Metabolism of 8-Chloro-6-phenyl-4H-s-triazolo[4,3-α][1,4]-benzodiazepine (D–40TA), a New Central Depressant. II. Species Difference in Metabolism

Abstract

1. Urinary and faecal excretion of radioactivity in 24 h after oral administration of [¹⁴C]D–40TA was 78% of the dose in dogs, 78% in mice, 51% in rats, 48% in rabbits and 44% in guinea-pigs. The five species were classified into two groups according to excretory patterns; dogs and rabbits excreted more radioactivity in urine than faeces, whereas rats, mice and guinea-pigs excreted more in faeces.

2. In all species, most urinary and faecal radioactivity was due to metabolites, indicating that absorption of D–40TA was essentially complete and followed by extensive biotransformation. Marked species variations occurred in urinary metabolic composition.

3. In rats (faecal excretor), the blood level of D–40TA after oral administration reached a peak at 30 min and then declines, with a half-life of 60 min. In dogs (urinary excretor), the max. was attained in 30 to 60 min and the half-life was 140 min.

4. Biliary excretion of radioactivity was complete within 32 h in rats, 16 h in dogs and 48 h in rabbits, about 60, 19 and 19% of the dose appearing in bile, respectively.

5. The difference in excretory pattern between the two animal groups might be largely due to the extent of biliary excretion and subsequent re-absorption of the metabolites.