Pharmacokinetics and psychomotor performance of alprazolam: concentration-effect relationship.

The relationship between the pharmacokinetics of alprazolam and dose and the relationship between the concentration of alprazolam and psychomotor performance in healthy male volunteers were investigated in this double-blind, placebo-controlled, modified crossover study. Twenty-four volunteers received placebo in Phase I and then received single 2-mg, 4-mg, 8-mg, and 10-mg doses of a sustained-release formulation in Phases II through V, according to, a crossover design. Blood samples were collected at several times throughout each phase to 48 hours after the dose; the harvested plasma was assayed for concentrations of alprazolam, 4-hydroxyalprazolam, and alpha-hydroxyalprazolam by high-performance liquid chromatography. Sedation was rated at each blood-sampling time and psychomotor performance tests, consisting of digit-symbol substitution and card-sorting tasks, were conducted at several times after each dose. Area under the concentration-time curve and peak concentration for alprazolam increased proportionally with each higher dose; clearance did not differ significantly between treatments. The concentrations of 4-hydroxyalprazolam and alpha-hydroxyalprazolam increased proportionally with dose and the combined plasma concentration of the metabolites were less than 15% of unchanged concentrations of alprazolam for all doses. Maximum sedation increased with each increase in dose up to 8 mg, and psychomotor performance decreased with each increase in dose. Performance versus concentration curves for alprazolam exhibited a clockwise hysteresis loop in contrast to the counterclockwise hystereses previously reported for both intravenous and oral doses of immediate-release tablets. Data through 6 hours after dose were well described by a sigmoid Emax model. Alprazolam exhibits linear pharmacokinetics after single oral doses of sustained-release tablets between 2 mg and 10 mg. Reversal of the concentration-effect curve to a clockwise loop suggests the counterclockwise hystereses of rapidly absorbed doses was caused by the differing distribution rates into the systemic circulation and effect site and not by metabolite activity.