Clinical Pharmacokinetics of Fluoxetine

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Fluoxetine is well absorbed orally and highly protein bound with a long elimination half-life. Its metabolism is nonlinear and it can interact with other drugs.

SSRIs are a class of antidepressants that work by increasing serotonin availability in the brain. Fluoxetine is a widely used SSRI.

Studies show fluoxetine may downregulate presynaptic inhibitory autoreceptors, facilitating serotonin transmission, though its exact effects are still debated.

DRUG DISPOSITION

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


0312-5963/94/0003-0201/$07.00/0
Adis International Limited. All rights reversed

Clinical Pharmacokinetics of Fluoxetine


Alfredo C. Altamura,1 Anna R. Moro2 and Mauro Percudani3
1 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
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Summary

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

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 1 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 g/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 antipsychotics 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 pharmacodynamic 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 neurotransmitter 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 pharmacokinetics of these agents readers are referred to a
review recently published in the Journal (van
Harten 1993).
Down regulation of 5-HT1 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 5HT1 receptors were evaluated in 15 experiments. It
was found that the number of receptors was reduced, without a change in receptor affinity for its
ligand (reviewed by Beasley et al. 1992).
More controversial is the activity of fluoxetine on 5-HT1 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 autoreceptors (Beasley et al. 1992), with no effect on
muscarinic receptors and doubtful effects on
-adrenergic receptors (Byerley et al. 1988). Initially, it was suggested that the effective dose of
fluoxetine was at least 80 mg/day, but more recently 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 administration of fluoxetine 20mg 3 times weekly
to be clinically effective.
The pharmacokinetic profile of fluoxetine is dif-

Clin. Pharmacokinet. 26 (3) 1994

ferent from that of other drugs of its class. For example, it has a longer half-life, active metabolites
and non-linear pharmacokinetics. Knowledge of
the differences allows improved clinical management during administration of fluoxetine. Moreover, fluoxetine plasma concentration-effect data
seem useful in the rationalisation of therapy in depressed patients (Altamura & Montgomery 1990).
This article reviews the pharmacokinetic profile of
fluoxetine, emphasising the relevance of pharmacokinetics 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 determine 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 (Roethger 1990; Rohrig & Prouty 1989) have also been
used, but these methods are helpful only when
fluoxetine is present at potentially toxic concentrations.
A simple HPLC procedure allows fluoxetine or
norfluoxetine (formed by N-demethylation) 20
g/L to be detected in a sample of only 0.5ml (data
on file, Eli Lilly). This procedure is, therefore, particularly suitable for clinical application. Suckow
et al. (1992b) determined the plasma concentration
of fluoxetine and norfluoxetine using HPLC with
fluorescence detection. The highly fluorescent derivatives were separated in a reversed-phase C18
column with a mobile phase of phosphate buffer
and acetonitrile. Dansylated fluoxetine, norfluoxetine 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 chromatographic method with ultraviolet detection for samples 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 g/L. No
major antidepressant, or antipsychotic drug, or metabolite of these drugs, interfered with the quantification 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 g/L. 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 gastrointetinal tract after oral administration, and its bioavailability is not affected by the presence of food
(Bergstrom etal. 1984). Absolute bioavailability of
oral fluoxetine in dogs is about 72% of the intravenous dose (Bergstrom et al. 1986b).
Following the oral administration of
[14 C]fluoxetine to humans, the plasma concentrations of fluoxetine, its N-demethylated metabolite
norfluoxetine), and total radioactivity were maximal 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 deuterium-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
radiolabelled dose of [14C]fluoxetine was administered to the volunteers, and the disposition and melabolism of this radiolabelled dose was determined. Approximately 75% of the administered

203

I4

C-radioactivity was excreted in the urine over a


subsequent 30-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 established (table I). After a single dose, peak plasma
fluoxetine concentrations (Cmax) in humans occurred between 6 and 8 hours postdose, regardless
of whether the drug was administered as a capsule
or as a solutipn (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 fluoxetine 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

204

Clin. Pharmacokinet. 26 (3) 1994

fluoxetine 60mg was administered to both (data on


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 patients.
3.1 Distribution in the Brain

Fig. 1. Plasma versus brain fluoxetine plus norfluoxetine concentrations in 8 patients who received different dosages of fluoxetine
(from Renshaw et al. 1992, with permission).

differences in Cmax values are apparent after standard daily dosages. For example, a 3- to 4-fold interindividual variation in Cmax (15 to 55 g/L) was
observed after administration of a single dose of
fluoxetine 40mg to 25 healthy volunteers [Aronoff
etal. 1984].
During long term administration steady-state
plasma fluoxetine concentrations were achieved
within 2 to 4 weeks (Bergstrom et al. 1986a). Furthermore, no accumulation occurred after administration of the drug for up to 3 years.
3. Distribution
Fluoxetine and norfluoxetine each have a volume of distribution (Vd) of 20 to 42 L/kg. This
large Vd is the result of high plasma protein binding (>95%) and extensive tissue distribution. The
ratio of fluoxetine to norfluoxetine concentrations
were similar in the cerebral cortex, striatum, hippocampus, hypothalamus, brain stem and cerebellum of rat brains 1 hour after a single dose (reviewed 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

