Distribution and metabolic fate in mammals of the potent convulsant and GABA antagonist t-butyl-bicyclophosphate and its methyl analog

Abstract

32P-Labeled preparations are used to compare the distribution and metabolic fate in mammals of the potent convulsant (mouse and rat ip LD50 ∼ 0.04 mg/kg) and γ-aminobutyric acid (GABA) antagonist 4-t-butyl-1-oxo-1-phospha-2,6,7-trioxabicyclo[2.2.2]octane (t-butyl-bicyclophosphate) and its 1000-fold less toxic 4-methyl analog (methyl-bicyclophosphate). Intraperitoneally treated mice, rats, and rabbits rapidly eliminate the parent compounds and their metabolites from the body, mostly by urinary excretion, giving overall half-life values of 4 to 16 hr. Metabolism is primarily a hydrolytic process and is more rapid for the t-butyl than for the methyl derivative and in mice and rabbits than in rats. The peak brain concentration is reached within 1 hr after ip treatment of mice and is two- to threefold higher for the t-butyl than for the methyl derivative without significant localization in the cerebellum or other brain regions. The much higher toxicity of the t-butyl compound compared to its methyl analog is not attributable to differences in their localization or detoxification so it probably results from their differential potencies at the relevant neuroreceptor.