Consequences of inhibition of bumetanide metabolism in rodents on brain penetration and effects of bumetanide in chronic models of epilepsy.

Abstract

The diuretic bumetanide, which acts by blocking the Na-K-Cl cotransporter (NKCC), is widely used to inhibit neuronal NKCC1, particularly when NKCC1 expression is abnormally increased in brain diseases such as epilepsy. However, bumetanide poorly penetrates into the brain and, in rodents, is rapidly eliminated because of extensive oxidation of its N-butyl sidechain, reducing the translational value of rodent experiments. Inhibition of oxidation by piperonyl butoxide (PBO) has previously been reported to increase the half-life and diuretic activity of bumetanide in rats. Here we studied whether inhibition of bumetanide metabolism by PBO 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 PBO in mice. Mice eliminated bumetanide less rapidly than rats (elimination half-life 47 min vs. 13 min). Pretreatment with PBO increased the half-life in mice to average values (70 min) previously determined in humans, and markedly elevated brain levels of bumetanide. In rats, the increase in plasma and brain levels of bumetanide by PBO was less marked than in mice. PBO significantly increased the diuretic activity of bumetanide in rats and, less effectively, in mice. In epileptic mice, bumetanide (with PBO) did not suppress spontaneous seizures. In the rat kindling model, bumetanide (with or without PBO) did not exert anticonvulsant effects on fully kindled seizures, but dose-dependently altered kindling development. These data indicate that PBO offers a simple means to enhance the translational properties of rodent experiments with bumetanide, particularly when using mice.

• Authors: Manuel Töpfer, Kathrin Töllner, Claudia Brandt, Friederike Twele, Sonja Bröer, Wolfgang Löscher
• Journal: The European journal of neuroscience (Eur J Neurosci) Vol. 39 Issue 4 Pg. 673-87 (Feb 2014) ISSN: 1460-9568 [Electronic] France
• PMID: 24251546 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Chemical References

• Antioxidants
• Diuretics
• Sodium Potassium Chloride Symporter Inhibitors
• Bumetanide
• Piperonyl Butoxide
• Kainic Acid

Topics

• Animals
• Antioxidants (pharmacology, therapeutic use)
• Brain (drug effects, physiopathology)
• Bumetanide (pharmacokinetics, pharmacology, therapeutic use)
• Diuretics (pharmacokinetics, pharmacology, therapeutic use)
• Kainic Acid (toxicity)
• Mice
• Piperonyl Butoxide (pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Rats, Wistar
• Sodium Potassium Chloride Symporter Inhibitors (pharmacokinetics, pharmacology, therapeutic use)
• Status Epilepticus (chemically induced, drug therapy)