Pharmacokinetics and pharmacodynamics of alprazolam after oral and IV administration

Abstract

Six fasting male subjects (20–32 years of age) received an oral tablet and an IV 1.0-mg dose of alprazolam in a crossover-design study. Alprazolam plasma concentration in multiple samples during 36 h after dosing was determined by electron-capture gas-liquid chromatography. Psychomotor performance tests, digit-symbol substitution (DSS), and perceptual speed (PS) were administered at 0, 1.25, 2.25, 5.0, and 12.5 h. Sedation was assessed by the subjects and by an observer using the Stanford Sleepiness Scale and a Nurse Rating Sedation Scale (NRSS), respectively. Mean kinetic parameters after IV and oral alprazolam wre as follows: volume of distribution (V _d) 0.72 and 0.84 l/kg; elimination half-life (t _1/2) 11.7 and 11.8 h; clearance (Cl) 0.74 and 0.89 ml/min/kg. There were no significant differences between IV and oral alprazolam in V _d, t _1/2, or area under the curve. The mean fraction absorbed after oral administration was 0.92. Performance on PS and DSS tests was impaired at 1.25 and 2.5 h, but had returned to baseline at 5.0 h for both treatments. Onset of sedation was rapid after IV administration and the average time of peak sedation was 0.48 h. Sedation scores were significantly lower during hour 1 after oral administration than after IV, but were not significantly different at later times. Alprazolam is fully available after oral administration and kinetic parameters are not affected by route of administration. With the exception of rapidity of onset, the pharmacodynamic profiles of IV and oral alprazolam are very similar after a 1.0-mg dose.