In vivo, 19fluorine nuclear magnetic resonance


spectroscopy was used to measure the brain concentration of fluoxetine and norfluoxetine in 5 patients with obsessive-compulsive disorder and 3
patients with major depression (Rensbaw 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 concentrations were significantly higher (2.6 times) than
their corresponding plasma concentrations. The
daily dosage correlated with calculated brain concentrations more closely than did plasma concentration (fig. 1). However, the poor correlation between plasma and brain concentrations (r = 0.58,
d.f = 7) was disproportionately affected by values
obtained from 1 of the 8 patients whose brain concentration of fluoxetine plus norfluoxetine was 4.9
times higher than the corresponding plasma concentration. When data from this patient were excluded from the analysis, the correlation coefficient between plasma and brain concentrations
improved (r = 0.82; d.f = 7). Although there were
some limitations to this study (e.g. inactive fluorine-containing metabolites of fluoxetine would
have been detected by this technique), these results
were consistent with data derived from animal experiments.
4. Metabolism and Elimination
The main metabolite of fluoxetine is norfluoxetine. Norfluoxetine has similar potency and selectivity of 5-HT uptake inhibition compared with the
parent compound (Fuller & Wong 1987). Therefore, knowledge of its pharmacokinetic profile is
relevant because the metabolite can influence the
clinical efficacy of fluoxetine.

Pharmacokinetics of Fluoxetine

The urinary elimination of metabolites of


fluoxetine has been studied under steady-state conditions in normal volunteers. In one study, volunteers received a single oral 60mg dose of 14Clabelled drug on the thirty-ninth day of
administration of 60 mg/day for 45 days (Farid et
al. 1986). Approximately 75% of the I4C-radioactivity was excreted in the urine during the 30 days
postdose, and 10% was recovered in the faeces during 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, studies have revealed that about 11% of the administered dose was excreted as fluoxetine, 7% was excreted as norfluoxetine, and 7 and 8% were
fluoxetine and norfluoxetine glucuronides, respectively. 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 (t) of
about 1 to 4 days, whereas the t of norfluoxetine
ranged from 7 to 15 days. Steady-state plasma concentrations of both fluoxetine and its major metabolite were achieved within about 4 weeks when
fluoxetine was administered daily. Some accumulation of the drug appears to occur in the first 4
weeks of therapy before steady-state concentrations are achieved, e.g. areas under the plasma concentration-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 t (1.9 vs 5.7 days) and clearance (CL)

205

[35.5 vs 10.8 L/h] 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 patients with depression. Higher dosages of fluoxetine 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 t was longer (5.7 vs
1.9 days) and CL was lower (10.8 vs 35.5 L/h) after
multiple-dose administration than after singledose administration. This change in pharmacokinetics 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 depression (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 volunteers and patients who had been given fluoxetine
for 4 to 6 weeks. Therefore, it would appear that
steady-state concentrations do not change following prolonged administration. Data obtained after
4 to 6 weeks' treatment with 20 to 80 mg/day in
patients with depression showed no clinically important differences, when male and female depressed 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 dextromethorphan 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

206

Clin. Pharmacokinet. (3) 1994

Pharmacokinetics of Huoxetine

interindividual variability, and polymorphic oxidative drug metabolism may account for this variability (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 antimode separating the O-demethylation ratio values
observed in 208 extensive metabolisers from that
observed in a control group of 15 poor metabolisers (Otton et al. 1993). Moreover, fluoxetine and
norfluoxetine inhibited the O-demethylation
(catalysed CYP2D6) of oxycodone to oxymorphone in hepatic microsomes from both individuals 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
opietas 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
CY2D6 to varying degrees, the relevant clinical
implications for individuals drugs will differ.
Individuals who were poor metabolisers of
fluoxetine (t greater than 3 days after a single
dose) were shown to be poor metabolisers of dextromethorphan. 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 metabolism (Brsen & Skjelbo 1991). The main consequence of CYP2D6 inhibition is that fluoxetine
(and paroxetine) inhibit their own metabolism,
thus, showing a non-linear pharmacokinetic profile the dose is increased (see section 5).

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 because the elimination of tricyclic and atypical antidepressant drugs can be reduced, and the bioavailability 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 metabolism is the rate-controlling process in the disposition of this drug. The pharmacokinetic profile of
fluoxetine was not significantly different in patients with varying degrees of renal impairment.
Patients with creatinine clearance values of >90,
10 to 70, or <10 ml/min (>5.4, 0.6 to 4.2, or <0.6
L/h. had a t of 3.6, 4.8 or 1.8 days, CL of 20.8,
17.3 or 29.2 L/h and Vd of 25.8,36.5 or 24.0 L/kg,
respectively (Aronoff et al. 1984) [fig. 3]. These
differences, however, were not significant.
6.3 Patients with Hepatic Dysfunction
The pharmacokinetics of fluoxetine were affected by hepatic dysfunction. The ty2p was signif-

