A novel prodrug-based strategy to increase effects of bumetanide in epilepsy
Kathrin Töllner DVM, PhD
Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Hannover, Germany
Center for Systems Neuroscience, Hannover, Germany
Search for more papers by this authorClaudia Brandt PhD
Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Hannover, Germany
Center for Systems Neuroscience, Hannover, Germany
Search for more papers by this authorManuel Töpfer DVM, PhD
Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Hannover, Germany
Center for Systems Neuroscience, Hannover, Germany
Search for more papers by this authorGerda Brunhofer PhD
Department of Medicinal Chemistry, University of Vienna, Vienna, Austria
Search for more papers by this authorThomas Erker PhD
Department of Medicinal Chemistry, University of Vienna, Vienna, Austria
Search for more papers by this authorMario Gabriel DI(FH)
Department of Medicinal Chemistry, University of Vienna, Vienna, Austria
Search for more papers by this authorPeter W. Feit PhD
Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Hannover, Germany
Search for more papers by this authorJenna Lindfors BSc
Department of Biosciences and Neuroscience Center, University of Helsinki, Helsinki, Finland
Search for more papers by this authorKai Kaila PhD
Department of Biosciences and Neuroscience Center, University of Helsinki, Helsinki, Finland
Search for more papers by this authorCorresponding Author
Wolfgang Löscher DVM, PhD
Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Hannover, Germany
Center for Systems Neuroscience, Hannover, Germany
Address correspondence to Dr Löscher, Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Bünteweg 17, D-30559 Hannover, Germany. E-mail: [email protected]Search for more papers by this authorKathrin Töllner DVM, PhD
Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Hannover, Germany
Center for Systems Neuroscience, Hannover, Germany
Search for more papers by this authorClaudia Brandt PhD
Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Hannover, Germany
Center for Systems Neuroscience, Hannover, Germany
Search for more papers by this authorManuel Töpfer DVM, PhD
Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Hannover, Germany
Center for Systems Neuroscience, Hannover, Germany
Search for more papers by this authorGerda Brunhofer PhD
Department of Medicinal Chemistry, University of Vienna, Vienna, Austria
Search for more papers by this authorThomas Erker PhD
Department of Medicinal Chemistry, University of Vienna, Vienna, Austria
Search for more papers by this authorMario Gabriel DI(FH)
Department of Medicinal Chemistry, University of Vienna, Vienna, Austria
Search for more papers by this authorPeter W. Feit PhD
Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Hannover, Germany
Search for more papers by this authorJenna Lindfors BSc
Department of Biosciences and Neuroscience Center, University of Helsinki, Helsinki, Finland
Search for more papers by this authorKai Kaila PhD
Department of Biosciences and Neuroscience Center, University of Helsinki, Helsinki, Finland
Search for more papers by this authorCorresponding Author
Wolfgang Löscher DVM, PhD
Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Hannover, Germany
Center for Systems Neuroscience, Hannover, Germany
Address correspondence to Dr Löscher, Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Bünteweg 17, D-30559 Hannover, Germany. E-mail: [email protected]Search for more papers by this authorAbstract
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.
Interpretation
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. ANN NEUROL 2014;75:550–562
Supporting Information
Additional Supporting Information may be found in the online version of this article.
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