DRUG DISPOSITION

Clin. Phannacokinet. 26 (3): 201-214,1994

0312-5963/94/0003-02011$07.00/0
Adis International Limited. All rights reserved.

Clinical Pharmacokinetics of Fluoxetine

Alfredo C. Altamura, 1 Anna R. Moro 2 and Mauro Percudani3
I Department of Psychiatry, University of Cagliari, Cagliari, Italy
2 Department of Psychiatry, University of Milan, Milan, Italy
3 Department of Psychiatry, General Hospital of Magenta, Milan, Italy

Contents
201 Summary
202 1. Analytical Methods
203 2. Absorption and Bioavailability
204 3. Distribution
204 3.1 Distribution in the Brain
204 4. Metabolism and Elimination
205 5. Nonlinear Pharmacokinetic Profile
205 5.1 Polymorphic Metabolism
207 6. Pharmacokinetics in Special Populations
207 6.1 Elderly Patients
207 6.2 Patients with Renal Impairment
207 6.3 Patients with Hepatic Dysfunction
208 6.4 Obese Patients
208 7. Concentration-Response Studies
209 8. Drug Interactions
2// 9. Conclusions

Summary Fluoxetine is well absorbed after oral intake, is highly protein bound, and has a large volume
of distribution. The elimination half-life of fluoxetine is about I to 4 days, while that of its
metabolite norfluoxetine ranges from 7 to 15 days.
Fluoxetine has a nonlinear pharmacokinetic profile. Therefore, the drug should be used with
caution in patients with a reduced metabolic capability (i.e. hepatic dysfunction).
In contrast with its effect on the pharmacokinetics of other antidepressants, age does not affect
fluoxetine pharmacokinetics. This finding together with the better tolerability profile of fluoxetine
(compared with tricyclic antidepressants) makes this drug particularly suitable for use in elderly
patients with depression. Furthermore, the pharmacokinetics of fluoxetine are not affected by
either obesity or renal impairment.
On the basis of results of plasma concentration-clinical response relationship studies, there
appears to be a therapeutic window for fluoxetine. Concentrations of fluoxetine plus norfluoxetine
above 500 Ilg/L appear to be associated with a poorer clinical response than lower concentrations.
Fluoxetine interacts with some other drugs. Concomitant administration of fluoxetine in-
creased the blood concentrations of anti psychotics or antidepressants. The interactions between
fluoxetine and lithium, tryptophan and monoamine oxidase inhibitors, in particular, are potentially
serious, and can lead to the 'serotonergic syndrome' . This is because of synergistic pharmacody-
namic effects and the influence of fluoxetine on the bioavailability of these compounds.
202
The selective serotonin (5-hydroxytryptamine;
5-HT) reuptake inhibitors (SSRIs) are a relatively
novel class of compounds with antidepressant
properties. They are structurally heterogeneous,
but share similar actions on 5-HT brain pathways,
because they increase the availability of this neu-
rotransmitter at cerebral receptor sites. Fluoxetine
is a bicyclic derivative of phenylpropylamine. It is
the most widely used SSRI, and is prescribed for a
variety of psychopathological conditions including
mood and eating disorders, obsessive-compulsive
disorders, depression in the elderly and dysthymia
(Altamura & Mauri 1991; Altamura et al. 1989;
Benfield et al. 1986; Rosenthal et al. 1992). Other
SSRIs include paroxetine, sertraline, fluvoxamine
and citalopram. For an overview of the pharmaco-
kinetics of these agents readers are referred to a
review recently published in the Journal (van
Harten 1993).
Down regulation of 5-HT, receptors is the most
commonly reported central nervous system (CNS)
effect of subchronic exposure (i.e. for at least 10
days) of intact animal models to fluoxetine. The
5-HT, receptors were evaluated in 15 experiments.
It was found that the number of receptors was re-
duced, without a change in receptor affinity for its
ligand (reviewed by Beasley et al. 1992).
More controversial is the activity of fluoxet-
ine on 5-HT2 receptors. In fact, down regulation,
up regulation and no effect on receptors have all
been reported (Baron 1988; Dumbrille-Ross &
Tang 1983; Wamsley et al. 1987). Fluoxetine
seems to facilitate serotonergic transmission via
down regulation of presynaptic inhibitory au-
toreceptors (Beasley et al. 1992), with no effect
on muscarinic receptors and doubtful effects on
~-adrenergic receptors (Byerley et al. 1988). Ini-
tially, it was suggested that the effective dose of
fluoxetine was at least 80 mg/day, but more re-
cently a dosage of 20 mg/day has been shown to
have a better benefit-to-risk ratio (Altamura et al.
1988). Indeed, in the elderly, we have found ad-
ministration of fluoxetine 20mg 3 times weekly
to be clinically effective.
The pharmacokinetic profile offluoxetine is dif-
Clin. Pharmacokinet. 26 (3) 1994
ferent from that of other drugs of its class. For ex-
ample, it has a longer half-life, active metabolites
and non-linear pharmacokinetics. Knowledge of
the differences allows improved clinical manage-
ment during administration of fluoxetine. More-
over, fluoxetine plasma concentration-effect data
seem useful in the rationalisation of therapy in de-
pressed patients (Altamura & Montgomery 1990).
This article reviews the pharmacokinetic profile
of fluoxetine, emphasising the relevance of phar-
macokinetics to the appropriate clinical use of the
drug.
1. Analytical Methods
High performance liquid chromatography
(HPLC) with ultraviolet or fluorescence detection