6. Pharmacokinetics in Special
Population
6.1. Elderly Patients
When a single dose of fluoxetine 40mg was administered orally to 11 healthy elderly male and
female volunteers (age ranging from 65 to 77

Fig.3 Pharmacokinetic 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 L/h) in patients with alcohol (ethanol)-related cirrhosis of the liver than in individuals with normal hepatic function. The Vd was similar in patients with cirrhosis and healthy
individuals (46.8 and 42.5 L/h, 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 unlikely to change significantly as patients lose or
gain body weight because it appears that fluoxetine
and nortluoxetine do not readily distribute into adipose tissue (data on file, Eli Lilly).
7. Concentration-Response Studies
Interest in the use of plasms fluoxetine concentrations 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 correlated positively with plasma fluoxetine concentrations (Lemberger at 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. However, because of study design factors such as increasing 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 provide evidence of a therapeutic window for fluoxetine. They studied the plasma concentrationresponse relationship in 2 groups of patients. The
first group was treated with fluoxetine 60mg daily,
and the second group of patients received fluoxetine 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 negative 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 antidepressant norzimeldine, and suggests that the dosage of fluoxetine was too high in the group of patients receiving the drug daily (Montgomery et al.
1990).
The plasma concentrations of norfluoxetine
achieved in the patients receiving fluoxetine onceweekly were in the same range as those observed
in patients receiving fluoxetine 60mg daily who
responded to therapy. As expected plasma concentrations of fluoxetine were very low, thus suggesting 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 of fluoxetine 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
norflouxetine 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 concentrations 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 overdosage show that combined plasma concentrations of
fluoxetine plus norfluoxetine must exceed therapeutic concentrations by several-fold before seri-

Pharmacokinetics of Fluoxetine

209

ous complications arise (Kincaid et al. 1990; Roett - lism can lead to alteration in pharmacokinetic
profile of CYP2D6 substrates. Because tricyclic
ger 1990; Rohrig & Prouty 1989).
antidepressants require biotransformation mediIn summary, routine determination of plasma
ated by CYP2D6 prior to excretion (Potter & Manji
fluoxetine concentrations are not necessary, but
1990), they can be used to test the in vivo effect of
may be warranted to check compliance. They may
concomitant administration of drugs such as
also be used in the case of overdosage, when
fluoxetine, paroxetine and sertraline on CYP2D6fluoxetine is used in combination with monoamine
metabolism (Brsen et al. 1992). In studies underoxidase inhibitors (see section 8), and when pa taken with desipramine, fluoxetine and paroxetine
tients do not respond to standard daily dosages of
both 20 mg/day caused greater than a 400% reducthe drug. Of course, when a patient fails to respond
tion in the CL of desipramine, and consequently
to therapy, clinical factors should also be consid important increases in the plasma concentration of
ered, (Altamura 1990, 1991). In ou r experience, a
the drug. In contrast, sertraline 50 mg/day had a
dosage that is too high can be as ineffective as one
negligible effect (i.e. < 30% change in clearance of
that is too low. Furthermore, it has been
the tricyclic antidepressant) [Preskorn 1993]. Alhypothesised that suicidal ideation may occur as a
though both paroxetine (20 mg/day) and fluoxetine
of
high
plasma
fluoxetine
concentratioris
(20 mg/day) had a similar effect on the CL of de(Fichtner et al.1991).
sipramine, the effect of paroxetine will be shorter
because it has a shorter half-life. However, higher
8. Drug Interactions
dosages of paroxetine will result in a prolonged
and enhanced effect due to the nonlinear pharmaFluoxetine can interact with different classes of
cokinetics of paroxetine (Preskorn 1993). For
antipsychotic drugs. Because of the long t of
those substrates with a narrow therapeutic range,
fluoxetine and norfluoxetine (Benfield et al, 1986),
this interaction could have clinical significance.
drug interactions may oc cur several weeks after
Human hepatic microsomes were used in in
fluoxetine therapy has been discontinued. Signs of
vitro
studies to compare the inhibitory potency of
tricyclic antidepressant toxicity, including seda SSRIs.
Paroxetine was the most potent inhibitor,
tion, decreased energy and alertness, tinnitus,
memory impairment and dry mouth, have been re - on a molar basis, of the CYP2D6-catalysed oxidaported to occur 1 to 2 weeks after fluoxetine was tion of sparteine [inhibitory rate constant (Ki) of
combined with nortriptyline or desipramine 0.15 mol/L]. However, fluoxetine (Ki = 0.60
(Goodnick 1989; Vaughan 1988). Fluoxetine sig - mol/L) and sertraline (Ki = 0.70 mol/L) had Ki
nificantly increased the t and plasma concentra - values in the same range. Fluvoxamine (Ki = 8.2
iton
tricyclic antidepressants when the 2 drugs mol/L) and citalopram (Ki = 5.1 mol/L) also inwere given concurrently (Jarvis 199 1; von Ammon hibited CYP2D6 activity, but to a lesser extent than
Cavanaugh 1990). It appears that fluoxetine causes did paroxetine or fluoxetine. Although the major
an inhibition of tricyclic 2 -hydroxylation and de - metabolites of paroxetine produced negligible increases first-pass and systemic metabolism of tri - hibition, norfluoxetine was a potent CYP2D6 incyclic antidepressant drugs (Bergstrom et al hibition ( K = 0.43 mol/L). CYP2D6 was
i
1992).
also inhibited by tricyclic antidepressant drugs,
I n v i t r o ( B l o o m e r e t al. 1991) and in vivo including clomipramine (Ki = 2.2 mol/L),
(Sindrup et al. 1991) studies have demonstrated desipramine (Ki = 2,3 mol/L) and amitriptyline (Ki =
that SSRIs are also a substrate for CYP2D6 (see 4.0 mol/L)
section 5.1). Recent reports suggest that paroxet As a consequence of inhibition of CYP2D6,
ine, fluoxetine and other members of this alass in - when imipramine or desipramine are codminisinhibit CYP2D6 (Brsen & Skjelbo 1991; Preskorn
tered with fluoxetine, a lower dosage of the tricy1993). Inhibition of CYP2D6 -catalysed metabo - clic antidepressants may be needed to avoid ad-

