In vitro and in vivo metabolism of flutoprazepam and fludiazepam in mice.

Abstract

The metabolism of flutoprazepam (FP) and fludiazepam (FD) in mice, in vitro and in vivo, was investigated. In vitro experiments with mouse liver 9, 000 × g supernatant have shown that FP was mainly metabolized to N-desalkylflutoprazepam (DFP) and 3-hydroxyflutoprazepam (HFP), wheares 3-hydroxyfludiazepam (HFD) was the major metabolite in the case of FD when used substrate concentrations were high (more than 100 μM). The N1-dealkylation activity of the liver 9, 000 × g supernatant for FP was approximately four times higher than that for FD, but the C3-hydroxylation activity for FP was one-half of that of FD at 100 μM of substrate concentration. When substrate concentrations were low (2.5 ?? 10 μM), FP was mainly metabolized to DFP, and HFP was not detected. In the case of FD, approximately equal amounts of DFP and HFD were generated. In both substrates, N-desalkyl-3-hydroxyflutoprazepam (DHF) was the minor metabolite. FP and FD were also administered orally (0.64 mg/kg) to mice and plasma concentrations of metabolites were determined. When FP was administered, DFP and DHF were the major metabolites, and FP and HFP were below the detection limit. The similarity of the metabolites detected in plasma during in vivo experiments to those formed in vitro, at low substrate concentrations, was observed in FP. In the case of FD, the major metabolites in plasma were also DFP and DHF, but a small amount of FD and HFD were detected at the early period of time after administration. These results were also explained by observations that the in vitro metabolic rate of FD was slower than that of FP, that C3-hydroxylation activity for FD was higher than that for FP, and that the fraction of DFP to total metabolites at low substrate concentrations was increased more than that at high concentrations.