High-Performance Liquid Chromatographic Determination of Fluvoxamine and Fluvoxamino Acid in Human Plasma

Abstract

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...

Electroanalytical study of fluvoxamine

“…Most FVX analysis is performed by high-perfor-mance liquid chromatography (HPLC) coupled with spectrometric detectors, ultraviolet/diode array [4][5][6][7][8][9][10][11][12][13][14][15][16][17], mass spectrometric [18,19] and fluorimetric [20][21][22], for analysis of pharmaceuticals [8] and human serum or plasma [4][5][6][7][10][11][12][13][14][15][16][17][18][19][20][21][22]. This widespread usage of HPLC methods is justified by the high sensitivity and the low limit of detection usually obtained and the possibility of simultaneous analysis of the drug and its metabolites, which increases its use even further.…”

Bcl1 Polymorphism of the Glucocorticoid Receptor Gene and Treatment Response to Milnacipran and Fluvoxamine in Japanese Patients with Depression

“…The present study analyzed the data from previous prospective pharmacogenetic [17,18,19,20] and pharmacokinetic [21,22] studies that had been reported individually. For the present study, subjects treated with fluvoxamine were added to those in our previous studies.…”

“…The GR Bcl1 polymorphism was determined by PCR restriction fragment length polymorphism as previously reported [22]. Samples (20 μl) were of a PCR mixture containing 100 ng of genomic DNA template, 1.5 m M MgCl 2 , each 0.5 μmol of forward primer (5′-TGC TGC CTT ATT TGT AAA TTC GE-3′) and reverse primer (5′-AAG CTT AAC AAT TTT GGC CAT C-3′), 200 μ M of dNTP mixture and 1.25 units of HotStar Taq DNA polymerase (Qiagen, Tokyo, Japan).…”

“…Details of the method have been described previously [21,22]. Genotyping and measurement of plasma concentrations were performed by laboratory personnel blinded to the subjects and their clinical scores.…”

Automated analysis of fluvoxamine in rat plasma using a column‐switching system and ion‐pair high‐performance liquid chromatography

“…The usual dose of FLV ranges from 50 to 300 mg per day, and the steady-state plasma concentration is correlated with the therapeutic outcome (Wilde et al, 1993;Kent et al, 2000). FLV is absorbed well following oral administration, with the plasma concentration peaking after 2-8 h; it is extensively bound to plasma proteins (77%) and has a wide intersubject variability in its elimination half-life (Katzung, 2001;Ohkubo et al, 2003).…”