and gas chromatography with electron capture
(GC-EC) detection are most commonly used to de-
termine serum concentrations of fluoxetine and its
metabolites (Kelly et al. 1989; Nichols et al. 1992;
Orsulak et al. 1988; Suckow et al. 1992b). Flame
ionisation or nitrogen selective detection (Roeth-
ger 1990; Rohrig & Prouty 1989) have also been
used, but these methods are helpful only when
fluoxetine is present at potentially toxic concentra-
tions.
A simple HPLC procedure allows fluoxetine or
norfluoxetine (formed by N-demethylation) 20
flglL to be detected in a sample of only O.5ml (data
on file, Eli Lilly). This procedure is, therefore, par-
ticularly suitable for clinical application. Suckow
et al. (1992b) determined the plasma concentration
of fluoxetine and norfluoxetine using HPLC with
fluorescence detection. The highly fluorescent de-
rivatives were separated in a reversed-phase C18
column with a mobile phase of phosphate buffer
and acetonitrile. Dansylated fluoxetine, nor-
fluoxetine and internal standard were eluted in less
than 14 minutes, and there was no interference
from endogenous material. Assay variability was
confirmed via comparison of these results with
those obtained by the use of a liquid chromato-
graphic method with ultraviolet detection for sam-
ples from 110 patients (r = 0.993 for fluoxetine, r
= 0.957 for norfluoxetine). Furthermore, the iden-
Pharmacokinetics of Fluoxetine
tity of the dansylated derivatives was verified by
positive chemical ionisation mass spectroscopy.
The lower limit of detection was about 3 JlglL. No
major antidepressant, or antipsychotic drug, or me-
tabolite of these drugs, interfered with the quanti-
fication of plasma fluoxetine and norfluoxetine
concentrations.
Determination of fluoxetine and norfluoxetine
using GC-EC was originally described by Nash et
al. (1982). However, a more rapid, selective and
sensitive method, using a solid-phase extraction
column, has since been described (Dixit et al.
1991). Linear quantitative response curves for
fluoxetine and norfluoxetine were generated over
a concentration range of 20 to 200 JlglL. However,
HPLC remains the most widely used analytical
method and, in our opinion, it appears to allow
more selective and sensitive determination of
fluoxetine and its metabolite.
2. Absorption and Bioavailability
Fluoxetine is well absorbed from the gastroin-
testinal tract after oral administration, and its bio-
availability is not affected by the presence of food
(Bergstrom et al. 1984). Absolute bioavailability of
oral fluoxetine in dogs is about 72% of the intrave-
nous dose (Bergstrom et al. 1986b).
Following the oral administration of
[14C]fluoxetine to humans, the plasma concentra-
tions of fluoxetine, its N-demethylated metabolite
(norfluoxetine), and total radioactivity were maxi-
mal within 4 to 8 hours postdose, and then declined
over a long period (Bergstrom et al. 1988). In a
metabolism study undertaken at steady-state, a
50/50 mixture of unlabelled fluoxetine and deute-
rium-labelled fluoxetine (fluoxetine with 5 of the
hydrogens replaced by deuterium) was given to
volunteers at a dosage of 60mg daily over a period
of 45 days (Farid et al. 1986). Steady-state plasma
fluoxetine concentrations were achieved by about
day 30. On the following day (day 31), a
e
radiolabelled dose of 4C]fluoxetine was adminis-
tered to the volunteers, and the disposition and me-
tabolism of this radiolabelled dose was deter-
mined. Approximately 75% of the administered
203
14C-radioactivity was excreted in the urine over a
subsequent 3D-day period, and 10% of the dose
was recovered in the faeces over a 20-day period.
Extrapolation of the excretion profile in urine and
faeces to infinite time indicated that approximately
80% of the radioactivity was excreted in urine and
15% of the dose was excreted in faeces. Thus, mass
balance accounted for a total excretion of about
95% of the administered 14C-dose.
The pharmacokinetic profile of fluoxetine after
administration of a single oral dose has been estab-
lished (table I). After a single dose, peak plasma
fluoxetine concentrations (Cmax) in humans oc-
curred between 6 and 8 hours postdose, regardless
of whether the drug was administered as a capsule
or as a solution (Lemberger et al. 1985). Maximal
CNS efficacy, assessed by electroencephalogram
monitoring, occurred between 8 and 10 hours
postdose. The time lag between Cmax and maximal
pharmacodynamic effects may be due, in part, to a
delay in the formation of the active metabolite
(Saletu & Grunberger 1985).
The mean time taken to achieve Cmax values
(tmax) was delayed by 3 to 5 hours when fluoxet-
ine was administered with food. However, the
extent of absorption and the Cmax values were
virtually unchanged by food (Lemberger et al.
1985).
Over an oral dose range of 20 to 80mg, Cmax
values were dose-proportional (Lemberger et al.
1985). However, because fluoxetine (in common
with other SSRIs) undergoes extensive first-pass
metabolism in the liver, marked interindividual
Table I. Pharmacokinetic parameters of fluoxetine after adminis-
tration of a Single oral dose of 30 or 40mg to healthy volunteers
Peak plasma concentration (Cma~ [Ilg/Lj 15-55a
lime to achieve Cmax (h) 6-8a
Volume of distribution (Ukg) 12-43b
Elimination half-life (days) 1-4b
Clearance (Uh) 36-50c
Protein binding (%) 94a
a Aronoff et al. (1984).
b Lemberger et al. (1985).
c Data on file, Eli Lilly.
204 Clin. Pharmacokinet. 26 (3) 1994

