Metabolism of loprazolam in rat, dog and man in vivo

Abstract

1. The metabolism of ¹⁴C-loprazolam has been studied in rat, dog and man in vivo.

2. In rat, the major metabolic pathways were hydroxylation on the benzodiazepine ring, and reduction and acetylation of the nitro group. Both metabolites were identified by co-chromatography with standards, and were present in urine and bile conjugated with glucuronic acid.

3. In both dog and human urine and bile significant amounts of the piperazine-N-oxide were found. This N-oxide was identified by co-chromatography with authentic compound and by mass spectroscopy.

4. Both loprazolam and the dog biliary metabolites were hydrolysed spontaneously to polar material. Neither treatment with β-glucuronidase nor incubation with gut microflora had any further effect. Only polar metabolites were found in dog and human faeces.

5. The principal non-polar material found in rat plasma was the diazepine-hydroxy compound, and little loprazolam was present. Significant levels of loprazolam and lower levels of an unidentified metabolite were found in ether extracts of dog and human plasma. Both the piperazine-N-oxide and loprazolam were found in similar quantities in chloroform extracts of human plasma, and at two hours after dosage, the N-oxide and loprazolam accounted for > 90% of the radioactivity present in the plasma.