Identification of human cytochrome P450 enzymes involved in the major metabolic pathway of fluvoxamine

Article abstract of DOI:10.1080/00498250600718464

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 of fluvoxamine 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 μM 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 μM, 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.

Full text of DOI:10.1080/00498250600718464

Xenobiotica, February 2007; 37(2): 169–179
Identification of human cytochrome P450 enzymes
involved in the major metabolic pathway of fluvoxamine
M. MIURA1 & T. OHKUBO2
1Department of Pharmacy, Akita University Hospital, Akita, Japan and 2Clinical Research Center,
Hirosaki University Hospital, Hirosaki, Japan
(Received 22 February 2006; accepted 27 March 2006)
Abstract
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 of fluvoxamine 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 mM 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 mM, 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.
Keywords: Fluvoxamine, cytochrome P450 (CYP) 2D6, fluvoxamino alcohol, fluvoxamino acid, alcohol
dehydrogenase
Introduction
Fluvoxamine (5-methoxy-1-[4-(trifluoromethyl)-phenyl]-1-pentanone-O-(2-aminoethyl)-
oxime) (Figure 1) is a selective serotonin re-uptake inhibitor (SSRI) widely used in
the treatment of major depression and other affective disorders (Benfield and Ward 1986;
Correspondence: T. Ohkubo, Clinical Research Center, Hirosaki University Hospital, 53 Hon-cho, Hirosaki 036-8563, Japan.
Tel: 81-172-33-5295. Fax: 81-172-39-5295. E-mail: ok1231@mail.cc.hirosaki-u.ac.jp
ISSN 0049-8254 print/ISSN 1366-5928 online ꢀ 2007 Informa UK Ltd.
DOI: 10.1080/00498250600718464

170
M. Miura & T. Ohkubo
H C
C
N
O
CH
CH
CH
CH
CH
3
3
2
2
2
2
O
NH
CH
CH
2
2
2
Fluvoxamine
CYP2D6
CH
OH
H C
C
N
CH
CH
2
CH
2
3
2
2
NH
CH
CH
O
2
2
2
Fluvoxamino alcohol
CH
CH
CH
H C
C
N
COOH
2
2
2
3
CH
CH NH
2 2
O
2
Fluvoxamino acid
Figure 1. Metabolism of fluvoxamine to its principal metabolites: fluvoxamino alcohol and
fluvoxamino acid.
Wilde et al. 1993). Fluvoxamine is extensively metabolized in the liver and the major
metabolite present in the urine is fluvoxamino acid (4-carboxy-1-[4-(trifluoromethyl)-
phenyl]-1-butane-O-(2-aminoethyl)-oxime) (Figure 1) (Perucca et al. 1994). Previous
in vivo studies have shown that fluvoxamine is eliminated predominantly by oxidation
through cytochrome P450 (CYP) (Spigset et al. 1995; 1997, 2001, Carrillo et al. 1996;
Hartter et al. 2000; Christensen et al. 2002). Although the identity of the CYP involved in
the oxidation of fluvoxamine is not conclusively known, there is evidence that the CYP2D6
is of major importance. Spigset et al. have reported that the metabolic clearance (Clm) for
fluvoxamino acid was 78% lower in CYP2D6 poor metabolizers (PMs) than in CYP2D6
extensive metabolizers (EMs) after intake of a single oral dose of 50 mg fluvoxamine
(211 ꢀ 143 vs. 969 ꢀ 704 ml min–1, respectively) (Spigset et al. 2001). And Hartter et al.
have reported that the area under concentration–time curve (AUC) of fluvoxamine in
CYP2D6 PM (*4/*6) was higher than in CYP2D6 EM (*1/*1) (612 vs. 150–231 mg h ml–1)
(Hartter et al. 2000). On the other hand, CYP1A2 was also shown to catalyse fluvoxamine
metabolism (Spigset et al. 1999; 2001). Up to now, the enzymes involved in
fluvoxamine metabolism have not yet been fully clarified. The metabolism of fluvoxamine