5000 060 mg/day fluoxetine 60mg was administered to both (data on

.80 mg/day
... 100 mg/day
~4000
Cl
2-
c
~ 3000
"E 0
CD
2000
t.l
0
0
C
~
0
1000
0 tients with obsessive-compulsive disorder and 3
300 600 900 1200
Plasma concentration (I-lg/L)
Fig. 1. Plasma versus brain fluoxetine plus norfluoxetine concen-
trations in 8 patients who received different dosages of fluoxetine
(from Renshaw et aI. 1992, with pennission).
differences in Cmax values are apparent after stand-
ard daily dosages. For example, a 3- to 4-fold in-
terindividual variation in Cmax (15 to 55 ~glL) was
observed after administration of a single dose of
fluoxetine 40mg to 25 healthy volunteers [Aronoff
et al. 1984].
During long term administration steady-state
plasma fluoxetine concentrations were achieved
within 2 to 4 weeks (Bergstrom et al. 1986a). Fur-
thermore, no accumulation occurred after adminis-
tration of the drug for up to 3 years.
3. Distribution
Fluoxetine and norfluoxetine each have a vol-
ume of distribution (Vd) of 20 to 42 L/kg. This
large Vd is the result of high plasma protein bind-
ing (>95%) and extensive tissue distribution. The
ratio of fluoxetine to norfluoxetine concentrations
were similar in the cerebral cortex, striatum, hip-
pocampus, hypothalamus, brain stem and cerebel-
lum of rat brains I hour after a single dose (re-
viewed in Benfield et al. 1986).
Long term administration of fluoxetine to rats
and dogs led to highest concentrations of the drug
in the lungs (rats) and liver (dogs) [reviewed in
Benfield et al. 1986]. Moreover, in humans, plasma
concentrations of fluoxetine and norfluoxetine
were similar in obese and lean individuals when
file, Eli Lilly). Therefore, it would appear that the
...
drug distributes to a small degree only in adipose
tissue, as suggested by the findings in obese pa-
tients .
3.1 Distribution in the Brain
In vivo, 19f1uorine nuclear magnetic resonance
spectroscopy was used to measure the brain con-
centration of fluoxetine and norfluoxetine in 5 pa-
1500
patients with major depression (Renshaw et al.
1992). All patients had been taking fluoxetine 60
to 100 mg/day for a minimum of 3 months (mean
of 13 6 months). No patient had their dosage
changed in the 4 weeks prior to initiation of the
study. Fluoxetine and norfluoxetine brain concen-
trations were significantly higher (2.6 times) than
their corresponding plasma concentrations. The
daily dosage correlated with calculated brain con-
centrations more closely than did plasma concen-
tration (fig. 1). However, the poor correlation be-
tween plasma and brain concentrations (r = 0.58,
d.f =7) was disproportionately affected by values
obtained from 1 of the 8 patients whose brain con-
centration offluoxetine plus norfluoxetine was 4.9
times higher than the corresponding plasma con-
centration. When data from this patient were ex-
cluded from the analysis, the correlation coeffi-
cient between plasma and brain concentrations
improved (r = 0.82; d.f = 7). Although there were
some limitations to this study (e.g. inactive fluo-
rine-containing metabolites of fluoxetine would
have been detected by this technique), these results
were consistent with data derived from animal ex-
periments.
4. Metabolism and Elimination
The main metabolite offluoxetine is norfluoxet-
ine. Norfluoxetine has similar potency and selec-
tivity of 5-HT uptake inhibition compared with the
parent compound (Fuller & Wong 1987). There-
fore, knowledge of its pharmacokinetic profile is
relevant because the metabolite can influence the
clinical efficacy of fluoxetine.
Phannacokinetics of Fluoxetine
The urinary elimination of metabolites of
fluoxetine has been studied under steady-state con-
ditions in normal volunteers. In one study, volun-
teers received a single oral 60mg dose of 14C_
labelled drug on the thirty-ninth day of
administration of 60 mg/day for 45 days (Farid et
al. 1986). Approximately 75% ofthe 14C-radioac-
