Heterogeneous brain distribution of bumetanide following systemic administration in rats.
| Autor: | Löscher W; Translational Neuropharmacology Laboratory, NIFE, Department of Experimental Otology of the ENT Clinics, Hannover Medical School, Hannover, Germany.; Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Hannover, Germany.; Center for Systems Neuroscience Hannover, Hannover, Germany., Gramer M; Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Hannover, Germany., Römermann K; Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Hannover, Germany. |
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| Jazyk: | angličtina |
| Zdroj: | Biopharmaceutics & drug disposition [Biopharm Drug Dispos] 2024 Jun; Vol. 45 (3), pp. 138-148. Date of Electronic Publication: 2024 Jun 01. |
| DOI: | 10.1002/bdd.2390 |
| Abstrakt: | Bumetanide is used widely as a tool and off-label treatment to inhibit the Na-K-2Cl cotransporter NKCC1 in the brain and thereby to normalize intra-neuronal chloride levels in several brain disorders. 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-brain 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 mg/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-fold 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 (© 2024 The Author(s). Biopharmaceutics & Drug Disposition published by John Wiley & Sons Ltd.) |
| Databáze: | MEDLINE |
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