No 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.

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 undersøgelser 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 catalyzing the metabolism of alprazolam. Enhanced side effects of alprazolam by itraconazole coadministration were probably reflected by these pharmacokinetic changes.

The triazolobenzodiazepine alprazolam is used extensively in the treatment of anxiety and panic disorders (Greenblatt and Wright 1993). A significant concentration-effect relationship for alprazolam has been suggested in the treatment of panic disorder; optimal reduction of anxiety occurs in the plasma concentration range of 20-40 ng/ml, whereas the central nervous system (CNS) depressant side effects increase progressively at higher plasma concentrations (Greenblatt and Wright 1993).Alprazolam is metabolized primarily by the hepatic microsomal oxidation, yielding 4-and ␣ -hydroxyalprazolam as its principal metabolites (Greenblatt and Wright 1993). Previous studies have suggested that neither cytochrome P450 (CYP) 2D6 (Bertilsson et al. 1988) nor CYP2C19 (Otani et al. 1997a) is involved in the metabolism of alprazolam. Meanwhile, the in vitro study by von Moltke et al. (1994) has shown that ketoconazole, an inhibitor of CYP3A4 (Olkkola et al. 1994;Watkins 1994), inhibits the 4-and ␣ -hydroxylation of alprazolam, suggesting that alprazolam is metabolized by CYP3A4. Furthermore, Yasui et al. (1996) have reported that erythromycin, an inhibitor of CYP3A4 (Olkkola et al. 1993;Watkins 1994) Carbamazepine has been used increasingly in the treatment of psychiatric disorders (Siris 1993;Post et al. 1994;Otani et al. 1996a). However, it has been suggested that carbamazepine induces the metabolism of several psychotropic drugs (Arana et al. 1986;Backman et al. 1996;Otani et al. 1996b;1997b) by a not fully characterized enzyme induction. Previous studies have suggested that carbamazepine induces CYP3A4 (Wietholtz et al. 1989;Pirmohamed et al. 1994;Yue et al. 1994), but not CYP1A2 (Wietholtz et al. 1989), CYP2D6 (Yue et al. 1994) nor UDP-glucuronosyltransferases (Yue et al. 1994). Therefore, carbamazepine may decrease plasma concentration of alprazolam by inducing its metabolism. In fact, Arana et al. (1988) has reported that carbamazepine decreased plasma concentration of alprazolam in one psychiatric patient. However, there has been no systematic study on the effect of carbamazepine on the plasma concentration and/or metabolism of alprazolam.Therefore, we studied the effect of carbamazepine on the single oral dose pharmacokinetics of alprazolam in healthy volunteers. We also expected that the present study would provide further evidence for the involvement of CYP3A4 in the metabolism of alprazolam. METHODS SubjectsThe subjects were seven healthy male volunteers. The mean Ϯ SD of age was 32.7 Ϯ 6.6 years, and that of body weight was 60.9 Ϯ 4.6 kg. Three subjects were smokers ( Ն 10 cigarettes/day), and the remaining four were nonsmokers. The study protocol was approved by the Ethics Committee of Hirosaki University Hospital, and each subject gave his written informed consent before the study. ProtocolThe study was conducted in a double-blind, randomized crossover manner, with at least a 6-week washout period. The subjects were allocated randomly to one of the two treatment sequences, placebo-carbamazepine or carbamazepin...

This study suggests that the urinary ratio of 6beta-hydroxycortisol to cortisol is unlikely to predict pharmacokinetics of alprazolam.