tivity was excreted in the urine during the 30 days
postdose, and 10% was recovered in the faeces dur-
ing the 20 days postdose. By extrapolation of the
excretion profile to infinite time, it was shown that
approximately 80% of the administered dose
would be eliminated in the urine and 15% of the
dose in the faeces (see section 2). Moreover, stud-
ies have revealed that about 11 % of the adminis-
tered dose was excreted as fluoxetine, 7% was ex-
creted as norfluoxetine, and 7 and 8% were
fluoxetine and norfluoxetine glucuronides, respec-
tively. Finally, more than 20% of the radioactivity
was excreted in urine as hippuric acid, a glycine
conjugate of benzoic acid (Bergstrom et al. 1988).
After administration of a single 30mg oral
dose of radiolabelled fluoxetine to 3 volunteers,
60% of the dose was recovered in urine and 16%
of the dose was recovered in the faeces after 35
and 28 days postdose, respectively. Only 2 to 5%
of the drug excreted in the urine was unchanged,
suggesting that fluoxetine undergoes extensive
hepatic metabolism (Lemberger et al. 1985). A
proposed schema for fluoxetine metabolism is
shown in figure 2.
Fluoxetine has an elimination half-life (tI/zp) of
about 1 to 4 days, whereas the t1/zp of norfluoxetine
ranged from 7 to 15 days. Steady-state plasma con-
centrations of both fluoxetine and its major meta-
bolite were achieved within about 4 weeks when
fluoxetine was administered daily. Some accumu-
lation of the drug appears to occur in the first 4
weeks of therapy before steady-state concentra-
tions are achieved, e.g. areas under the plasma con-
centration-time curve (AUC) were larger after
multiple-dose administration than those observed
after single-dose administration of the same dose
(data on file, Eli Lilly). This seems to be due to
changes in tYzP (1.9 vs 5.7 days) and clearance (CL)
205
[35.5 vs 10.8 LIb] after administration of a single dose
compared with multiple doses (Bergstrom et al.
1985). However, after achievement of steady-state no
further accumulation occurs (see section 2).
5. Nonlinear Pharmacokinetic Profile
The pharmacokinetics of fluoxetine was shown
to be non-linear in both healthy volunteers and pa-
tients with depression. Higher dosages of fluox-
etine resulted in disproportionately higher plasma
concentrations (Bergstrom et al. 1986a; Sommi et
al. 1987). A comparison of single-dose versus
steady-state pharmacokinetics in men (Bergstrom
et al. 1985) showed that the tYzP was longer (5.7 vs
1.9 days) and CL was lower (10.8 vs 35.5 Lib) after
multiple-dose administration than after single-
dose administration. This change in pharmacoki-
netics leads to a larger AUC at steady-state than is
observed after a single dose. The non-linear nature
of the pharmacokinetics of fluoxetine was also
shown in a steady-state study in patients with de-
pression (Bergstrom et al. 1986b). Steady-state
concentrations of fluoxetine and norfluoxetine in
these depressed patients, who had been treated
with fluoxetine for more than 1 year, were similar
to the steady-state concentrations observed in vol-
unteers and patients who had been given fluoxetine
for 4 to 6 weeks. Therefore, it would appear that
steady-state concentrations do not change follow-
ing prolonged administration. Data obtained after
4 to 6 weeks' treatment with 20 to 80 mg/day in
patients with depression showed no clinically im-
portant differences, when male and female de-
pressed patients were compared, or when these
data were further stratified according to age
(Bergstrom et al. 1986b).
5.1 Polymorphic Metabolism
Debrisoquine and sparteine or dextro-
methorphan oxidation polymorphism has been
used to assess interindividual variability in drug
metabolism (Sjoqvist 1988). The absence of
CYP2D6 enzyme from the liver appears to cause
polymorphic metabolism of these 3 compounds
(Zanger et al. 1988). Fluoxetine displays a large
 ~
01

