Fluvoxamine Concentration Research Articles

Determination of Fluvoxamine and Paroxetine in Human Serum with High-Performance Liquid Chromatography and Ultraviolet Detection

We optimized an isocratic reversed phase high performance liquid chromatography with ultraviolet detection to quantify, simultaneously, the selective serotonin reuptake inhibitors (SSRIs) fluvoxamine and paroxetine in human serum. Fluvoxamine was used as the internal standard for the determination of paroxetine, and paroxetine served as internal standard for the fluvoxamine assay. The method involved a pre-column technique for the on-line liquid-solid extraction with direct injection of serum samples and for their pre-concentration. Automation was achieved by column switching. The chromatographic separation was performed on an Ultrasep ES 100 CN-column with acetonitrile/methanol/phosphate buffer (58/19/23, v/v/v) as mobile phase. A linear relationship (r2 > 0.99) was noted between the concentrations of fluvoxamine or paroxetine and the detector signal. The lower limits of detection in human serum of fluvoxamine and paroxetine were 5 and 2 μg/L, respectively. The accuracy of the quality control samples deviated by m± 8% with a within-day and between-day precision of less than 12.1%, and 10.5% for fluvoxamine and paroxetine, respectively. The method is presently being applied in our clinic for the routine therapeutic drug monitoring of both SSRIs.

Simultaneous determination of plasma levels of fluvoxamine and of the enantiomers of fluoxetine and norfluoxetine by gas chromatography-mass spectrometry

A gas chromatographic-mass spectrometric method is presented which allows the simultaneous determination of the plasma concentrations of fluvoxamine and of the enantiomers of fluoxetine and norfluoxetine after derivatization with the chiral reagent, ( S)-(-)-N-trifluoroacetylprolyl chloride. No interference was observed from endogenous compounds following the extraction of plasma samples from six different human subjects. The standard curves were linear over a working range of 10 to 750 ng/ml for racemic fluoxetine and norfluoxetine and of 50 to 500 ng/ml for fluvoxamine. Recoveries ranged from 50 to 66% for the three compounds. Intra- and inter-day coefficients of variation ranged from 4 to 10% for fluvoxamine and from 4 to 13% for fluoxetine and norfluoxetine. The limits of quantitation of the method were found to be 2 ng/ml for fluvoxamine and 1 ng/ml for the ( R)- and ( S)-enantiomers of fluoxetine and norfluoxetine, hence allowing its use for single dose pharmacokinetics. Finally, by using a steeper gradient of temperature, much shorter analysis times are obtained if one is interested in the concentrations of fluvoxamine alone.

Effect of cigarette smoking on fluvoxamine pharmacokinetics in humans

Although fluvoxamine inhibits the biotransformation of drugs known to be metabolized by CYP1A2, there are no data available with regard to the importance of CYP1A2 for the metabolism of fluvoxamine itself. Because smoking induces the metabolism of drugs catalyzed by CYP1A2, this study investigated the pharmacokinetics of fluvoxamine in smokers and nonsmokers. The serum concentration of fluvoxamine was determined by high-performance liquid chromatography for 48 hours after oral administration of a single dose of 50 mg fluvoxamine to 12 smokers (> or = 10 cigarettes per day) and 12 nonsmokers. The smokers had significantly lower areas under the serum concentration-time curve and significantly lower maximal serum concentrations than the nonsmokers (mean +/- SD, 771 +/- 346 versus 1110 +/- 511 nmol.hr.L-1 [p = 0.012] and 39.1 +/- 17.3 versus 57.7 +/- 21.5 nmol.L-1 [p = 0.012], respectively). The terminal elimination half-life did not differ significantly between smokers and nonsmokers (10.1 +/- 1.9 and 10.7 +/- 2.3 hours, respectively). The oral clearance was high among both smokers (4.1 +/- 1.9 L.min-1) and nonsmokers (3.3 +/- 2.7 L.min-1; difference not significant). Smokers had lower serum concentrations of fluvoxamine than nonsmokers after a single oral dose of fluvoxamine. This finding is consistent with a possible role of CYP1A2 in fluvoxamine metabolism.

