Interaction of doxapram and pentobarbital in mice

We found a statistically significant increase in duration of pentobarbital-induced narcosis in doxapram-treated mice. The influence of doxapram (a respiratory stimulant) pretreatment on pentobarbital metabolism in mice was assessed by measurements of sleeping times, hypothermia, LD50 values, hepatic microsomal metabolism and relative plasma and brain levels of pentobarbital. When doxapram was given intraperitoneally 60 min. prior to administration of pentobarbital, doxapram potentiated pentobarbital-induced narcosis in a dose- and time-dependent manner, but had no effect on onset time. Doxapram potentiated hypothermia, increased acute toxicity, and prolonged the pentobarbital half-life in brain and plasma, but measurement of the concentration of pentobarbital in the brain and plasma immediately upon recovery from narcosis showed that there were no differences in any of the groups examined. Also, brain-to-plasma ratios of pentobarbital did not differ between the control and doxapram-treated groups. Doxapram competitively inhibited the hepatic metabolism of pentobarbital in 9000 x g supernatant incubation mixtures. The results obtained from these experiments indicate that inhibition of drug-metabolizing enzymes by doxapram may account for its enhancement of the duration of pentobarbital-induced narcosis.