210

verse effects caused by increased tricyclic antidepressant 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 tricyelic antidepressant. Furthermore, it is likely that this combination will be
used clinically, because the combination can reduce the latency of antidepressant response (Altamura 1991; Nelson et al. 1991) or improve response in patients who are resistant to the
individual therapies (Eisen 1989; Suckow et al.
1992a).
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 (tremulousness, myoclonus, dysarthria, incoordination), cardiovascular (tachycardia, hypertension), and psychological (confusion, mania-like symptoms, etc.)
symptoms. It is also associated with other vegetative symptoms (e.g. diaphoresis). Coma and possibly death from heart block or cardiovascular collapse can also occur (Boyer & Feighner).
There have been a number of reports of serious
adverse reactions, including 4 deaths from what
appeared to be neuroleptic malignant syndrome,
when monoamme oxidase inhibitors were administered soon after fluoxetine treatment was withdrawn. Therefore, the manufacturer recommends
that monoamine oxidase inhibitors are not introduced until 5 weeks after discontinuation of
fluoxetine.
There have also been occasional reports of interactions between fluoxetine and both tryptophan
and lithium, resulting in restlessness, agitation and
movement disorders (Committee on Safety of
Medicines 1989). Therefore, although these combinations are potentially beneficial, they should be
used cautiously.
Fluoxetine has been reported to interact with
both diazepanm and alprazolam (table II),
although

Clin. 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 indicated that fluoxetine may have blocked the anxiolytic 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 fluoxetine will cause an increase in the plasma concentration of antiepileptic drugs.
Fluoxetine appears to inhibit the metabolism of
antipsychotics. Its use in combination with clozapine, haloperidol, pimozide, fluphenazine and perphenazine 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, pretreatment with fluoxetine for 1 week markedly increased concentrations of clozapine and its metabolite norclozapine in both serum (86%) and brain
(61%). These findings are consistent with those observed in patients receiving clozapine and fluoxetine concomitantly (Centorrino et al. 1994).
The addition of the narcotic pentazocine to
fluoxetine treatment is potentially dangerous, leading to severe CNS excitatory responses (Hansen et
al. 1990). The effect of fluoxetine on psychomotor
performance, physiological response, and pharmacokinetic disposition of alcohol have been examined. Fluoxetine (30 or 60mg) administered with
alcohol (45 ml absolute alcohol per 70 kg bodyweight) did not alter the plasma fluoxetine
concentrations or the blood alcohol concentrations
compared with concentrations obtained, after administration of either drug alone. Furthermore,
there was no significant effect on standing or recumbent blood pressure or heart rate after single or
multiple doses of fluoxetine were administered ei-

ttf Fluoxetine

211

(F)

ther alone or in combination with alcohol. Single


or multiple doses of fluoxetine had no effect on the
pasychomotor activity (stability of stance, motor
performance, manual coordination) or subjective
effects alcohol. (Lemberger et al. 1985).
9. Conclusions
Fluoxetine, and its major metabolite norfluoxetIne, block 5-HT reuptake in the CNS, to produce a
clinical effect. The unusual pharmacokinetic profile of this drug appears to influence its therapeutic
efficacy.
Fluoxetine is well, absorbed after oral administration, and Cmax values are reached 6 to 8 hours
postdose. Foof reduces the rate, but not extent, of
absorption. Fluoxetine is highly protein bound, with
a large Vd. The drug has a long t of 1 to 4
days, while norfluoxetine has an even longer t.
(7 to 15 days). Because of its long t, multiple
daily dose are unnecessary in the treatment of
acute deperssion. Furthermore, it would be expected that occasional noncompliance would cause

little fluctuation in plasma fluoxetine concentrations (Altamura & Percudani 1993).