Fluvoxamine treatment of alcoholic amnestic disorder

The serotonin uptake inhibitor fluvoxamine was assessed in treatment of alcohol-induced Korsakoff's syndrome (KS) using fixed (4 weeks, 200 mg/day) or individualized (6 weeks, plasma concentration ⩾400 ng/ml) dosing in randomized placebocontrolled double-blind crossover studies. Cognitive functions and concentrations of the major cerebrospinal fluid (CSF) metabolites of serotonin (5-HIAA), norepinephrine (MHPG), and dopamine (HVA) were determined in abstinent, nondepressed KS patients (aged 45–75), at baseline and placebo (3–4 weeks), and after 3–4 ( n = 10) or 6 ( n = 4) weeks of fluvoxamine administration. Fluvoxamine decreased CSF 5-HIAA compared to placebo ( P < 0.003) without consistent changes in HVA or MHPG. Reductions in 5-HIAA correlated with improvements on the Wechsler Memory Scale Memory Quotient ( P < 0.05), independent of effects on attention/vigilance or Beck Depression Inventory scores. Reductions in 5-HIAA correlated with plasma fluvoxamine ( P < 0.03) only for fluvoxamine concentrations below 450 ng/ml. These findings suggest improvement of memory consolidation and/or retrieval in patients with Korsakoff's syndrome by fluvoxamine via serotonergic mechanisms.

Chronic treatment with fluvoxamine by osmotic minipumps fails to induce persistent functional changes in central 5-HT1A and 5-HT1B receptors, as measured by in vivo microdialysis in dorsal hippocampus of conscious rats

This study investigated the alterations of the 5-HT1A and 5-HT1B autoreceptor function following chronic treatment with fluvoxamine using osmotic minipumps. The 5-HT1A and 5-HT1B autoreceptor function were studied using microdialysis in the dorsal hippocampus. The effect of the 5-HT1A receptor agonist 8-OH-DPAT (0.3 mg/kg, SC) and the 5-HT1B receptor agonist RU-24969 (100 nM through the dialysis probe for 30 min) on 5-HT release was compared with rats chronically treated with saline. 8-OH-DPAT decreased 5-HT release to 55% and 60% of baseline, while RU-24969 decreased 5-HT release to 66% and 70% of baseline value in the saline and fluvoxamine group, respectively. In both cases, differences between the saline and fluvoxamine groups were not statistically significant. Plasma levels of fluvoxamine after 21 days of treatment ranged from 3 to 5 ng/ml. Fluvoxamine concentration in rat brain during treatment was estimated between 100 and 200 nM, which approximates to the IC50 value of fluvoxamine on the 5-HT transporter in synaptosomes and is 50 times higher than the Kd value for the 5-HT reuptake site. In conclusion, no evidence was found for changes in 5-HT1A,B receptor function using 8-OH-DPAT and RU-24969 as probes after continuous treatment with fluvoxamine by means of osmotic minipumps.

Overview of the pharmacokinetics of fluvoxamine.

The pharmacokinetics of fluvoxamine, a selective serotonin reuptake inhibitor (SSRI) with antidepressant properties, are well established. After oral administration, the drug is almost completely absorbed from the gastrointestinal tract, and the extent of absorption is unaffected by the presence of food. Despite complete absorption, oral bioavailability in man is approximately 50% on account of first-pass hepatic metabolism. Peak plasma fluvoxamine concentrations are reached 4 to 12 hours (enteric-coated tablets) or 2 to 8 hours (capsules, film-coated tablets) after administration. Steady-state plasma concentrations are achieved within 5 to 10 days after initiation of therapy and are 30 to 50% higher than those predicted from single dose data. Fluvoxamine displays nonlinear steady-state pharmacokinetics over the therapeutic dose range, with disproportionally higher plasma concentrations with higher dosages. Plasma fluvoxamine concentrations show no clear relationship with antidepressant response or severity of adverse effects. Fluvoxamine undergoes extensive oxidative metabolism, most probably in the liver. Nine metabolites have been identified, none of which are known to be pharmacologically active. The specific cytochrome P450 (CYP) isoenzymes involved in the metabolism of fluvoxamine are unknown. CYP2D6, which is crucially involved in the metabolism of paroxetine and fluoxetine, appears to play a clinically insignificant role in the metabolism of fluvoxamine. The drug is excreted in the urine, predominantly as metabolites, with only negligible amounts ( < 4%) of the parent compound. Fluvoxamine shows a biphasic pattern of elimination with a mean terminal elimination half-life of 12 to 15 hours after a single oral dose; this is prolonged by 30 to 50% at steady-state. Plasma protein binding of fluvoxamine (77%) is low compared with that of other SSRIs. Fluvoxamine pharmacokinetics are substantially unaltered by increased age or renal impairment. However, its elimination is prolonged in patients with hepatic cirrhosis. Fluvoxamine inhibits oxidative drug metabolising enzymes (particularly CYP1A2, and less potently and much less potently CYP3A4 and CYP2D6, respectively) and has the potential for clinically significant drug interactions. Drugs whose metabolic elimination is impaired by fluvoxamine include tricyclic antidepressants (tertiary, but not secondary, amines), alprazolam, bromazepam, diazepam, theophylline, propranolol, warfarin and, possibly, carbamazepine. Fluvoxamine is a second generation antidepressant that selectively inhibits neuronal reuptake of serotonin (5-hydroxytryptamine; 5-HT). Fluvoxamine exhibits antidepressant activity similar to that of the tricyclic antidepressants, but has a somewhat improved tolerability profile, particularly with respect to a lower incidence of anticholinergic effects and reduced cardiotoxic potential. However, gastrointestinal adverse effects, especially nausea, are seen more frequently with fluvoxamine than with the tricyclic antidepressants. Fluvoxamine does not have an asymmetric carbon in its structure (fig. 1) and therefore does not exist as optical isomers. For this reason, the potentially confounding problem of stereoisomerism does not arise with fluvoxamine.