F3C f
to
')-O_OCH_~_ ~-r . F3C f ' ) - O_oCH_
co ~- ~-r
1 co Fluoxetlne

R_OO_~Q ~OH: 0 H

F3C~0-OCH - ~- NI2 CH-~- ~-NH

+
"==J
Norlluoxetine
CI-I:!- F3C f ' ) - 0 -

co 0
Norlluoxetine glururonide
H
0

to co
OH
/' /" /' HO

"I""
F3C~0-OCH-~-~OH----+-F3C~0-OCH-~-COOH---+-F3C~0-OCH-~-COO
"==J 1 "==J j~
F~ ')-OH
"==J
~~
~~J

to r
CH-~- COOH

co
/' I OH
:"...
I

~0-oCH-~0~~0
~-oxidation

F3C"==J 0 F3C~ 0 - "cH - ~- co - glu1arnine

COOH
"==J - glycine
Proposed Q
;;.
OH
HO
OH co_ NH - CI-I:!- COOH ~
Hippuric acid
lS
~
~

3......
Fig. 2. Outline of the metabolism of fluoxetine, on the basis of the metabolites identified in urine following administration of a single oral dose of [14C]fluoxetine
given on the thirty-ninth day of administration of fluoxetine 60 mg/day to healthy volunteers for 45 days. ~
Pharmacokinetics of Fluoxetine
interindividual variability, and polymorphic oxida-
tive drug metabolism may account for this variabil-
ity (De Vane 1991). More recently in 19 patients
receiving fluoxetine, the ratio of O-demethylated
dextrometorphan to parent drug (suggestive of
CYP2D6 activity) fell into the region of the anti-
mode separating the O-demethylation ratio values
observed in 208 extensive metabolisers from that
observed in a control group of 15 poor metabo-
lisers (Otton et al. 1993). Moreover, fluoxetine and
norfluoxetine inhibited the O-demethylation
(catalysed by CYP2D6) of oxycodone to oxymor-
phone in hepatic microsomes from both individu-
als who were both extensive metabolisers and
those who were poor metabolisers of the drug. This
indicates that fluoxetine and its metabolite are not
selective inhibitors of CYP2D6 activity (Otton et
al. 1993), and also that the analgesic effect of oral
opiates that are bioactivated by CYP2D6 may be
impaired during treatment with fluoxetine. It
should be stressed that as all the 5-HT reuptake
inhibitors affect the activity of microsomal
CYP2D6 to varying degrees, the relevant clinical
implications for individuals drugs will differ.
Individuals who were poor metabolisers of
fluoxetine (t~p greater than 3 days after a single
dose) were shown to be poor metabolisers of dex-
tromethorphan. Furthermore, poor metabolisers of
debrisoquine were also poor metabolisers of
fluoxetine. These results suggest that fluoxetine
pharmacokinetics are influenced by the type of
polymorphic oxidative metabolism characteristic
of debrisoquine and dextromethorphan metabo-
lism (Brl/Ssen & Skjelbo 1991). The main conse-
quence of CYP2D6 inhibition is that fluoxetine
(and paroxetine) inhibit their own metabolism,
thus, showing a non-linear pharmacokinetic pro-
file when the dose is increased (see section 5).
6. Pharmacokinetics in Special
Populations
6.1 Elderly Patients
When a single dose of fluoxetine 40mg was ad-
ministered orally to 11 healthy elderly male and
female volunteers (age ranging from 65 to 77
207
years), the pharmacokinetics of fluoxetine and
norfluoxetine did not differ from those in younger
volunteers (Bergstrom et al. 1983). The lack of
age-related differences is clinically important be-
cause the elimination of tricyclic and atypical an-
tidepressant drugs can be reduced, and the bio-
availability of these drugs can be increased, in
elderly patients (Altamura et al. 1982, 1983; Nies
et al. 1977).
6.2 Patients with Renal Impairment
Renal impairment does not significantly affect
the pharmacokinetics of fluoxetine, because meta-
bolism is the rate-controlling process in the dispo-
sition of this drug. The pharmacokinetic profile of
fluoxetine was not significantly different in pa-
tients with varying degrees of renal impairment.
Patients with creatinine clearance values of >90,
10 to 70, or <10 mVmin (>5.4, 0.6 to 4.2, or <0.6
LIb) had a tY2P of 3.6, 4.8 or 1.8 days, CL of 20.8,
17.3 or 29.2 LIb and Vd of25.8, 36.5 or 24.0 Ukg,
respectively (Aronoff et al. 1984) [fig. 3]. These
differences, however, were not significant.
6.3 Patients with Hepatic Dysfunction
The pharmacokinetics of fluoxetine were af-
fected by hepatic dysfunction. The t~p was signif-
------------------------ 6
.0
------:-_':"lo....!::.:,.---:.::.....-:-.:--------- 5
~31
~
~
6 21
~
..J
eCL(Uh)
() 11
DVd (LJkg)
- -OElimTnatlOii - - - - - - - - -- - -- --
Half-life (h)
~-----------.------------~o
>5.4 0.6 to 4.2 <0.6
Creatinine clearance (Uh)
Fig. 3. Phannacokinetic parameters of fluoxetine in patients with
varying degrees of renal impairment (data from Aronoff et al.
1984). Abbreviations: CL = total body clearance; Vd = apparent
volume of distribution.
208
icantly longer (7.6 vs 2.8 days) and CL was lower
(14.5 vs 45.31 Lib) in patients with alcohol (etha-
nol)-related cirrhosis of the liver than in individu-
als with normal hepatic function. The Vd was sim-
ilar in patients with cirrhosis and healthy
individuals (46.8 and 42.5 Llh, respectively)
[Schenker et al. 1988].
6.4 Obese Patients
The pharmacokinetic profiles of fluoxetine and
norfluoxetine in obese individuals were similar to
those observed in lean individuals (data on file, Eli
Lilly). Steady-state plasma concentrations are un-
likely to change significantly as patients lose or
gain bodyweight because it appears that fluoxetine
and norfluoxetine do not readily distribute into ad-
ipose tissue (data on file, Eli Lilly).
7. Concentration-Response Studies
Interest in the use of plasma fluoxetine concen-
trations to rationalise clinical response stemmed
from evidence that platelets harvested from
healthy volunteers inhibited tritiated 5-HT uptake
by 65%. Furthermore, the inhibition of uptake cor-
related positively with plasma fluoxetine concen-
trations (Lemberger et al. 1985).
Most studies have found a possible therapeutic
window for fluoxetine. In fact, combined plasma
concentrations of fluoxetine plus norfluoxetine