Fluvoxamine metabolism by CYP2D6
171
to fluvoxamino acid is known to involve a two-step oxidation process via an alcohol
intermediate, fluvoxamino alcohol (Ruijten et al. 1984). The purpose of the current study
was to identify the CYP enzymes involved in formation of the major metabolite of
fluvoxamine, fluvoxamino alcohol, by using human liver microsomes and cDNA-expressed
human CYP enzymes.
Materials and methods
Reagents and chemicals
Fluvoxamine maleate was donated by Meiji Seika Kaisha Ltd (Tokyo, Japan). Fluvoxamino
alcohol and fluvoxamino acid were synthesized in the authors’ laboratory (Ohkubo et al.
2003; Miura and Ohkubo 2006). The chemical purities of fluvoxamine, fluvoxamino acid
and fluvoxamino alcohol were more than 98 (data were provided by Meiji Seika Kaisha), 98
and 97%, respectively (Ohkubo et al. 2003; Miura and Ohkubo, 2006). Moperone was
kindly donated by the Yamanouchi Pharmaceutical (Tokyo, Japan). The Oasis HLB
extraction cartridge was purchased from Waters Co. (Milford, MA, USA). All solvents used
were of high-performance liquid chromatography (HPLC) grade (Wako Pure Chemical
Industries, Osaka, Japan), and all other reagents and chemicals were purchased from Wako
Chemical Industries or Nacalai Tesque (Kyoto, Japan). Furafylline, sulfaphenazole,
quinidine and sodium diethyldithiocarbamate (DDC) were purchased from ULTRAFINE
Chemicals Ltd (Manchester, UK), and ꢀ-naphtflavone, omeprazole, erythromycin and
4-methylpyrazole were purchased from Sigma Chemical Co. (St Louis, MO, USA).
Itraconazole was donated from Yansen Pharmaceutical Co. (Beerse, Belgium). The
cofactors (nicotinamide adenine dinucleotide phosphate [NADP], glucose 6-phosphate
dehydrogenase, and glucose 6-phosphate) were purchased from Sigma. Human liver
microsomes (pooled, HH31, HH35, HH40, HH48, HH54, HH61 HH69, HH86, HH89,
HH91 and HH108), human liver cytosol and human cytochrome P450 (CYP) enzymes plus
reductase microsomes (CYP1A2, 2A6, 2B6, 2C9*1, 2C19, 2D6*1, 3A4 and 2E1) were
purchased from GENTEST Corporation (Woburn, MA, USA). These microsomal
preparations were prepared from the human B-lymphoblastoid cell line. The data for
bufuralol 10-hydroxylase activities (pmol min–1 mg–1 protein) in individual human liver
microsomes were provided by GENTEST.
Analytical procedures
The concentrations of fluvoxamine and its metabolites were measured by the reverse-phase
HPLC method (Miura and Ohkubo 2006). The apparatus consisted of a Waters HPLC
system equipped with a model 510 chromatography pump (Waters) and a Waters 486
ultraviolet detector. The wavelength was set at 254 nm. Test samples were introduced using
a Waters 712 WISP autosampler with an effective volume of 50 ml. The HPLC column used
was a Grand-pak C4-5 (150 ꢁ 4.6 mm i.d.; Owani, Aomori, Japan); the mobile phase, which
consisted of 0.5% KH2PO4 (pH 2.5)–acetonitrile (75:25, v/v), was degassed in an ultrasonic
bath before use. Before mixing with acetonitrile, the pH of the 0.5% KH2PO4 was adjusted
with 50% phosphoric acid, and it was degassed ultrasonically. A flow rate of 1.0 ml min–1
was used at an ambient temperature of 27ꢂC. The lower limits of quantification of this assay
for fluvoxamino alcohol and fluvoxamino acid were 82.2 and 78.6 nM, respectively.