Because fluoxetine has nonlinear pharmacokinetics and a long t1/2, the dosage regimen for elderly patients or those with a reduced metabolic
capacity should be carefully selected. Furthermore, the ability of fluoxetine to inhibit metabolism of other psychotropic drugs (e.g.tricyclic antidepressant drugs) may lead to an increased
incidence of adverse effects when combination
therapy is employed (despite continued use of
standard daily doses). The combination of fluoxetine with monoamine oxidase inhibitors, lithium or
tryptophan is particularly dangerous because these
compounds have a synetgisic, 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 treatment of patients who do not respond to tricyclic
antidepressant monotherapy. With this exceptipn,

Clin. Pharmacokinet. 26 (3) 1994

212

the coadministration of fluoxetine with other psychotropic medications should be avoided, particularly in the elderly and in individuals with concomitant somatic disorders.
In the elderly, the possible disadvantages to administering fluoxetine (e.g. nonlinear pharmacokinetics and long t) are counterbalanced by the obvious 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 particularly useful for treating depression in the elderly.
The t 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-effect relationship for fluoxetine. In fact, plasma
concentrations of fluoxetine plus norfluoxetine
above 500 g/L seem to be associated with poorer
response than lower concentrations. Therefore,
fluoxetine 20 to 40 mg/day should result in a satisfactory 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 understanding has the potential to minimise adverse
effects that often arise from the unnecessary use of
combination treatments.

References
Altamura AC. Drug resistance phenomena in major psychoses : their
discrimination and causal mechanisms. Clinical Neuropharmacology 13 (Suppl. 1): 1-15,1990
Altamura AC. Drug-resistance in major depression: definition, discrimination and possible pharmacological strategies. In Meltzer &
Nerozzi (Eds) Current practices and future developments in the
pharmacotherapy of mental disorders, pp. 139-148, Excerpta Medica, Amsterdam, 1991
Altamura AC, De Novellis P, Guercetti-G, Invernizzi G, Percudani
M, et al. Fluoxetine compared with amitriptyline in elderly depression: a controlled clinical trial. International Journal of Clinical
Pharmacological Research 9: 391-396, 1989
Altamura AC, Mauri MC. Aspects of treatment of elderly depression:
the fluoxetine experience, in Freeman (Ed) The use of fluoxetine in
clinical practice, Vol. 183, pp. 53-59, Royal Society of Medicine
Services, London, New York, 1991
Altamura AC, Melorio T, Invernizzi G, Colacurcio F, Gomeni R.
Age-related differences in kinetics and side-effects of viloxazine
in man and their clinical implications. Psychopharmacology 81:
281-285,1983

Altamura AC, Melorio T, Invernizzi G, Gomeni R. Influence of age


on mianserin pharmacokinetics. Psychopharmacology 78: 380382,1982
Altamura AC, Montgomery SA. Fluoxetine dose, pharmacokinetics
and clinical efficacy. Reviews in Contemporary Pharmacotherapy
1:75-81,1990
Altamura AC, Montgomery SA, Wernicke JF. The evidence for 20
mg a day fluoxetine as the optimal dose in the treatment of depression. British Journal of Psychiatry 153 (Suppl. 3): 103-106, 1988
Altamura AC, Percudani M. The use of antidepressants for longterm treatment of recurrent depression: rationale, current
methodolo-gies, and future directions. Journal of Clinical
Psychiatry 54 (Suppl. 8): 29-37, 1993
Aronoff GR, Bergstrom RF, Pottratz ST, Sloan RS, Wolen RL, et al.
Fluoxetine kinetics and protein binding in normal and impaired
renal function. Clinical Pharmacology and Therapeutics 36: 138144, 1984
Baldessarini RJ, Centorrino F, Flood JG, Vplpicelli SA, Huston-Lyons D, et al. Tissue concentrations of clozapine and its metabolites
in the rat. Neuropsychopharmacology 9: 117-124, 1993
Baron B. Ogden A, Siegel B, Stegeman J, Ursillo R, et al. Rapid
downregulation of beta-adrenoceptors by coadministration of desipramine and fluoxetine. European Journal of Pharmacology 164:
125-134, 1988
Beasley Jr CM, Bosomworth JC, Wernick JF. Fluoxetine: relationships among dose, response, adverse events, and plasma concentrations in the treatment of depression. Psychopharmacology
Bulletin 26: 13-24, 1990
Beasley CM, Masica DM, Potvin JH. Fluoxetine: a review of receptor
and functional effects and their clinical implications. Psychopharmacology 107:1-10, 1992
Benfield P, Heel RC, Lewis SP. Fluoxetine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness. Drugs 32: 481-508, 1986
Bergstrom R, Wolen RL, Dhahir P, Hatcher B, Werner N, et al. Effect
of food on the absorption of fluoxetine in normal subjects. Abstracts of the American,Pharmaceutical Association Academy of
Pharmaceutical Science 14:110, 1984
Bergstrom RF, Farid KZ, McClurg JE, Lemberger L. The pharmacokinetics of fluoxetine in elderly subjects. II World Conference
on Clinical Pharmacology and Therapeutics, Washington, 31 July-5
August, 1983. Abstract no. 699, p. 120,1983
Bergstrom RF, Lemberger L, Farid NA, Wolen RL. Clinical pharmacology and pharmacokinetics of fluoxetine: a review. British Journal of Psychiatry 153 (Suppl. 3): 47-50,1988
Bergstrom RF, Peyton AL, Lemberger L. Quantification and mechanism of the fluoxetine and tricyclic antidepressant interaction
Clinical Pharmacology and Therapeutics 51 (3): 239-248, 1992
Bergstrom RF, vanLier RBL, Lemberger L,Tenbarge JL. Absolute
bioavailability of fluoxetine in beagle dogs. Abstracts of the American Pharmaceutical Association Academy of Pharmaceutical Sciences 16: 126, 1986a
Bergstrom RF, Wolen RL, Lemberger L, Dhahir P, Barrett JL.
Fluoxetine single dose-multiple dose kinetics. 39th National Meeting of the American Pharmaceutical Association Academy of Pharmaceutical Sciences, Washington, 1985. Vol. 15, p. 137, 1985
Bergstrom RF, Wolen RL, Lemberger L, Tenbarge JL, Masco HL
Fluoxetine steady state pharmacokinetics in depressed patients,
133rd Annual Meeting of the American Pharmaceutical Association, San Francisco, 16-20 March, 1986. Vol. 16, No. 1, Abstract
no. P55,1986b
Bloomer JG, Woods FR, Haddock RE, Lennard MS, Tucker GT. The
role of cytochrome P4502D6 in the metabolism of paroxetine by
human liver microsomes. British Journal of Clinical Pharmacology
33: 521-523, 1992
Bodkin JA, Teicher MH. Fluoxetine may antagonize the anxiolytic
action of buspirone. Journal of Clinical Psychopharmacology 9:
150,1989