above 500 ~g/L seem to be associated with a poorer
response than lower plasma concentrations. How-
ever, because of study design factors such as in-
creasing doses, study duration, sample size, etc.,
some studies (e.g. Beasley et al. 1990; Kelly et al.
1989; Martensson et al. 1989) have not found a
concentration-response relationship for fluoxetine.
Montgomery et al. (1986) were the first to pro-
vide evidence of a therapeutic window for fluoxet-
ine. They studied the plasma concentration-
response relationship in 2 groups of patients. The
first group was treated with fluoxetine 60mg daily,
and the second group of patients received fluoxet-
ine 80mg once weekly. In the former group, mean
plasma concentrations ranged from 200 to 531
~g/L for fluoxetine and from 103 to 465 ~g/L for
Clin. Pharmacokinet. 26 (3) 1994
norfluoxetine after the first week of therapy. No
relationship was seen between plasma fluoxetine
concentration and response, but a significant neg-
ative relationship was observed between plasma
concentrations of norfluoxetine and response. The
group of patients that responded at the end of the
study had significantly lower plasma norfluoxetine
concentrations than non-responders. This finding
almost exactly parallels that reported for the anti-
depressant norzimeldine, and suggests that the dos-
age of fluoxetine was too high in the group of pa-
tients receiving the drug daily (Montgomery et al.
1990).
The plasma concentrations of norfluoxetine
achieved in the patients receiving fluoxetine once-
weekly were in the same range as those observed
in patients receiving fluoxetine 60mg daily who
responded to therapy. As expected plasma concen-
trations of fluoxetine were very low, thus suggest-
ing that fluoxetine scarcely contributed to the
therapeutic response. Indeed, it would seem that
the active pharmacological agent may be
norfluoxetine. Since this study included only 20
patients in each group, firm conclusions cannot be
drawn. However, the hypothesis that the optimal
dosage offluoxetine dosage is less than 60mg daily
should be considered.
Subsequently, Goodnick (1991) found that, of
15 patients receiving fluoxetine 20 to 80 mg/day,
9 patients had combined plasma fluoxetine plus
norfluoxetine concentrations of 200 to 499 ~g/L.
The Beck Depression Inventory decreased by 50%
in 6 of these 9 patients, whereas none of these 6
had plasma fluoxetine plus norfluoxetine concen-
trations above 500 ~g/L.
It is unclear whether common adverse effects of
fluoxetine, including nausea, are related to plasma
concentrations of the drug. However, it is clear that
with higher dosages of the drug, the incidence of
nausea and vomiting increases (Altamura et al.
1988). Data from patients who had taken an over-
dosage show that combined plasma concentrations
of fluoxetine plus norfluoxetine must exceed ther-
apeutic concentrations by several-fold before seri-
Pharmacokinetics of Fluoxetine
ous complications arise (Kincaid et al. 1990; Roett-
ger 1990; Rohrig & Prouty 1989).
In summary, routine determination of plasma
fluoxetine concentrations are not necessary, but
may be warranted to check compliance. They may
also be used in the case of overdosage, when
fluoxetine is used in combination with monoamine
oxidase inhibitors (see section 8), and when pa-
tients do not respond to standard daily dosages of
the drug. Of course, when a patient fails to respond
to therapy, clinical factors should also be consid-
ered (Altamura 1990, 1991). In our experience, a
dosage that is too high can be as ineffective as one
that is too low. Furthermore, it has been
hypothesised that suicidal ideation may occur as a
result of high plasma fluoxetine concentrations
(Fichtner et al. 1991).
8. Drug Interactions
Fluoxetine can interact with different classes of
antipsychotic drugs. Because of the long tIt2~ of
fluoxetine and norfluoxetine (Benfield et al. 1986),
drug interactions may occur several weeks after
fluoxetine therapy has been discontinued. Signs of
tricyclic antidepressant toxicity, including seda-
tion, decreased energy and alertness, tinnitus,
memory impairment and dry mouth, have been re-
ported to occur 1 to 2 weeks after fluoxetine was
combined with nortriptyline or desipramine
(Goodnick 1989; Vaughan 1988). Fluoxetine sig-
nificantly increased the tt;2~ and plasma concentra-
tions of tricyclic antidepressants when the 2 drugs
were given concurrently (Jarvis 1991; von Ammon
Cavanaugh 1990). It appears that fluoxetine causes
an inhibition of tricyclic 2-hydroxylation and de-
creases first-pass and systemic metabolism of tri-
cyclic antidepressant drugs (Bergstrom et al.
1992).
In vitro (Bloomer et al. 1992) and in vivo
(Sindrup et al. 1991) studies have demonstrated
that SSRIs are also a substrate for CYP2D6 (see
section 5.1). Recent reports suggest that paroxet-
ine, fluoxetine and other members of this class in-
hibit CYP2D6 (Brfl}sen & Skjelbo 1991; Preskom
1993). Inhibition of CYP2D6-catalysed metabo-
209
lism can lead to alterations in the pharmacokinetic
profile of CYP2D6 substrates. Because tricyclic
antidepressants require biotransformation medi-
ated by CYP2D6 prior to excretion (Potter & Manji
1990), they can be used to test the in vivo effect of
concomitant administration of drugs such as
fluoxetine, paroxetine and sertraline on CYP2D6-
metabolism (Brfl}sen et al. 1992). In studies under-
taken with desipramine, fluoxetine and paroxetine
both 20 mg/day caused greater than a 400% reduc-
tion in the CL of desipramine, and consequently
important increases in the plasma concentration of
the drug. In contrast, sertraline 50 mg/day had a
negligible effect (i.e. < 30% change in clearance of
the tricyclic antidepressant) [Preskom 1993]. Al-
though both paroxetine (20 mg/day) and fluoxetine
