Abstract

The intravenous administration of 0.30 mg of bromazepam-2-¹⁴C per kg to mice resulted in a fairly uniform distribution of unchanged drug in plasma, brain, and muscle. While the drug was eliminated monoexponentially with a half-life of only 18 min, 3-hydroxybromazepam, the only metabolite detected in plasma, brain, and muscle, rose to peak levels at 1 hr and then was eliminated with an apparent half-life of 4.1 hr. The anticonvulsant activity of bromazepam given intravenously to mice 1 min to 6 hr before the intravenous injection of 70 mg (CD₁₀₀) of pentylenetetrazol (Metrazol) per kg decreased from an ED₅₀ of 0.27 mg/kg to an ED₅₀ of 1.4 mg/kg. At 1 min, the activity was due solely to unchanged drug; at 1 hr and later, brain levels of intact drug were barely detectable or nonmeasurable, and the metabolite was apparently responsible for the anticonvulsant activity of bromazepam. From the brain levels which resulted from each bromazepam ED₅₀, it was estimated that protection of 50% of the mice against the Metrazol CD₁₀₀ was afforded by 0.22 µg of bromazepam per g or 0.18 µg of 3-hydroxybromazepam per g. Whereas bromazepam and 3-hydroxybromazepam had almost the same intrinsic activity, the activity of the metabolite given intravenously 1 min before Metrazol was only one-third that of bromazepam given similarly. This suggests that the uptake of 3-hydroxybromazepam by brain was less efficient than that of bromazepam. Finally, the rate of 3-hydroxybromazepam elimination obtained from the tissue level data was shown to approximate that obtained by pharmacokinetic evaluation of the anticonvulsant activity data.