172
M. Miura & T. Ohkubo
The mean recoveries of these compounds were more than 92.8%, with a coefficient of
variation less than 5.8%.
Microsomal and expressed CYP incubation conditions
Incubations were carried out in duplicate with the reconstituted human liver microsomes
in 5-ml test tubes, on three separate occasions (n ¼ 3), using a shaking water bath at 37ꢂC.
A typical incubation mixture consisted of a cofactor solution (100 ml), microsomal
preparation (50 ml, 0.5 mg of microsomal protein), and substrate (5 ml, 0–346 mM) in a
total volume of 0.2 ml. The cofactor solution consisted of NADPþ (1.3 mM), glucose
6-phosphate (3.3 mM), glucose 6-phosphate dehydrogenase (0.4 units) and magnesium
chloride (3.3 mM) in sodium phosphate buffer (0.1 M, pH 7.4). The metabolic reaction was
initiated by the addition of the cofactor solution and terminated by immersing in an ice bath
and the addition of 1.0 ml of 1.0 M sodium chloride. Before the extraction, moperone
(50 ng) in methanol (10 ml) was added as an internal standard to the incubation mixture. The
reactions with pooled human liver microsomes were carried out for 30 min. Microsomal
enzyme was inactivated by heat treatment in control incubations. On the other hand,
the reactions with CYP enzymes expressed in a cell line were carried out for 60 min.
Controls for human CYP enzymes were expressed in a cell line containing control
microsomes (i.e. a cell line transfected with a control vector).
Inhibition studies
Eight different relatively selective inhibitors were used in order to define the role of
individual CYP enzymes involved in fluvoxamine metabolism. The CYP inhibitors used
were ꢀ-naphtflavone (50 mM) and furafylline (50 mM) for CYP1A2, sulfaphenazole (50 mM)
for CYP2C9, omeprazole (50 mM) for CYP2C19, quinidine (5.0 mM) for CYP2D6, DDC
(50 mM) for CYP2A6 and CYP2E1, and itraconazole (10 mM) and erythromycin (50 mM)
for CYP3A4. The inhibitors were pre-incubated with human liver microsomes and the
ꢁ-nicotinamide adenine dinucleotide phosphate (NADPH)-generating system for 5 min at
37ꢂC under the same conditions described above before the reaction was started by addition
of fluvoxamine, which was at a fixed concentration of 11.5 mM. Furthermore, inhibition of
fluvoxamino alcohol formation was studied with three concentrations of quinidine (1.0, 5.0
and 10 mM) using a varying concentration of fluvoxamine. After incubation for 30 min
at 37ꢂC, reactions were terminated as described above.
Cytosol incubation conditions
Fluvoxamino alcohol was incubated with human liver cytosol (50 ml, 1.0 mg protein) in
sodium phosphate buffer (0.1 M, pH 7.4) containing NAD (7.5 mM). Incubations were
carried out in duplicate in 5-ml test tubes, on three separate occasions (n ¼ 3), using
a shaking water bath for 30 min at 37ꢂC. 4-Methylpyrazole (10, 50, 100 250 and 1000 mM)
was pre-incubated with human liver cytosol and NAD for 5 min at 37ꢂC before the reaction
was started by addition of fluvoxamino alcohol (8.2 mM). After incubation for 30 min
at 37ꢂC, reactions were terminated as described above.

