The present study suggests that there is a therapeutic threshold for the Css of FLV and probably also for the Css of FLA, and the Css of FLV+FLA above 180 ng/ml best predicts a good therapeutic response.

The effects of the cytochrome P450 (CYP) 2D6 genotype and cigarette smoking on the steady-state plasma concentrations (C(ss)) of fluvoxamine (FLV) and its demethylated metabolite fluvoxamino acid (FLA) were studied in 49 Japanese depressed patients receiving FLV 200 mg/d. The C(ss) of FLV and FLA were measured by HPLC, and the wild-type allele (*1) and two mutated alleles causing absent (*5) or decreased (*10) CYP 2D6 activity were identified by PCR methods. The patients were divided into three genotype groups by the number of mutated alleles: 12 cases with no (*1/*1), 27 cases with one (*1/*5 and *1/*10), and 10 cases with two (*5/*10 and *10/*10) mutated alleles. The means +/- SD of the C(ss) of FLV and FLA and the FLA/FLV ratio of all patients were 169.1 +/- 147.5 ng/mL, 83.9 +/- 52.7 ng/mL, and 0.71 +/- 0.50, respectively. The C(ss) of FLV and FLA were not significantly different among the three genotype groups. However, the FLA/FLV ratio was significantly lower in the patients with one (P < 0.05) and two (P < 0.01) mutated alleles than in those with no mutated allele. There was no significant difference between nonsmokers (n = 34) and smokers (n = 15) in these values. In the stepwise multiple regression, the C(ss) of FLA (P < 0.05) and FLA/FLV ratio (P < 0.001) showed significant negative correlations with the number of mutated alleles, and the FLA/FLV ratio was significantly (P < 0.05) lower in women than in men. The present study suggests that the CYP 2D6 genotype and cigarette smoking have no major impact on the C(ss) of FLV and FLA, though CYP 2D6 is involved in the demethylation of FLV.

IntroductionFluvoxamine, 5-methyl-4′-trifluoromethylvalerophenone(E)-O-2-aminoethyloxime monomaleate, is one of several antidepressant agents known as selective serotonin reuptake inhibitors (SSRIS). The efficacy of fluvoxamine in depression has been reviewed in previous papers. 1,2 The clinical pharmacokinetics of fluvoxamine were also described in a previous paper. 3 Negligible amounts of fluvoxamine are excreted unchanged in the human urine. Urinary fluvoxamine metabolites have been identified as consisting of at least 9 different compounds. About 65% of these metabolites resulted from oxidative demethylation of the aliphatic methoxyl group, and 15% of metabolites are formed by degradation at the primary amino group. Fluvoxamino acid is the main primary metabolite in humans. 4 Therefore, the monitoring of fluvoxamino acid on the drug interaction study of fluvoxamine will be able to detect slight changes of fluvoxamine metabolism by co-administered drug in healthy volunteers and/or patients.The pharmacokinetics of fluvoxamino acid in human has not yet been studied sufficiently.Methods for the fluvoxamine by GC-MS, 12 HPLC with liquidliquid extraction of plasma samples [13][14][15][16][17] and HPLC with solidphase in-line extraction 18,19 were described in previous papers. The liquid-liquid extraction methods are not completely satisfactory because they are time-consuming and require a tedious procedure. We have reported a simple extraction method of several drugs and their metabolites by using a solid phase extraction cartridge. [20][21][22][23] However, an off-line solid phase extraction method for fluvoxamine has not been reported in previous papers. There is also no report for simultaneous determination of fluvoxamine and fluvoxamino acid in human plasma by HPLC.The extraction of fluvoxamine and fluvoxamino acid in human plasma using a solid phase method has some problems: one is the simultaneous extraction from a complex mixture of both acidic and basic compounds. Therefore, a specific extraction method and an efficient chromatographic system without interfering peaks was needed A high-performance liquid chromatographic (HPLC) method has been developed for the simultaneous determination of fluvoxamine and its major metabolite fluvoxamino acid in plasma. Fluvoxamine and fluvoxamino acid in plasma were extracted using a C18 bonded-solid phase cartridge, followed by C4 reversed-phase HPLC separation. Fluvoxamine, fluvoxamino acid and moperone as an internal standard were detected by ultraviolet absorbance at 254 nm. It was possible to determine both fluvoxamine and fluvoxamino acid in the concentration range of 25.0 -200.0 ng/mL, respectively. The detection limits of both fluvoxamine and fluvoxamino acid were 10.0 ng/mL, respectively. The mean recoveries of fluvoxamine and fluvoxamino acid added to plasma were more than 94.0% and 96.5%, with a coefficient of variation of less than 7.6% and 8.2%, respectively. This method has been used for the simultaneous determination of steady-state plasma concentration (C...

A high-performance liquid chromatographic method was developed for the measurement of carbamazepine (CBZ) and carbamazepine 10,11-epoxide (CBZE) in human breast milk and plasma. The method involves rapid C18 solid-phase extraction of CBZ and CBZE. Chromatographic separation was achieved with a reversed-phase C8 column using a mobile phase of potassium dihydrogenphosphate (pH 2.5) and acetonitrile (67:33 v/v), with ultraviolet detection at 254 nm. 2-Methyl CBZ was used as the internal standard. Determination of both CBZ and CBZE was possible in the range of 0.01-6.0 mg/L and 0.02-6.0 mg/L in milk and plasma, respectively. The recoveries of CBZ and CBZE added to the milk and plasma were 90.6-98.0% and 88.9-104.0%, respectively, with coefficients of variation less than 8.3% and 10.5%, respectively. The method has been used for drug level monitoring in milk and plasma samples obtained from CBZ-treated patients. The mean (SD) levels for CBZ in milk and plasma samples were 3.50 (0.4) mg/L and 6.18 (2.9) mg/L, and for CBZE were 1.28 (0.3) mg/L and 1.85 (1.0) mg/L, respectively. The mean (SD) milk/plasma ratios of CBZ and CBZE were 0.64 (0.2) and 0.79 (0.3), respectively. The milk/plasma ratio of CBZE was slightly higher than that of CBZ.

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...