Kinetic and pharmacological studies on estazolam in mice and man

1. After i.v. and oral doses of estazolam (5 mg/kg) to mice, the drug was rapidly cleared with a half-life (t_1/2 of 0.7 h. 2. The active metabolite, 1-oxo-estazolam, was present in traces in mouse plasma and brain. Its elimination t_1/2 ( determined after i.v. injection of 1-oxo-estazolam (5 mg/kg) to mice, was similar to that of the parent drug in both plasma and brain. 3. After a single oral dose of estazolam (4mg) to four human volunteers the drug was rapidly absorbed and reached maximum plasma concentrations in one to three hours. Elimination t_1/2 of estazolam in humans was 19 h. 4. The metabolite was undetectable in human plasma after either single or multiple doses of estazolam. 5. These results, together with the finding that 1-oxo-estazolam was less effective than estazolam, in terms of ED₅₀ and brain concentrations necessary to antagonize leptazol convulsions and disrupt rota-rod performance in mice, indicate that the metabolite does not contribute significantly to the pharmacological effects of its parent drug.