(20 mg/day) had a similar effect on the CL of de-
sipramine, the effect of paroxetine will be shorter
because it has a shorter half-life. However, higher
dosages of paroxetine will result in a prolonged
and enhanced effect due to the nonlinear pharma-
cokinetics of paroxetine (Preskom 1993). For
those substrates with a narrow therapeutic range,
this interaction could have clinical significance.
Human hepatic microsomes were used in in
vitro studies to compare the inhibitory potency of
SSRls. Paroxetine was the most potent inhibitor,
on a molar basis, of the CYP2D6-catalysed oxida-
tion of sparteine [inhibitory rate constant (Ki) of
0.15 IlmollL]. However, fluoxetine (Ki = 0.60
IlmollL) and sertraline (Ki = 0.70 IlmollL) had Ki
values in the same range. Fluvoxamine (Ki = 8.2
IlmollL) and citalopram (Ki =5.1IlmollL) also in-
hibited CYP2D6 activity, but to a lesser extent than
did paroxetine or fluoxetine. Although the major
metabolites of paroxetine produced negligible in-
hibition, norfluoxetine was a potent CYP2D6 in-
hibitor (Ki =0.43 IlmollL). CYP2D6 was also in-
hibited by tricyclic antidepressant drugs, including
clomipramine (Ki =2.2 IlmollL), desipramine (Ki
=2.3 IlmollL) and amitriptyline (Ki =4.0 IlmollL).
As a consequence of inhibition of CYP2D6,
when imipramine or desipramine are coadminis-
tered with fluoxetine, a lower dosage of the tricy-
clic antidepressants may be needed to avoid ad-
210
verse effects caused by increased tricyclic antide-
pressant concentrations (Eisen 1989; Preskorn et
al. 1990; Wilens et al. 1992). It is predicted that
plasma fluoxetine concentrations will not increase,
because fluoxetine is a more potent inhibitor of
CYP2D6 than is the tricyclic antidepressant. Fur-
thermore, it is likely that this combination will be
used clinically, because the combination can re-
duce the latency of antidepressant response (AI-
tamura 1991; Nelson et al. 1991) or improve re-
sponse in patients who are resistant to the
individual therapies (Eisen 1989; Suckow et al.
I 992a).
Pharmacodynamic interactions between
fluoxetine and antidepressants may also occur. For
example, when a monoamine oxidase inhibitor and
fluoxetine are used in combination a 'serotonergic
syndrome' has resulted (Ciraulo & Shader 1990).
This syndrome is characterised by gastrointestinal
(abdominal cramping), neurological (tremulous-
ness, myoclonus, dysarthria, incoordination), car-
diovascular (tachycardia, hypertension), and psy-
chological (confusion, mania-like symptoms, etc.)
symptoms. It is also associated with other vegeta-
tive symptoms (e.g. diaphoresis). Coma and possi-
bly death from heart block or cardiovascular col-
lapse can also occur (Boyer & Feighner 1991).
There have been a number of reports of serious
adverse reactions, including 4 deaths from what
appeared to be neuroleptic malignant syndrome,
when monoamine oxidase inhibitors were admin-
istered soon after fluoxetine treatment was with-
drawn. Therefore, the manufacturer recommends
that monoamine oxidase inhibitors are not intro-
duced until 5 weeks after discontinuation of
fluoxetine.
There have also been occasional reports of in-
teractions between fluoxetine and both tryptophan
and lithium, resulting in restlessness, agitation and
movement disorders (Committee on Safety of
Medicines 1989). Therefore, although these com-
binations are potentially beneficial, they should be
used cautiously.
Fluoxetine has been reported to interact with
both diazepam and alprazolam (table II), although
CZin. Pharmacokinet. 26 (3) 1994
the drug does not appear to interfere with the
nitroreduction of clonazepam (Greenblatt et al.
1992) or the disposition of triazolam (Wright et al.
1992). However, investigators recommended that
patients' clinical response to therapy be monitored
when triazolam is administered concurrently with
fluoxetine (Wright et al. 1992). Another report in-
dicated that fluoxetine may have blocked the an-
xiolytic effects of buspirone (Bodkin & Teicher
1989). Fluoxetine has been shown to interact with
carbamazepine (table II). Therefore, concomitant
use of these 2 drugs should be accompanied by
careful monitoring, because it is likely that fluoxet-
ine will cause an increase in the plasma concentra-
tion of antiepileptic drugs.
Fluoxetine appears to inhibit the metabolism of
antipsychotics. Its use in combination with clozap-
ine, haloperidol, pimozide, fluphenazine and per-
phenazine has been associated with potentiation of
extrapyrimidal symptoms (Cassady & Thaker
1992; Ciraulo & Shader 1990; Ketai 1993; Lock et
al. 1990; Tate 1989). A recent paper from
Baldessarini and colleagues (1993) showed that in
rats treated with intraperitoneal clozapine, pre-
treatment with fluoxetine for 1 week markedly in-
creased concentrations of clozapine and its meta-
bolite norclozapine in both serum (86%) and brain
(61 %). These findings are consistent with those ob-
served in patients receiving clozapine and fluoxet-
ine concomitantly (Centorrino et al. 1994).
The addition of the narcotic pentazocine to
fluoxetine treatment is potentially dangerous, lead-
ing to severe CNS excitatory responses (Hansen et
al. 1990). The effect of fluoxetine on psychomotor
performance, physiological response, and pharma-
cokinetic disposition of alcohol have been exam-
ined. Fluoxetine (30 or 60mg) administered with
alcohol (45ml absolute alcohol per 70kg body-
weight) did not alter the plasma fluoxetine
concentrations or the blood alcohol concentrations
compared with concentrations obtained after ad-
ministration of either drug alone. Furthermore,
there was no significant effect on standing or re-
cumbent blood pressure or heart rate after single or
multiple doses of fluoxetine were administered ei-
Phannacokinetics of Fluoxetine 211

