PHARMACOKINETIC-PHARMACODYNAMIC MODELING OF STIMULATORY AND SEDATIVE EFFECTS OF ALPRAZOLAM - TIMING PERFORMANCE DEFICITS

Alprazolam decreased the reinforcement rate and increased the shorter- response rate of contingency-controlled timing behavior under a differ ential reinforcement of low-rate schedule (DRL 45-s) in rats. An integ rated pharmacokinetic-pharmacodynamic (PK-PD) model was developed to d escribe and characterize the effects of i.v. and s.c. administration o f alprazolam. The onset, peak and disappearance of alprazolam effects were evaluated during a 3-hr session. After s.c. alprazolam administra tion, two peak increases in shorter-response rate occurred at moderate alprazolam serum levels, first in the ascending and then in the desce nding limb of the concentration-time profile. We used a stimulation-se dation PD model incorporating two opposing ef feet-link sigmoidal Emax functions to model the two peaks after s.c. alprazolam administration . The model suggested that alprazolam possesses both stimulatory and s edative effects in a continuous but sequential fashion, which correspo nded to low and high-concentration effects as indicated by the EC50 va lues of 0.09 and 0.18 mu g/ml, respectively. Owing to the rapid onset of i.v. administration, the first peak (a transition phase before the onset of the sedative effect) was absent, with the presence of the sec ond peak again coinciding with the offset of the sedative effect. The reinforcement rate (IC50 = 0.02 mu g/ml) characterized by the indirect response model to account for the initial hysteresis is an index for evaluating the deficit in timing performance. Although the effects of alprazolam can be described in behavioral terms, simultaneous PK-PD op timization numerically defines the performance and hypothesizes the co existence of stimulation and sedation components for alprazolam. The s timulation-sedation model may help in delineating the possible mechani sms for adverse rebound side effects and of tolerance in humans.