Fluvoxamine metabolism by CYP2D6
173
Metabolite extraction method
Each mixture was applied to an Oasis HLB extraction cartridge that had been previously
activated with methanol and water (1.0 ml of each) (Miura and Ohkubo 2006). The
cartridge was then washed with 40% methanol in water (1.0 ml), and then eluted with 100%
methanol (1.0 ml). The eluate was evaporated to dryness in vacuum at 60ꢂC by a rotary
evaporator (Iwaki, Tokyo, Japan). The residue was dissolved in 50 ml of methanol and 50 ml
of mobile phase, and each aliquot (50 ml) of the solution was injected into the HPLC
apparatus.
Data analysis
The kinetics of the fluvoxamine biotransformation by human liver microsomes and cDNA-
expressed CYP enzymes were described by the Michaelis–Menten equation for a
one-enzyme system using a non-linear least-squares regression program, MULTI
(Yamaoka et al. 1981), and apparent Km, Vmax and enzyme inhibition constant (Ki)
values were estimated. Correlations of metabolite formation velocities with enzyme activities
were calculated using Stat View software, version 5.0 (SAS Institute, Cary, NC, USA).
Results
The kinetics for the formation of fluvoxamino alcohol from fluvoxamine by human liver
microsomes were consistent with the Michaelis–Menten model (Figure 2A) and the Eadie–
Hofstee plot for the formation of fluvoxamino alcohol from fluvoxamine is shown in
Figure 2B. The Km and Vmax values for the formation of fluvoxamino alcohol by pooled
human liver microsomes were 76.3 ꢀ 5.4 mM and 37.5 ꢀ 2.1 pmol min–1 mg protein–1,
respectively. Consequently, the intrinsic clearance (Vmax/Km) value for fluvoxamino alcohol
was 0.49 ꢀ 0.06 ml min–1 mg protein–1.
The effects of specific CYP inhibitors on the formation of fluvoxamino alcohol in human
liver microsomes are shown in Table I. ꢀ-Naphtflavone (50 mM, CYP1A2 inhibitor),
furafylline (50 mM, CYP1A2 inhibitor), sulfaphenazole (50 mM, CYP2C9 inhibitor),
40
35
30
25
20
15
10
5
40
35
30
25
20
15
10
5
(A)
(B)
0
0
0
50 100 150 200 250 300
350
0
0.1
0.2
0.3
0.4
Fluvoxamine (mM)
Velocity/fluvoxamine
Figure 2. (A) Velocity vs. substrate concentration plots for fluvoxamino alcohol formation from
fluvoxamine by human liver microsomes. (B) Eadie–Hofstee plots for velocity vs. the velocity/
concentration of fluvoxamine in the same liver sample. Symbols are experimental data points
representing an average of triplicate incubations.

174
M. Miura & T. Ohkubo
Table I. Effects of various CYP inhibitors on the formation of fluvoxamino alcohol from fluvoxamine in human
liver microsomes.
Inhibitor
mM
CYP targeted
Activity (% of control)
None
–
–
100.0
39.9
84.2
99.9
110.7
107
SKF-525A
Cimitidine
ꢀ-Naphtflavone
Furafyline
50
50
50
50
50
50
50
5
Non-specific
Non-specific
CYP1A2
CYP1A2
CYP2C9
CYP2C19
CYP2E1
CYP2D6
CYP3A4
CYP3A4
Sulphaphenazole
Omeprazole
DDC
97.4
97.4
44.5
97.1
104.4
Quinidine
Itraconazole
Erythromycin
10
50
Incubations were carried out at a fluvoxamine concentration of 11.5 mM. Results are the mean values obtained from
three incubations.
2.5
2
1.5
1
Control
Quinidine (10mM)
0.5
Quinidine (5mM)
Quinidine (1mM)
0
0
0.1
0.2
0.3
−0.1
0.4
1/fluvoxamine (mM−1
)
Figure 3. Inhibitory effect of quinidine on fluvoxamino alcohol formation in human liver microsomes.
Lineweaver–Burk plots were obtained from a 30-min incubation of fluvoxamine with 0 (œ), 1 (m), 5
(ꢂ) and 10 (.) mM quinidine after a 5-min pre-incubation in human liver microsomes. Data are an
average of triplicate experiments.
omeprazole (50 mM, CYP2C19 inhibitor), DDC (50 mM, CYP2A6 and CYP2E1 inhibitor),
itraconazole (10 mM, CYP3A4 inhibitor) and erythromycin (50 mM, CYP3A4 inhibitor) did
not have any effect on the formation of the alcohol metabolite at a concentration of 11.5 mM
of fluvoxamine. However, quinidine (5 mM, CYP2D6 inhibitor) inhibited the formation of
fluvoxamino alcohol to 44.5% of the control activity. In addition, quinidine showed dose-
dependent inhibition of the metabolism of fluvoxamine (Figure 3). The Ki value of quinidine
for fluvoxamino alcohol formation in human liver microsomes was 2.2 mM.

