Metabolism of 8-Chloro-6-phenyl-4H-s-triazolo[4,3-α][1,4]-benzodiazepine (D–40TA), a New Central Depressant. I. Absorption, Distribution and Excretion in Rats

Abstract

1. [¹⁴C]D–40TA was quantitatively absorbed from the rat small intestine by the portal route.

2. The blood level of oral D–-40TA reached a peak at 30 min and then declined with a half-life of 60 min. The level after intravenous injection fell off with a half-life of 32 min. D–40TA and its metabolites could enter erythrocytes. The drug was not bound to plasma protein.

3. Oral administration of [¹⁴C]D–40TA caused a rapid and wide distribution of radioactivity in tissues, with the peak levels at 1 h. T this time, the radioactivity was highest in adrenal, followed by liver and skeletal muscle, and lowest in testis.

4. D–40TA was detected in the brain 2 min after oral dosing. Brain levels of D–40TA were the same as, or slightly higher than the blood levels at all times, indicating that the drug easily passed through the blood–brain barrier. A pharmacologically active metabolite B also entered into the brain with ease.

5. The oral drug was completely eliminated from the body within 3 days, 18% in urine and 82% in faeces. More than 90% of the radioactivity both in urine and faeces was accounted for by the metabolites.

6. Biliary excretion was completed within 32 h after oral administration and within 18 h after intravenous injection, 60 and 68% of the dose being excreted, respectively. Entero-hepatic circulation of biliary metabolites was evidenced.