PHARMACOKINETICS AND PSYCHOMOTOR PERFORMANCE OF ALPRAZOLAM - CONCENTRATION-EFFECT RELATIONSHIP

The relationship between the pharmacokinetics of aIprazolam and dose a nd the relationship between the concentration of alprazolam and psycho motor performance in healthy male volunteers were investigated in this double-blind, placebo-controlled, modified crossover study. Twenty-fo ur volunteers received placebo in Phase I and then received single 2-m g, 4-mg, 8-mg and 10-mg doses of a sustained-release formulation in Ph ases II through V, according to a crossover design. Blood samples were collected at several times throughout each phase to 48 hours after th e dose; the harvested plasma was assayed for concentrations of aIprazo lam, 4-hydroxyalprazoIam, and alpha-hydroxyalprazolam by high-performa nce liquid chromatography. Sedation was rated at each blood-sampling t ime and psychomotor performance tests, consisting of digit-symbol subs titution and card-sorting tasks, were conducted at several times after each dose. Area under the concentration-time curve and peak concentra tion for alprazolam increased proportionally with each higher dose; cl earance did not differ significantly between treatments. The concentra tions of 4-hydroxyalprazolam and alpha-hydroxyalprazolam increased pro portionally with dose and the combined plasma concentrations of the me tabolites 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 i n dose. Performance versus concentration curves for alprazolam exhibit ed a clockwise hysteresis loop in contrast to the counterclockwise hys tereses previously reported for both intravenous and oral doses of imm ediate-release tablets. Data through 6 hours after dose were well desc ribed by a sigmoid E-max model. Alprazolam exhibits linear pharmacokin etics after single oral doses of sustained-release tablets between 2 m g and 10 mg. Reversal of the concentration-effect curve to a clockwise loop suggests the counterclockwise hystereses of rapidly absorbed dos es was caused by the differing distribution rates into the systemic ci rculation and effect site and not by metabolite activity.