Fluvoxamine metabolism by CYP2D6
175
0.12
0.1
0.08
0.06
0.04
0.02
0
N.D.
1A2
N.D.
2A6
N.D.
2B6
N.D.
2C9
N.D.
N.D.
2E1
N.D.
3A4
2C19
2D6
CYPs
Figure 4. Fluvoxamino alcohol formation from fluvoxamine by expressed human CYP enzymes.
Incubations with cDNA-expressed human CYP enzymes were carried out at a substrate concentration
of 11.5 mM of fluvoxamine. Data are means ꢀ standard deviation obtained from three experiments.
Furthermore, to confirm the findings from the inhibition study, the catalytic activities of
individual human CYP enzymes expressed in a cell line were examined. As shown in
Figure 4, only recombinant CYP2D6*1 exhibited a markedly high activity toward the
formation of alcohol metabolite, indicating that CYP2D6 had a high substrate specificity for
fluvoxamine, whereas other CYPs (1A2, 2A6, 2B6, 2C9, 2C19, 2E1 and 3A4) were not
involved (at a fluvoxamine concentration of 11.5 mM). The formation of fluvoxamino
alcohol by recombinant CYP2D6 followed one-enzyme Michaelis–Menten kinetics. The
estimated Km and Vmax values for the formation of fluvoxamino alcohol by recombinant
CYP2D6*1 were 73.2 ꢀ 0.4 mM and 0.69 ꢀ 0.08 pmol min–1 pmol–1 CYP, respectively.
The correlations between the formation rates of fluvoxamino alcohol from fluvoxamine
and the activity of CYP2D6 measured by bufuralol, which are marker probes for CYP2D6,
are shown in Figure 5. As shown, CYP2D6 activities were highly correlated with the
biotransformation of fluvoxamino alcohol from fluvoxamine (r ¼ 0.985, p < 0.0001, n ¼ 11).
The biotransformation to fluvoxamino acid from fluvoxamino alcohol was not observed
by pooled human liver microsomes and individual human CYP enzymes expressed in a cell
line (CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 or 3A4) (data not shown). However, the
oxidation of fluvoxamino alcohol in human liver cytosol was inhibited by 4-methylpyrazole,
which is an inhibitor of alcohol dehydrogenase, in a concentration-dependent manner over
the range 10–1000 mM (Figure 6).
Discussion
Fluvoxamine is mainly metabolized in human to fluvoxamino acid via fluvoxamino alcohol
by oxidative demethylation of the aliphatic methoxy group (65%), whereas lesser
metabolism proceeds at the primary amino group (15%) and by removal of the ethanolamine

176
M. Miura & T. Ohkubo
25
20
15
10
5
0
0
50
100
150
200
Bufuranol1′-hydroxylase activity
−1
−1
(pmolmin mg protein
)
Figure 5. Correlation between the fluvoxamino alcohol formation from fluvoxamine and the bufuralol
10-hydroxylase activity in individual human liver microsomes. Incubations with individual human liver
microsomes were carried out at a substrate concentration of 11.5 mM of fluvoxamine. Symbols are
experimental data points representing an average of triplicate incubations. The data of bufuralol
10-hydroxylase activities (pmol min–1 mg–1 protein) in individual human liver microsomes are provided
by GENTEST.
100
75
50
25
0
0
250
500
750
1000
4-Methylpyrazole concentration (mM)
Figure 6. Inhibition of fluvoxamino alcohol formation in human liver cytosol using 4-methylpyrazole.
Assays were performed at pH 7.4, 37ꢂC with a fluvoxamino alcohol concentration of 8.2 mM and
4-methylpyrazole concentrations of 0–1000 mM. Each point represents the mean of triplicate
experiments.

