The metabolic pathway by which diazepam is transformed in vitro by liver microsomes from control and phenobarbital-treated rats, mice and guinea pigs was studied in detail. The increased diazepam metabolism resulting from phenobarbital treatment led to the formation of increased amounts of hydroxylated metabolites in mice, and of both hydroxylated and N-demethylated metabolites in rats. In guinea pigs pretreatment with phenobarbital produced only an increased formation of N-demethylated metabolite. In all the animal species considered, in addition to the increased diazepam metabolism, phenobarbital treatment led to a decreased recovery of diazepam from incubation medium.
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