TY  - JOUR
PY  - 1997//
TI  - Pharmacokinetics and psychomotor performance of alprazolam: concentration-effect relationship
JO  - Journal of clinical pharmacology
A1  - Wright, C. E.
A1  - Sisson, T. L.
A1  - Fleishaker, J. C.
A1  - Antal, E. J.
SP  - 321
EP  - 329
VL  - 37
IS  - 4
N2  - 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.<p /> <p>Language: en</p>
LA  - en
SN  - 0091-2700
UR  - http://dx.doi.org/
ID  - ref1
ER  -