Fluvoxamine metabolism by CYP2D6
177
group (10%) (Ruijten et al. 1984; Perucca et al. 1994). The purpose of the current study was
to identify the CYP enzymes involved in the major metabolic pathway to fluvoxamino
alcohol from fluvoxamine and our present in vitro data demonstrate that CYP2D6 catalyses
the metabolism of fluvoxamine to fluvoxamino alcohol.
CYP2D6 polymorphisms have been extensively studied at both the phenotype and
genotype levels. Studies have shown that although there is a difference in enzyme activity
between CYP2D6 PMs and EMs, there is also variation in enzyme activity among patients
with CYP2D6 EMs (Droll et al. 1998). Due to the polymorphism of the CYP2D6 gene,
CYP2D6 activity varies markedly between individuals with *1, *2, *10 and *17 alleles
(Nakamura et al. 2002; Yu et al. 2002; Zanger et al. 2004). The biotransformation to
fluvoxamino alcohol from fluvoxamine was correlated to CYP2D6 activity. Therefore,
CYP2D6 PMs or individuals with a low activity of CYP2D6 should have a high plasma
concentration of fluvoxamine, thereby resulting in an enhancement of the in vivo inhibitory
effect on CYP1A2 and CYP2C19 for fluvoxamine (Sperber et al. 1991, Spina et al. 1993;
Donaldsson et al. 1994; Jeppesen et al. 1996a; b, Sproule et al. 1997).
In the present study, CYP1A2 was not involved in the formation of fluvoxamino alcohol.
Spigset et al. reported that the oral clearance (Cl/F) of fluvoxamine in CYP2D6 EMs was
significantly higher in smokers than in non-smokers (4111 vs. 3452 ml min–1, respectively,
p ¼ 0.017), whereas there was no significant difference in the metabolic clearance (Clm) to
fluvoxamino acid formation between these two groups (1056 vs. 969 ml min–1, respectively)
(Spigset et al. 1997; 2001). These latter results support our in vitro finding that CYP1A2,
which is induced by cigarette smoking, is not involved in fluvoxamino acid formation.
Furthermore, Carrillo et al. reported that there were no significant differences between the
mean AUC values of CYP2D6 EMs and PMs in smokers (1239 vs. 1539 nmol h l–1);
however, in non-smokers, AUC values of CYP2D6 PMs were significantly higher than those
of CYP2D6 EMs (Carrillo et al. 1996). These data together strongly suggest that CYP1A2 is
a minor enzyme involved in the metabolic pathway of fluvoxamine in humans. It is
conceivable that CYP1A2 contributes to other minor metabolic pathways of fluvoxamine.
Generally, the metabolism of primary alcohols to carboxylic acids is most commonly
mediated by cytosolic alcohol dehydrogenase or microsomal CYP (Mori et al. 1989;
Aasmore et al. 1998). In the present study, the formation of fluvoxamino acid from
fluvoxamino alcohol depends on alcohol dehydrogenase not CYP. Therefore, fluvoxamine
is first metabolized by CYP2D6 to the alcohol metabolite and is further completely
metabolized by a cytosolic alcohol dehydrogenase to the corresponding carboxylic acid.
In conclusion, the present in vitro studies indicate that only CYP2D6 catalyses the major
metabolic pathway of fluvoxamine. Therefore, whenever prescribing fluvoxamine, the effects
of CYP2D6 genotype on the pharmacological activities and CYP inhibitory effects of
fluvoxamine must be carefully taken into consideration.
Acknowledgements
This work was supported by a grant (No. 17923061) from the Japan Society for the
Promotion of Science, Tokyo, Japan.
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