Determination of fluvoxamine concentration in plasma by reversed-phase liquid chromatography.

Fluvoxamine, a serotonin re-uptake inhibitor, was quantified in plasma by modifying a previously published procedure for monitoring plasma concentrations of tricyclic antidepressants. Alkalinized plasma samples were extracted with n-hexane/isoamyl alcohol, followed by back-extraction with diluted phosphoric acid. The extracts were analysed by reversed-phase liquid chromatography using a C-18 column, with phosphate/acetonitrile as the mobile phase. The assay was linear from 10 to 800 micrograms/L. Precision studies showed within-run and day-to-day coefficients of variation to be 4.5 and 6.8%, respectively. Desipramine interfered with the detection of fluvoxamine. The assay was used to measure a total of 8 plasma samples from 4 alcohol-dependent patients medicated with fluvoxamine as an adjunct to relapse prevention psychotherapy. In these patients, the plasma concentrations ranged from 54 to 241 micrograms/L. Dosage of fluvoxamine, duration of treatment, interval between last dosage and blood collection were associated with effects on plasma concentrations that were consistent with the pharmacokinetic profile of fluvoxamine.

Clinical pharmacokinetics of fluvoxamine.

Fluvoxamine is a selective inhibitor of serotonin reuptake that is widely used in the management of depression. Following oral administration, the drug is absorbed efficiently from the gastrointestinal tract. Peak plasma concentrations are usually observed within 2 to 8 hours postdose for capsules and film-coated tablets and within 4 to 12 hours for enteric-coated tablets. Despite complete absorption, oral bioavailability may be incomplete probably because of first-pass metabolism. Approximately 77% of fluvoxamine is plasma protein bound. Only negligible amounts of fluvoxamine are excreted unchanged in urine. The drug is extensively biotransformed, mostly by oxidation, and at least 11 different metabolites have been detected in human urine. None of the metabolites is known to possess significant pharmacological activity. Following administration of single doses, fluvoxamine shows a biphasic elimination with a mean terminal elimination half-life of about 15 to 20 hours. Steady-state plasma fluvoxamine concentrations are achieved 5 to 10 days after initiation of therapy and are 30 to 50% higher than those predicted from single-dose data. Preliminary data also suggest that plasma drug concentrations may increase nonlinearly with increasing daily dosage. The relationship between plasma fluvoxamine concentration and clinical response has not been clearly defined. Fluvoxamine pharmacokinetics are substantially unaltered in the elderly, whereas higher plasma drug concentrations (relative to dose) are observed in patients with alcoholic cirrhosis of the liver. Fluvoxamine inhibits oxidative drug metabolising enzymes and, therefore, causes a number of clinically significant drug interactions. Drugs whose metabolic elimination is impaired by fluvoxamine include tricyclic antidepressants, alprazolam, bromazepam, diazepam, theophylline, phenazone (antipyrine), propranolol, warfarin, methadone and carbamazepine.

ACP Broadsheet No 138: May 1993. Gross examination of uterine specimens.

