fluvoxamine and fluvoxamino-acid

The effects of caffeine on the kinetics of fluvoxamine (FLV) and its major metabolite fluvoxamino acid (FLA) in plasma, after a single oral dose of the drug, were studied in 12 healthy male volunteers. The subjects received caffeine 300 mg/d or placebo for 11 days in a double-blind randomized crossover manner, and on the eighth day they received a single oral 50-mg dose of FLV. Blood sampling and pharmacodynamic evaluation were conducted up to 72 hours after FLV dosing. Plasma concentrations of FLV and FLA were measured by high-performance liquid chromatography. Caffeine significantly decreased the plasma concentrations at 6 time points (P<0.05) and total area under the plasma concentration-time curve (156.5+/-51.7 vs. 118.9+/-38.2 ng/h/mL, P<0.01) of FLV. Plasma concentration and pharmacokinetic parameters of FLA were not affected by caffeine. Caffeine induced no significant change in the pharmacodynamic effects of FLV. The present study suggests that caffeine slightly induces the metabolism of FLV, probably mediated by CYP1A2.

Topics: Adult; Amino Acids; Antidepressive Agents, Second-Generation; Area Under Curve; Caffeine; Cross-Over Studies; Cytochrome P-450 CYP1A2; Double-Blind Method; Fluvoxamine; Half-Life; Humans; Male; Metabolic Clearance Rate

The relationship between clinical effects of fluvoxamine (FLV) and the steady-state plasma concentrations (Css) of FLV and its major metabolite fluvoxamino acid (FLA) was studied.. The subjects were 49 Japanese patients with major depressive disorder receiving FLV 200 mg/day for 6 weeks. Depressive symptoms and side effects were evaluated by the Montgomery Asberg Depression Rating Scale (MADRS), and the UKU Side Effect Rating Scale, respectively. The Css of FLV and FLA were measured by HPLC, and the CYP2D6 genotyping was performed by PCR methods.. The Css of FLV and FLV+FLA showed significant negative correlations with the final MADRS score. The Css of FLV, FLA and FLV+FLA were significantly higher in the responders (final MADRS score < or =10) than in non-responders. The proportion of responders was significantly higher in the patients with the Css of FLV, FLA and FLV+FLA above 150, 55 and 180 ng/ml, respectively. In the multiple regression, the Css of FLV+FLA showed a significant negative correlation with the final MADRS score. In the logistic regression, the Css of FLA had a significant effect on the differentiation of responders from non-responders. The incidence of side effects was low, and the development of nausea, the most frequent one, was not dependent on any Css. The number of mutated CYP2D6 alleles causing absent or decreased enzyme activity was not related to the therapeutic response or development of nausea.. 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.

Topics: Adult; Aged; Amino Acids; Antidepressive Agents, Second-Generation; Cytochrome P-450 CYP2D6; Depressive Disorder, Major; Dose-Response Relationship, Drug; Female; Fluvoxamine; Humans; Japan; Male; Middle Aged; Psychiatric Status Rating Scales; Selective Serotonin Reuptake Inhibitors; Smoking; Treatment Outcome

The metabolism of fluvoxamine to fluvoxamino acid is known to involve a two-step oxidation process via an alcohol intermediate, fluvoxamino alcohol. The present study was carried out to identify the cytochrome P450 (CYP) enzyme(s) involved in the metabolism offluvoxamine to fluvoxamino alcohol using human liver microsomes and cDNA-expressed human CYP enzymes. The mean Km and Vmax values for the formation of fluvoxamino alcohol from fluvoxamine in human liver microsomes were 76.3 microM and 37.5 pmol min(-1) mg(-1) protein, respectively. The formation of fluvoxamino alcohol from fluvoxamine in pooled human liver microsomes was significantly inhibited by quinidine, a relatively specific CYP2D6 inhibitor, with a Ki value of 2.2 microM, whereas other several relatively specific CYP inhibitors did not inhibit the formation of fluvoxamino alcohol. In addition, only CYP2D6 of several cDNA-expressed human CYP enzymes examined showed substantial activity for the formation of fluvoxamino alcohol. Furthermore, the formation of fluvoxamino acid from fluvoxamino alcohol is potently inhibited by 4-methylpyrazole in human liver cytosol. These data suggest that CYP2D6 is the only enzyme predominantly responsible for the first-step oxidation of fluvoxamine to fluvoxamino alcohol, and alcohol dehydrogenase is involved in the second-step oxidation of fluvoxamino alcohol to the corresponding carbolic acid.

Topics: Alcohol Dehydrogenase; Amino Acids; Biotransformation; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2D6 Inhibitors; Cytochrome P-450 Enzyme System; Enzyme Inhibitors; Fluvoxamine; Humans; In Vitro Techniques; Kinetics; Microsomes, Liver; Oxidation-Reduction; Quinidine; Recombinant Proteins

This study describes a new simultaneous determination of fluvoxamine and fluvoxamino acid by automated column-switching high-performance liquid chromatography. The test compounds were extracted from 1.5 ml of plasma using chloroform-toluene (15:85, v/v), and the extract was injected into a hydrophilic metaacrylate polymer column for clean-up and a C18 analytical column for separation. The mobile phase for separation consisted of phosphate buffer (0.02 M, pH 4.6), acetonitrile and perchloric acid (60%) (62.4:37.5:0.1, v/v/v) and was delivered at a flow rate of 0.6 ml/min. The peak was detected using a UV detector set at 254 nm. The method was validated for the concentration range 0.8-153.6 ng/ml for fluvoxamine and 0.6-115.2 ng/ml for fluvoxamino acid, and their good linearity (r > 0.998) were confirmed. Intra-day coefficient variations (CVs) for fluvoxamine and fluvoxamino acid were less than 6.6 and 6.0%, respectively. Inter-day CVs for corresponding compounds were 6.3 and 6.5%, respectively. Relative errors ranged from -18 to 9% and mean recoveries were 96-100%. The limit of quantification was 1.2 and 0.9 ng/ml for fluvoxamine and fluvoxamino acid, respectively. This method shows successful application for pharmacokinetic studies and therapeutic drug monitoring.

Topics: Amino Acids; Chromatography, High Pressure Liquid; Fluvoxamine

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 (Css) of fluvoxamine and fluvoxamino acid in depressive patients treated with 200 mg of oral fluvoxamine dosed as 100 mg twice-daily. The Css values of fluvoxamine and fluvoxamino acid in twelve Japanese patients were showed individual variations, which were in the range of 48.3-532.9 ng/ml and 35.6-307.1 ng/ml, respectively.

Topics: Amino Acids; Antidepressive Agents, Second-Generation; Calibration; Chromatography, High Pressure Liquid; Depression; Fluvoxamine; Humans; Hydrogen-Ion Concentration; Reference Standards; Reproducibility of Results; Spectrophotometry, Ultraviolet