Some observations on the mechanism of benzodiazepine-barbiturate interactions in the mouse

1 The prolongation of pentobarbitone sleeping by five benzodiazepines, administered by prior intraperitoneal injection, was measured in mice. The pentobarbitone was injected either intraperitoneally or intracerebroventricularly. For each benzodiazepine, the prolongation was dose-related and differences in potency between benzodiazepines were not marked. 2 The percentage prolongation of sleeping times produced by most of the benzodiazepines was greater when the pentobarbitone was given intracerebroventricularly and was explained by a preferential addition of CNS depressant effects associated with this route. 3 To test whether the action of intraperitoneally administered pentobarbitone had been influenced by a metabolic component, the effects of nitrazepam on drug metabolism, measured by changes in plasma phenazone levels in the mouse, were studied. Nitrazepam (32 mg/kg, i.p.) produced a 23% reduction in the rate of phenazone metabolism. 4 Nitrazepam was also shown to have produced a transient fall in body temperature. Calculations based on Q10 values suggested that this hypothermia accounted, at most, for half the metabolic change measured.