Kinetic and dynamic interaction of brotizolam and ethanol.

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Abstract
Thirteen healthy male volunteers ingested a single 0.25 mg dose of the thienodiazepine hypnotic, brotizolam, on two occasions: once with a typical social cocktail (containing 60 ml of vodka), and in a second trial with an 'ethanol‐placebo' cocktail. Brotizolam kinetics were determined from multiple plasma concentrations measured during the 24 h after dosage. Coadministration of brotizolam with ethanol, as opposed to the placebo cocktail, slightly imparied brotizolam clearance (1.85 vs 2.19 ml min‐1 kg‐1 P less than 0.005), increased peak plasma concentrations (5.3 vs 4.3 ng ml‐1, P less than 0.05), and prolonged elimination half‐life (5.2 vs 4.4 h, P less than 0.05). There was evidence of impairment of performance, although not statistically significant, for the first 4‐6 h after brotizolam dosage in the reaction time test, the digit‐symbol substitution test, and a tracking task. None of these was enhanced by ethanol. In both trials, brotizolam produced significant increases in self‐rated perceptions of sedation, fatigue, feeling 'spaced‐out', and thinking slowed down. These effects were more intense during the brotizolam‐ethanol as compared to brotizolam‐placebo. In both trials, recovery was essentially complete by 6‐8 h after dosage. Coadministration of brotizolam with ethanol produces a small but significant impairment of brotizolam clearance. Brotizolam produced self‐rated perceptions of sedation and fatigue during 4‐6 h after dosage, but objective impairment of psychomotor performance was minimal. Subjective perceptions of sedation were enhanced by ethanol coadministration, but the effects on psychomotor performance were not.