Pharmacokinetics of Fluoxetine

Boyer WF, Feighner JP. Pharmacokinetics and drug interactions. In


Feighner & Boyer (Eds) Selective serotonin reuptake inhibitors,
pp. 81 -88, J. Wiley and Sons, New York, 1991
Brsen K, Gram IF, Sindrup S, et al. Pharmacokinetics of tricyclics
and Novel antidepressants: recent developments. Clinical NeuroPharmacology 15 (suppl. 1) : 80-81, 1992
Brsen K, Skjelbo E. Fluoxetine and norfluoxetine are potent inhibitors of P450IID6 - the source of the sparteine/debrisoquine oxidation polymorphism. British Journal of Clinical Pharmacology
32: 136-137, 1991
Byerley WF, McConnell EJ, McCabe RT, Dawson TM, Grosser BI,
et al. Decreased beta-adrenergic receptors in rat brain after chronic
administration of the selective serotonin uptake inhibitor fluoxetine. Psychopharmacology 94: 141-143, 1988
Cassady SL, Thaker GK. Addition of fluoxetine to clozapine. American Journal of Psychiatry 149:1274,1992
Centorrino F, Baldessarini RJ, Kondo J, Frankenburg FR, Volpicelli
SA, et al. Serum concentrations of clozapine and its metabolites:
effects of cotreatment with valproate or fluoxetine. American Journal of Psychiatry 151: 123-125,1994
Ciraulo DA, Shader RI. Fluoxetine drug-drug interactions: I. Antidepressants and antipsychotics. Journal of Clinical Psychopharmacology 10: 48-50, 1990
Committee on Safety of Medicines. Fluvoxamine and fluoxetine interaction with monoamine oxidase inhibitors, lithium and tryptophan. Current Problems No. P26:1989
Crewe HK, Lennard MS, Tucker GT, Woods FR, Haddock RE. The
effect of selective serotonin re-uptake inhibitors on cytochrome
P4502D6 (CYP2D6) activity in human liver microsomes. British
Journal of Clinical Pharmacology 34: 262-265, 1992
De Vane CL. Pharmacokinetics of the selective serotonin reuptake
inhibitors. Journal of Clinical Psychiatry 53 (Suppl.): 13-20, 1991
Dixit V, Nguyen H, Dixit VM. Solid-phase extraction of fluoxetine and
norfluoxetine from serum with gas chromatography-electroncapture detection. Journal of Chromatography 563: 379-384,1991
Dumbrille-Ross A, Tang SW. Manipulations of synaptic serotonin:
discrepancy of effects on serotonin S1 and S2 sites. Life Science
32:2677-2684,1983
Eisen A. Fluoxetine and desipramine: a strategy for augmenting antidepressant response. Pharmacopsychiatry 22: 272-273, 1989
Farid NA, Bergstrom RF, Lemberger L, Ziege EA, Tenbarge J, et al.
Studies on disposition of fluoxetine and radioactive isotopes. 15th
Collegium International Neuro-Psychopharmacologicum Congress, Puerto Rico, 1986
Fichtner CG, Johe LH, Braun BG. Does fluoxetine have a therapeutic
window? Lancet 7: 520-521, 1991
Fuller RW, Wong DT. Serotonin re-uptake blockers in vitro and in
vivo. Journal of Clinical Psychopharmacology 7: 365-435, 1987
Goff DC, Brotman AW, Waites RN, McCormick S. Trial of fluoxetine added to neuroleptics for treatment-resistant schizophrenic patients. American Journal of Psychiatry 147: 492-494, 1990
Goff DC, Midha KK, Brotman AW, Waites M, Baldessarini RJ. Elevation of plasma concentrations of haloperidol after the addition
of fluoxetine. American Journal of Psychiatry 148: 790-792,1991
Goodnick PJ. Influence of fluoxetine on plasma levels of desipramine. AmericanJournal of Psychiatry 146: 552, 1989
Goodnick PJ. Pharmacokinetics of second generation antidepressant: fluoxetine. Psychopharmacology Bulletin 27: 503-512, 1991
Greenblatt DJ, Preskorn SH, Cotreau MM, Horst WD, Harmatz JS.
Fluoxetine impairs clearance of alprazolam but not of clonazepam.
Clinical Pharmacology and Therapeutics 52:479-486, 1992
Grimsley SR, Jann MW, Garter JG, Mello AP, Souza MJ. Increased
carbamazepine
plasma
concentrations
after
fluoxetine
coadministration. Clinical Pharmacology and Therapeutics 50:1015,1991
Hansen TE, Dieter K, Keepers GA. Interaction of fluoxetine and
pentazocine. American Journal of Psychiatry 147: 949-950, 1990

