Lack of induction of rat liver mixed-function oxidases after chronic administration of high brotizolam doses to rats.

Rats were treated with 10, 200 or 400 mg/kg brotizolam (Lendormin) for 4 weeks, then liver microsomes were prepared and the in vitro transformation of several model substances studied. Furthermore, after similar treatment of rats, the metabolite pattern in the plasma was studied using [14C]brotizolam as a marker. Finally the same investigations were performed after pretreating the rats with the enzyme inducers, phenobarbital or 3-methylchol-anthrene, for 3 days instead of brotizolam. The amount of microsomal protein in the rat liver was increased after all 3 doses of brotizolam, the liver weight after the highest dose only. Activity of the flavoenzyme NADPH cytochrome-c reductase was the only enzyme activity increased after 200 and 400 mg/kg brotizolam, whereas cytochrome P-450 content decreased after 400 mg/kg brotizolam. Activities of the mixed-function oxidases studied were not changed at all. Marked changes after brotizolam administration were seen in the metabolite pattern. The higher doses led to reduced amounts of both of the very polar metabolites. Simultaneously metabolite We 964 (= brotizolam hydroxylated at the methyl group) and the unchanged brotizolam increased several-fold. Treatment of rats with phenobarbital or 3-methylcholanthrene showed the typical but different changes in enzyme activities. The metabolite pattern of brotizolam, however, was not changed. From the results it is concluded that a 4-week treatment of rats with up to 400 mg/kg brotizolam causes no induction of mixed-function oxidases in the liver. The changes of the metabolite pattern described can be discussed as an effect of liver enzyme saturation.