EFFECT OF ITRACONAZOLE ON THE SINGLE ORAL DOSE PHARMACOKINETICS AND PHARMACODYNAMICS OF ALPRAZOLAM

To assess the effect of itraconazole, a potent inhibitor of cytochrome P450 (CYP) 3A4, on the single oral dose pharmacokinetics and pharmaco dynamics of alprazolam, the study was conducted in a double-blind rand omized crossover manner with two phases of treatment with itraconazole -placebo or placebo-itraconazole. Ten healthy male subjects receiving itraconazole 200 mg/day or matched placebo orally for 6 days took an o ral 0.8 mg dose of alprazolam on day 4 of each treatment phase. Plasma concentration of alprazolam was measured up to 48 h after alprazolam dosing, together with the assessment of psychomotor function by the Di git Symbol Substitution Test, Visual Analog Scale and Udvalg for klini ske undersogelser side effect rating scale. Itraconazole significantly (P<0.01) increased the area under the concentration-time curves from Oh to infinity (252 +/- 47 versus 671 +/- 205 ng h/ml), decreased the apparent oral clearance (0.89 +/- 0.21 versus 0.35 +/- 0.10 ml/min per kg) and prolonged the elimination half-life (15.7 +/- 4.1 versus 40.3 +/- 13.5 h) of alprazolam. The test performed during itraconazole tre atment showed significantly depressed psychomotor function. It is sugg ested that itraconazole, a potent CYP3A4 inhibitor, increases plasma c oncentration of alprazolam via its inhibitory effects on alprazolam me tabolism. Thus, this study supports previous studies suggesting that C YP3A4 is the major enzyme catalyzing the metabolism of alprazolam. Enh anced side effects of alprazolam by itraconazole coadministration were probably reflected by these pharmacokinetic changes.