213

Jarvis MR. Clinical pharmacokinetics of tricyclic antidepressant


overdose. Psychopharmacology Bulletin 27: 541-550, 1991
Kelly MW, Perry PJ, Holstad SG, Garvey MJ. Serum fluoxetine and
norfluoxetine concentrations and antidepressant response. Thera peutic Drug monitoring 11:165-170, 1989.
Ketai R. interaction between fluoxetine and neurble ptics. American
Journal of Psychiatry 150 : 836-837, 1993
Kinkaid RL, McMullin MM, Crookman SB, Riders F. Report of a
fluoxetine fatality. Journal of Analytical Toxicology 14: 327-329, 1990
Lasher TA, Fleishaker JC, Steenwyk RC, Antal EJ. Pharmacokinetic
pharmacodynamic evaluation of the combined administration of
alprazolam and fluoxetine. Psychopharmacology 104: 323 -327,
1991
Lemberger L, Bergstrom RF, Wolen RL, Farid NA, Enas GG, et al.
Fluoxetine: clinical pharmacology and physiologic disposition.
Journal of Clinical Psychiatry 46: 14-19, 1985
Lemberger L, Rowe H, Bergstrom RF, Farid KZ, Enas GG. Effect of
fluoxetine on psychomotor performance, physiologic response, and
kinetics of ethanol. Clinical Pharmacology and Therapeutics 37: 658664, 1995
Lemberger L, Rowe H, Bosomworth JC, Tenbarge JB, Bergstrom RF.
The effect of fluoxetine on the pharmacokinetics and psycho -motor
response of diazepam. Clinical Pharmacology and Thera-peutics 43:
413-419, 1988
Lock JD, Gwirtsman HE, Targ EF, possible adverse drug interactions
between fluoxetine and other psychotropics. Journal of Clinical
Psychopharmacology 10: 383-384, 1990
Martensson B, Nyberg S, Toresson G, Brodin E, Bertilsson L.
Fluoxetine treatment of depression. Acta Psychiatric a
Scandinavica 79: 586-596, 1989
Montgomery SA, Baldwin D, Shah A, Green M, Fineberg N, et al.
Fluoxetine treatment of depression. Clinical Neuropharmacology 13
(Suppl. 1): 71-75, 1990
Montgomery S A, James D, de Ruiter M, et al. Weekly oral fluoxetine
treatment of major depressive disorder, controlled trial. 15th Col-legium
International Neuro-Psychopharmacologicum Congress, Puerto Rico,
1986
Nash JF, Bopp RJ, Carmichaell RH, et al. Determination of fluoxet -ine
and norfluoxetine in plasma by gas chromatography with elec -troncapture detection. Clinical Chemistry 28: 2100-2102, 1982
Nebert DW, Nelson DR, Coon MJ, Estabrook RW, Feyereisen R, et
al. The P450 superfamily: update on new sequences; gene map ping, and recommended nomenclature. DNA and Cell Biology 10:
1-4, 1991
Nelson JC. Mazure CM, Bowers Jr MB, Jatlow PI. A preliminary,
open study of the combination of fluoxetine and desipramine for
rapid treatment of major depression. Archives of General Psychi atry 48: 303-307, 1991
Nichols JH, Charlson JR, Lawson GM. Plasma fluoxetine and
norfluoxetine by automated HPLC. Clinical Chemistry 38 (6):
1012, 1992
Nies A, Robinson DS, Friedman MJ, et al. Relationship between age
and tricyclic antidepressant plasma levels. Ame rican Journal of
Psychiatry 134: 790-793, 1977
Orsulak PJ, Kenney JT, Debus JR, Crowley G, Wittman PD. Deter mination of the antidepressant fluoxetine and its metabolite
norfluoxetine in serum by reversed -phase HPLC, with ultraviolet
detection. Clinical Chemistry 34: 1875-1878, 1988
Otton SV, Wu D, Joffe RT, Cheung SW, Sellers EM. Inhibition by
fluoxetine of cytochrome P450 activity. Clinical Pharmacology &
Therapeutics 53: 401-409, 1993
Potter WZ, Manji HK. Antidepressants, metabolites and apparent
drug resistance Clinical Neuropharmacology (Suppl. 1) 13:45-53, 1 9 9 0
Preskorn SH. Pharmacokinetics of antidepressants: why and how
they are relevant to treatment? Journal of Clinical Psychiatry 54
(Suppl.):2-22,1993

