Studies on the fate of flurazepam. 2. The metabolism of flurazepam in rat

Abstract

The metabolic fate of Flurazepam hydrochloride, 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1, 3-dihydro-2H-1, 4-benzodiazepin-2-one monohydrochloride, having a sleep-inducing effect, was examined in a rat after oral administration of this compound labeled with 14C at the C-5 position. Radioactive metabolites in bile and urine were fractionated to be identified. Less than 3% of the bilary 14C could be extracted with ethyl acetate at pH 9.0 and no appreciable amount of intact Flurazepam was detected in this extract. In bilary metabolites, N-dealkylated compounds (>NCH2CH2NHC2H5, >NCH2CH2NH2), thier conjugates, and the conjugate of N1-ethanol (>NCH2CH2OH) were found. In urinary metabolites, N1-acetic acid (>NCH2COOH) was found in addition to the bilary metabolites. One of major metabolites in both bile and urine remained unidentified, but it was evident that this unidentified metabolite was soluble in water, had no acidic group, kept a benzodiazepine ring structure, and had an N1-aminoethyl group (>NCH2CH2N<). From these results, the pathway of Flurazepam in rat was postulated as shown in Chart 4.