title: Pharmacokinetics and psychomotor performance of alprazolam: concentration-effect relationship.
abstract: 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.
authors.affiliation: Clinical Pharmacokinetics Unit, Upjohn Company, Kalamazoo, Michigan 49001, USA.
authors.forename: C E
authors.initials: CE
authors.lastname: Wright
authors.forename: T L
authors.initials: TL
authors.lastname: Sisson
authors.forename: J C
authors.initials: JC
authors.lastname: Fleishaker
authors.forename: E J
authors.initials: EJ
authors.lastname: Antal
mesh_terms: D000328:Adult; D000525:Alprazolam / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D011597:Psychomotor Performance / Q000187:drug effects*
chemical_list: D014151:Anti-Anxiety Agents; D000525:Alprazolam