Table II. Pharmacokinetically based drug interactions between fluoxetine (F) and other drugs
Interacting drugs Pharmacokinetic effect Mechanism of effect Comments References
Tricyclic anti- i h1!~ F inhibits CYP2D6 Use lower doses of the Goodnick (1989);
depressant drugs activity TCA to avoid adverse Jarvis (1991);
(TCA) effects Vaughan (1988); von
Ammon Cavanaugh
(1990)
Diazepam i h.~ of diazepam and demethyl-diazepam Clinically inSignificant Lemberger et al.
-1 CL of diazepam and demethyl-diazapem interaction occurs with (1988)
F 60mg, but not with
F30mg
Alprazolam i Plasma alprazolam concentrations F impairs the -1 Psychomotor Greenblatt et al.
by 30% microsomal oxidation performance by (1992); Lasher et al.
-1 Clearance of alprazolam of alprazolam combination therapy (1991)
Carbamazepine i AUC of carbamazepine F inhibits the Grimsley et al. (1991)
i AUC of carbamazepine-1 0, 11-epoxide metabolism of
-1 CL of carbamazepine carbamazepine

Antipsychotics i Plasma concentrations Possible inhibition of iRiskof Cassady & Thaker

(e.g. haloperidol, metabolism extrapyramidal (1992); Ciraulo &
clozapine) symptoms and Shader (1990); Ketai
stiffness observed (1993); Lock et al.
clinically (1990); Tate (1989)
Abbreviations and symbols: AUC = area under the concentration-time curve; CL = clearance; t1h~ = elimination half-life; i indicates
increased; -1 indicates decreased.

ther alone or in combination with alcohol. Single
or multiple doses of fluoxetine had no effect on the
psychomotor activity (stability of stance, motor
performance, manual coordination) or subjective
effects of alcohol. (Lemberger et al. 1985)
9. Conclusions
Fluoxetine, and its major metabolite norfluoxet-
ine, block 5-HT reuptake in the CNS, to produce a
clinical effect. The unusual pharmacokinetic pro-
file of this drug appears to influence its therapeutic
efficacy.
Fluoxetine is well absorbed after oral adminis-
tration, and Cmax values are reached 6 to 8 hours
postdose. Food reduces the rate, but not extent, of
absorption. Fluoxetine is highly protein bound,
with a large Vd. The drug has a long tJ/2~ of 1 to 4
days, while norfluoxetine has an even longer tY2~
(7 to 15 days). Because of its long tY2~, multiple
daily doses are unnecessary in the treatment of
acute depression. Furthermore, it would be ex-
pected that occasional noncompliance would cause
little fluctuation in plasma fluoxetine concentra-
tions (Altamura & Percudani 1993).
Because fluoxetine has nonlinear pharmacoki-
netics and a long tY2~, the dosage regimen for el-
derly patients or those with a reduced metabolic
capacity should be carefully selected. Further-
more, the ability of fluoxetine to inhibit metabo-
lism of other psychotropic drugs (e.g. tricyclic an-
tidepressant drugs) may lead to an increased
incidence of adverse effects when combination
therapy is employed (despite continued use of
standard daily doses). The combination offluoxet-
ine with monoamine oxidase inhibitors, lithium or
tryptophan is particularly dangerous because these
compounds have a synergistic effect on the 5-HT
pathways.
The association of fluoxetine with a tricyclic
antidepressant drug seems to increase the speed
and consistency of antidepressant response. The
combination could be clinically useful in the treat-
ment of patients who do not respond to tricyclic
antidepressant monotherapy. With this exception,
212
the coadministration of fluoxetine with other psy-
chotropic medications should be avoided, particu-
larly in the elderly and in individuals with concom-
itant somatic disorders.
In the elderly, the possible disadvantages to ad-
ministering fluoxetine (e.g. nonlinear pharmacoki-
netics and long VI2~) are counterbalanced by the ob-
vious advantages of the drug over tricyclic
antidepressants (e.g. superior tolerability profile).
Furthermore, because age per se does not influence
the disposition of fluoxetine, this drug may be par-
ticularly useful for treating depression in the el-
derly.
The tY2~ of fluoxetine is not significantly
changed by renal impairment or obesity, but it is
altered in patients with cirrhosis.
It appears that there may be a concentration-ef-
fect relationship for fluoxetine. In fact, plasma
concentrations of fluoxetine plus norfluoxetine
above 500 flglL seem to be associated with poorer
response than lower concentrations. Therefore,
fluoxetine 20 to 40 mg/day should result in a sat-
isfactory clinical response, while avoiding the risk
of overdosage (particularly in elderly patients).
In conclusion, a complete understanding of the
pharmacokinetic profile of fluoxetine is necessary
for optimal clinical use of this drug. Such an un-
derstanding has the potential to minimise adverse
effects that often arise from the unnecessary use of
combination treatments.
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