Triazolam disposition

Abstract

Triazolam (T) (Halcion, 8-chloro-6-(o-chlorophenyl)-1-methyl-4H-s-triazolo[4,3-a][1,4]-benzodiazepine) is a new, potent hypnotic with a short duration of action in man. After an 0.88 mg oral dose of T-14C in 6 male subjects, mean recovery of 14C radioactivity was 85% in urine and 8% in feces. The major urinary metabolites were .alpha.-hydroxytriazolam (.alpha.-HT) and 4-hydroxytriazolam (4-HT), accounting for 69% and 11% of the urinary 14C and these were mostly in conjugated form. .alpha.,4-Dihydroxytriazolam and 3 dichlorotriazolylbenzophenone analogs were minor metabolites. At least 85% of the dose was rapidly absorbed; mean absorption half-life (t1/2A) was 2.8 min. After reaching a mean peak plasma level (Cmax) of 8.8 ng/ml at mean time (tmax) of 1.3 h, plasma T decreased rapidly with a mean elimination half-life (t1/2E) of 2.3 h. The remainder of the plasma 14C consisted predominantly of glucuronides of .alpha.-HT and 4-HT. Mean plasma parameters for these metabolites were as follows: .alpha.-HT-glucuronide, t1/2E = 3.9 h, tmax = 1.3 h, Cmax = 6.1 ng/ml; 4-HT-glucuronide, t1/2E = 3.8 h, tmax = 2.5 h, Cmax = 6.1 ng/ml. Nonconjugated .alpha.-HT and 4-HT were present in plasma but in insufficient amounts for kinetic analysis. The results are consistent with the short duration of action.