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Abstract To assess the effect of itraconazole, a potent inhibitor of cytochrome P450 (CYP) 3A4, on the single oral dose pharmacokinetics and pharmacodynamics of alprazolam, the study was conducted in a double-blind randomized 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 oral 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 Digit Symbol Substitution Test, Visual Analog Scale and Udvalg for kliniske undersogelser side effect rating scale. Itraconazole significantly (P<0.01) increased the area under the concentration-time curves from 0 h 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 treatment showed significantly depressed psychomotor function. It is suggested that itraconazole, a potent CYP3A4 inhibitor, increases plasma concentration of alprazolam via its inhibitory effects on alprazolam metabolism. Thus, this study supports previous studies suggesting that CYP3A4 is the major enzyme cat alyzing the metabolism of alprazolam. Enhanced side effects of alprazolam by itraconazole coadministration were probably reflected by these pharmacokinetic changes. [ABSTRACT FROM AUTHOR]

Abstract The relationship between the cytochrome P450 (CYP) 2D6 genotype and the steady-state plasma concentrations (Css) of trazodone and its active metabolite m-chlorophenylpiperazine (mCPP) was studied in 54 depressed Japanese patients receiving trazodone 150 mg at bedtime. By use of allele-specific PCR analysis, the wild type allele, three mutated alleles causing absent enzyme activity (CYP2D6A, CYP2D6B and CYP2D6D) and one mutated allele causing decreased enzyme activity (CYPZD6 Ch) were identified. The means (ranges) of the Css of trazodone, corrected to the median body weight in 17 cases with no mutated allele, 27 cases with one mutated allele and 10 cases with two mutated alleles, were 556 (281-1115), 643 (302-1362) and 671 (234-1418)ng/ml, respectively, while the values of mCPP were 60 (35-121), 65 (33-99) and 58 (38-112)ng/ml, respectively. Neither the Css of trazodone (F = 0.80, P = 0.45) nor that of mCPP (F = 0.49, P = 0.61) significantly differed among the three groups. The present study thus suggests that the CYP2D6 genotype cannot predict the Css of these compounds. [ABSTRACT FROM AUTHOR]