214

Preskorn SH, Beber JH, Paul JC, Hirschfeld RMA. Serious adverse
effects of combining fluoxetine and tricyclic antidepressants.
American Journal of Psychiatry 147: 532,1990
Renshaw PF, Guimaraes AR, Fava M, Rosenbaum JF, Pearlman JD, et al.
Accumulation of fluoxetine and norfluoxetine in human brain during
therapeutic administration. American Journal of Psychiatry 149: 15921594, 1992
Roethger JR. The importance of blood collection site for determina-tion
of basic drugs: a case with fluoxetine and diphenhydramine overdose.
Journal of Analytical Toxicology 14: 191-192, 1990
Rohrig TP, Prouty RW. Fluoxetine Overdose: a case report. Journal of
Analytical Toxicology 13: 305-307, 1989
Rosenthal J, Hemlock C, Hellerstein DJ, Yanowitch P, Kasch K, et al. A
preliminary study of serotonergic antidepressants in the treat-ment of
dysthymia. Progress in Neuro-Psychopharmacology and Biological
Psychiatry 16: 933-941, 1992
Saletu B, Grunberger J. Classification and determination of cerebral
bioavailability of fluoxetine: pharmacokinetic, pharmaco-EEG, and
psychometric analyses. Journal of Clinical Psychiatry 46: 45-52,1985
Schenker S, Bergstrom RF, Wolen RL, Lemberger L. Fluoxetine
disposition and elimination in cirrhosis. Clinical Pharmacology and
Therapeutics 44: 353-359, 1988
Sindrup SH, Brosen K, Gram LF, Hallas J, Skjelbo E, et al. The
relationship between paroxetine and sparteine oxidation polymorphism. Clinical Pharmacology and Therapeutics 51: 278-287, 1992
Sjoqvist F. Pharmacogenetics of antidepressants. In Dahl & Gram (Eds)
Clinical pharmacology: psychiatry, pp. 181-191, Springer-Verlag,
Berlin, Heidelberg, 19899
Sommi RW, Crismon ML, Bowden CL. Fluoxetine a serotonin-spe-cific,
second-generation antidepressant. Pharmacotherapy 7: 1-15, 1987

Clin. Pharmacokinet. 26 (3) 1994

Suckow RF, Roose SP, Cooper TB. Effect of fluoxetine on plasma


desipramine and 2-hydroxydesipramine. Biological Psychiatry 31: 200204, 1992a
Suckow RF, Zhang MF, Cooper TB. Sensitive and selective liquidchromatographic assay of fluoxetine and norfluoxetine in plasma with
fluorescence detection after precolumn derivatization. Clini-cal
Chemistry 38: 1756-1761, 1992b
Tate JL. Extrapyramidal symptoms in a patient taking haloperidol and
fluoxetine. American Journal of Psychiatry 146: 399-400, 1989
van Harten J. Clinical pharmacokinetics of selective serotonin
reuptake inhibitors. Clinical Pharmacokinetics 24 (3): 203-220, 1993
Vaughan DA. Interaction of fluoxetine with tricyclic antidepressants.
American Journal of Psychiatry 145: 1478, 1988
von Ammon Cavanaugh S. Drug-drug interactions of fluoxetine with
tricyclics. Psychosomatics 31: 273-276, 1990
Wamsley JK, Byerley WF, McCabe RT, et al. Receptor alterations
associated with serotonergic agents: an autoradiographic analysis.
Journal of Clinical Psychiatry 48: 19-25, 1987
Wilens TE, Biederman J, Baldessarini RJ, McDermott SP, Puopolo PR,
et al. Fluoxetine inhibits desipramine metabolism. Archives of General
Psychiatry 49: 752, 1992
Wright CE, Lasher Sisson TA, Steenwyk RC, Swanson CN. A pharmacokinetic evaluation of the combined administration of
triazolam and fluoxetine. Pharmacotherapy 12: 103-106, 1992
Zanger UM, Vilbois F, Hardwick JP, Meyer UA. Absence of hepatic
cytochrome P450I causes genetically deficient debrisoquine oxidation in man. Biochemistry 27: 5-447-5454,1988

Correspondence and reprints: Professor A. Carlo Altamura,


Dipartimento di Psichiatria, Universita di Cagliari, Viale Liguria 13,
09127 Cagliari, Italy.

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