","family":"R\u00f6mermann","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology, and Pharmacy University of Veterinary Medicine Hannover  Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,6]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/cimb45040227"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-387738-3.00015-9"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/bf00166986"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2009.03.003"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1523\/jneurosci.0633\u201010.2010"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2018.09.025"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010022\u201004654\u20109"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1177\/0271678X20985946"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0057148"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.m213148200"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/cphy.c170018"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/jphp.12341"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2015.12.001"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2011.08.005"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/0028\u20103908(78)90160\u20100"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.cd012776.pub3"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010019\u201041828\u20104"},{"key":"e_1_2_9_19_1","first-page":"45","article-title":"A relationship between the metabolism of bumetanide and its diuretic activity in the rat","volume":"6","author":"Halladay S. 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