A previous study suggested that fluvoxamine inhibition potency toward CYP1A2 is 10 times greater in vivo than in vitro. The present study was designed to determine whether the same gap exists for CYP2C19, another isozyme inhibited by fluvoxamine. In vitro studies examined the effect of nonspecific binding on the determination of inhibition constant (<i>K</i>_i) values of fluvoxamine toward CYP2C19 in human liver microsomes and in a cDNA-expressed microsomal (Supersomes) system using (<i>S</i>)-mephenytoin as a CYP2C19 probe.<i>K</i>_i values based on total added fluvoxamine concentration (<i>K</i>_i,total) and unbound fluvoxamine concentration (<i>K</i>_i,ub) were calculated, and interindividual variability in<i>K</i>_i values was examined in six nonfatty livers. <i>K</i>_i,total values varied with microsomal protein concentration, whereas the corresponding<i>K</i>_i,ub values were within a narrow range (70–80 nM). In vivo inhibition constants (<i>K</i>_iiv) were obtained from a study of the disposition of a single oral dose (100 mg) of the CYP2C19 probe (<i>S</i>)-mephenytoin in 12 healthy volunteers receiving fluvoxamine at 0, 37.5, 62.6, and 87.5 mg/day to steady state. In this population, the ratio of (<i>S</i>)-4-hydroxy-mephenytoin formation clearances (uninhibited/inhibited) was positively correlated with fluvoxamine average steady-state concentration with an intercept of 0.85 (<i>r</i>^<i>2</i> = 0.88,<i>p</i> &lt; 0.001). The mean (±S.D.) values of<i>K</i>_iiv based on total and unbound plasma concentrations were 13.5 ± 5.6 and 1.9 ± 1.1 nM, respectively. Comparison of in vitro and in vivo<i>K</i>_i values, based on unbound fluvoxamine concentrations, suggests that fluvoxamine inhibition potency is roughly 40 times greater in vivo than in vitro.

Spectrophotometric Determination of Fluvoxamine in Tablets Based on Charge-Transfer Complex with Chloranil

Abstract Fluvoxamine was reacted with chloranil in aqueous ethanolic medium buffered at pH 9 to yield a complex with maximum absorption at 347 nm. The estimated molar absorptivity and stability constant of the complex were (1.30 ± 0.03) × 104 L mol−1 cm−1 and (1.7 ± 0.5) × 104 L mol−1 respectively. Absorbance at (δmax) was linearly related to concentration of fluvoaxamine over the range 2 to 25 μg ml−1 with a detection limit of 0.4 μg ml−1. The slopes of log-log plots of initial concentrations of fluvoxamine or chloranil vs. initial rate of color development were both unity. When the reaction was applied to commercial tablets (Faverin ρ −50) labeled to contain 50 mg of fluvoxamine maleate per tablet, the mean percentage found was 100.4 ± 1.0. Recovery experiments after standard additions and analysis of variance (ANOVA) were carried out to investigate the accuracy and precision of the proposed method. Reversed-phase high-performance liquid chromatography, (RP-HPLC), using μ-Bondapak C18 (30 cm × 3.9 mm, i...

Plasma concentrations of fluvoxamine and maprotiline in major depression: implications on therapeutic efficacy and side effects

We examined the relationship between plasma concentrations of specific acting antidepressants (fluvoxamine/maprotiline) and clinical improvement as well as the impact of the magnitude of the plasma concentration of these antidepressants on side effects. Patients (32 patients with major depression) were treated within a double-blind parallel trial for four weeks and plasma concentrations were obtained before, on days 8 and 28 of the trial. Although there was a fixed-flexible dosage design it was apparent that 16 patients (89%) of the fluvoxamine group and all patients of the maprotiline group received a dosage between 200 and 300 mg/day in the last week of the trial. Plasma concentrations (mean ± SD μg/l) of fluvoxamine were 125 ± 91 and 142 ± 108 on days 8 and 28, respectively and the range of fluvoxamine plasma concentrations on day 28 was from 20 to 417 μg/l. Plasma concentrations (mean ± SD μg/l) of maprotiline were 146 ± 62 and 202 ± 134 on days 8 and 28, respectively and the range of maprotiline plasma concentration on day 28 was from 12 to 428 μg/l. There was no linear relationship between plasma concentrations of both antidepressants (fluvoxamine/maprotiline) and oral dosage. Whereas there was no correlation between fluvoxamine concentration and clinical response there was a tendency that higher maprotiline concentrations were associated with a better antidepressive efficacy at the end of the trial. Higher concentrations of fluvoxamine as well as of maprotiline were significantly ( P < 0.05) associated with more side effects.