title: A novel prodrug-based strategy to increase effects of bumetanide in epilepsy.
abstract: OBJECTIVE
  There is considerable interest in using bumetanide, a chloride importer Na-K-Cl cotransporter antagonist, for treatment of neurological diseases, such as epilepsy or ischemic and traumatic brain injury, that may involve deranged cellular chloride homeostasis. However, bumetanide is heavily bound to plasma proteins (~98%) and highly ionized at physiological pH, so that it only poorly penetrates into the brain, and chronic treatment with bumetanide is compromised by its potent diuretic effect.
  
  
  METHODS
  To overcome these problems, we designed lipophilic and uncharged prodrugs of bumetanide that should penetrate the blood-brain barrier more easily than the parent drug and are converted into bumetanide in the brain. The feasibility of this strategy was evaluated in mice and rats.
  
  
  RESULTS
  Analysis of bumetanide levels in plasma and brain showed that administration of 2 ester prodrugs of bumetanide, the pivaloyloxymethyl (BUM1) and N,N-dimethylaminoethylester (BUM5), resulted in significantly higher brain levels of bumetanide than administration of the parent drug. BUM5, but not BUM1, was less diuretic than bumetanide, so that BUM5 was further evaluated in chronic models of epilepsy in mice and rats. In the pilocarpine model in mice, BUM5, but not bumetanide, counteracted the alteration in seizure threshold during the latent period. In the kindling model in rats, BUM5 was more efficacious than bumetanide in potentiating the anticonvulsant effect of phenobarbital.
  
  
  CONCLUSIONS
  Our data demonstrate that the goal of designing bumetanide prodrugs that specifically target the brain is feasible and that such drugs may resolve the problems associated with using bumetanide for treatment of neurological disorders.
authors.affiliation: Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Hannover, Germany; Center for Systems Neuroscience, Hannover, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Töllner
authors.forename: Claudia
authors.initials: C
authors.lastname: Brandt
authors.forename: Manuel
authors.initials: M
authors.lastname: Töpfer
authors.forename: Gerda
authors.initials: G
authors.lastname: Brunhofer
authors.forename: Thomas
authors.initials: T
authors.lastname: Erker
authors.forename: Mario
authors.initials: M
authors.lastname: Gabriel
authors.forename: Peter W
authors.initials: PW
authors.lastname: Feit
authors.forename: Jenna
authors.initials: J
authors.lastname: Lindfors
authors.forename: Kai
authors.initials: K
authors.lastname: Kaila
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Löscher
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002034:Bumetanide / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D003292:Convulsants / Q000633:toxicity; D004195:Disease Models, Animal; D004232:Diuretics / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy*; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D009474:Neurons / Q000187:drug effects; D010433:Pentylenetetrazole / Q000633:toxicity; D010634:Phenobarbital / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D044967:Serum / Q000187:drug effects*; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D013045:Species Specificity; D013997:Time Factors
chemical_list: D003292:Convulsants; D004232:Diuretics; D049994:Sodium Potassium Chloride Symporter Inhibitors; D002034:Bumetanide; D010433:Pentylenetetrazole; D010634:Phenobarbital