Biotransformation of a 1,5-benzodiazepine, triflubazam, by man.

The biotransformation of triblubazam (ORF 8063; 1-methyl-5-phenyl-7-trifluoromethyl-1H-1,5-benzodiazepin-2,4-[3H,5H]-dione) was studied in man. Seven male subjects received a chronic regimen of orally administered triblubazam for 19 consecutive days and their urine was collected for 29 days. Seven urinary metabolites were isolated by application of Sephadex LH-20 column chromatography and preparative thin-layer chromatography. Six of the purified compounds were subsequently characterized by utilizing thin-layer and gas-liquid chromatography and infrared, nuclear magnetic resonance, and mass spectrometry. The structure of a seventh metabolite was established by the use of an enzymatic assay involving catechol O-methyl-transferase. These compounds included unchanged triflubazam, the N-desmethyl catechol derivative, the 4'-hydroxyphenyl derivative, N-desmethyltriflubazam, the N-desmethyl dihydrodiol derivative, the N-desmethyl-4'-hydroxy compound, and the N-desmethyl-3'-methoxy-4'-hydroxy derivative. Unlike the situation in the metabolism of 1,4-benzodiazepines by man, no C3-hydroxylated derivatives of triflubazam were isolated. The metabolism of triblubazam by man is characterized by extensive N-demethylation, aromatic hydroxylation, aromatic O-methylation, and dihydrodiol formation.