Metabolism of 8-chloro-6-(o-chlorophenyl)-1-methyl-4H-s-triazolo [4,3-a] [1,4]benzodiazepine, triazolam, a new central depressant. II. Identification and determination of metabolites in rats and dogs

Abstract

1. Eight metabolites of triazolam have been identified, namely, triazolam, dichloro-triazolobenzophenone (DCTB), 1'-hydroxytriazolam, dichloro-α-hydroxytriazolobenzo-phenone (1'-hydroxy-DCTB), Ar-hydroxytriazolam, 4-hydroxytriazolam, Ar-1'-dihydroxytriazolam and 1',4-dihydroxytriazolam.

2. Major metabolites found in the urine were 1',4-dihydroxytriazolam, 1'-hydroxy-DCTB and DCTB m rats; 1'-hydroxytriazolam, 4-hydroxytriazolam and conjugated 1'-hydroxytriazolam in dogs.

3. Major metabolites found in the faeces were 4-hydroxytriazolam in rats; 1'-hydroxytriazolam and 4-hydroxytriazolam in dogs.

4. Conjugated 4-hydroxytriazolam was the major metabolite in both the original and reabsorbed bile of rats.

5. Major metabolites in free form in the plasma were 4-hydroxytriazolam and 1'-hydroxytriazolam in rats; triazolam and 1'-hydroxytriazolam in dogs.

6. The major metabolite in the brain was triazolam, but those in the liver were 4-hydroxytriazolam and triazolam, and in the kidneys were 4-hydroxytriazolam and 1',4-dihydroxytriazolam.

7. Major metabolites in the urine, faeces, plasma ard brain after 7-, 14- or 21-day repeated dosing in rats were not much different in type and ratio from those after single dosing.

8. Unchanged triazolam and 1'-hydroxytriazolam were the major metabolites in the plasma, placenta, foetus and amniotic fluid in pregnant rats.

9. There was no change in hepatic aniline hydroxylase and aminopyrine-N-demethylase activity from controls in rats given oral dose of [¹⁴C]triazolam for 14 days.