Effects of enzyme induction and inhibition on microsomal oxidation of 1,4-benzodiazepines.

Metabolic oxidative profiles of diazepam (I) were obtained by aromatic C-4'-hydroxylation, N-1-demethylation, and 3-hydroxylation using a supernatant of rat liver. Incubation of 3-methyldiazepam (VI), which suppressed 3-hydroxylation, and N-1-nor-3-methyldiazepam (VII), were used to separately investigate these three oxidative pathways. Treatment of animals with phenobarbital enhanced N-1-demethylation and 3-hydroxylation, and to a variable extent C-4'-hydroxylation. Application of metyrapone reduced metabolite formation by 3-hydroxylation and N-1-demethylation, but had no effect on C-4'-hydroxylation. Metyrapone inhibition was more pronounced following than prior to phenobarbital treatment. C-2-hydroxylation was studied using medazepam (XX) incubations. This pathway was increased by phenobarbital pretreatment and reduced by metyrapone inhibition which was again more pronounced following than prior to phenobarbital pretreatment. These results support earlier conclusions on the heterogeneity of liver microsomes and suggests the presence of different species of hepatic microsomal terminal oxidases. Phenobarbital treatment and metyrapone change the metabolic profile via induction and inhibition, respectively, and, thus, in the case of 1,4-benzodiazepines, the formation of metabolites with varying pharmacological activity. This could become important in clinical situations as a diagnostic mean to determine induction under various treatment or, possibly, during cumulation of metabolites with a long half-life.