Clin Pharmacokinet 2005; 44 (6): 571-590

REVIEW ARTICLE 0312-5963/05/0006-0571/$34.95/0

© 2005 Adis Data Information BV. All rights reserved.

Clinical Pharmacokinetics
of Atomoxetine
John-Michael Sauer,1 Barbara J. Ring2 and Jennifer W. Witcher2
1 Elan Pharmaceuticals, Inc., South San Francisco, California, USA
2 Department of Drug Disposition, Lilly Research Laboratories, Eli Lilly and Company,
Indianapolis, Indiana, USA

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 571
1. Overview of Pharmacological Agents Used for the Treatment of Attention-Deficit Hyperactivity
Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 572
2. Physicochemical Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 574
3. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 574
3.1 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 574
3.2 Absorption and Bioavailability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 576
3.3 Distribution and Protein Binding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 577
3.4 Metabolism and Excretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 577
4. Overview of Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 581
4.1 Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 581
4.2 In Vitro and In Vivo Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 581
4.3 Clinical Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 582
5. Pharmacokinetic Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 583
5.1 Interactions with Food . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 583
5.2 Interactions with Paroxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 583
5.3 Interactions with Desipramine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 584
5.4 Interactions with Midazolam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 584
6. Implications of Pharmacokinetic Properties for Therapeutic Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 585
6.1 Dosages and Therapeutic Range . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 585
6.2 Sex and Racial Differences in Atomoxetine Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . 585
6.3 Influence of Age and Bodyweight on Atomoxetine Pharmacokinetics . . . . . . . . . . . . . . . . . . . . 585
6.4 Diseases and the Pharmacokinetics of Atomoxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 586
6.4.1 Chronic Impairment of Renal Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 586
6.4.2 Hepatic Insufficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 586
7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 587

Abstract Atomoxetine (Strattera®), a potent and selective inhibitor of the presynaptic

norepinephrine transporter, is used clinically for the treatment of attention-deficit
hyperactivity disorder (ADHD) in children, adolescents and adults. Atomoxetine
has high aqueous solubility and biological membrane permeability that facilitates
its rapid and complete absorption after oral administration. Absolute oral bioavai-
lability ranges from 63 to 94%, which is governed by the extent of its first-pass
metabolism. Three oxidative metabolic pathways are involved in the systemic
clearance of atomoxetine: aromatic ring-hydroxylation, benzylic hydroxylation
572 Sauer et al.

and N-demethylation. Aromatic ring-hydroxylation results in the formation of the

primary oxidative metabolite of atomoxetine, 4-hydroxyatomoxetine, which is
subsequently glucuronidated and excreted in urine. The formation of 4-hydroxy-
atomoxetine is primarily mediated by the polymorphically expressed enzyme
cytochrome P450 (CYP) 2D6. This results in two distinct populations of individu-
als: those exhibiting active metabolic capabilities (CYP2D6 extensive metabolis-
ers) and those exhibiting poor metabolic capabilities (CYP2D6 poor metabolisers)
for atomoxetine.
The oral bioavailability and clearance of atomoxetine are influenced by the
activity of CYP2D6; nonetheless, plasma pharmacokinetic parameters are predict-
able in extensive and poor metaboliser patients. After single oral dose, atomoxe-
tine reaches maximum plasma concentration within about 1–2 hours of
administration. In extensive metabolisers, atomoxetine has a plasma half-life of
5.2 hours, while in poor metabolisers, atomoxetine has a plasma half-life of 21.6
hours. The systemic plasma clearance of atomoxetine is 0.35 and 0.03 L/h/kg in
extensive and poor metabolisers, respectively. Correspondingly, the average
steady-state plasma concentrations are approximately 10-fold higher in poor
metabolisers compared with extensive metabolisers. Upon multiple dosing there
is plasma accumulation of atomoxetine in poor metabolisers, but very little
accumulation in extensive metabolisers. The volume of distribution is 0.85 L/kg,
indicating that atomoxetine is distributed in total body water in both extensive and
poor metabolisers. Atomoxetine is highly bound to plasma albumin (approximate-
ly 99% bound in plasma). Although steady-state concentrations of atomoxetine in
poor metabolisers are higher than those in extensive metabolisers following
administration of the same mg/kg/day dosage, the frequency and severity of
adverse events are similar regardless of CYP2D6 phenotype.
Atomoxetine administration does not inhibit or induce the clearance of other
drugs metabolised by CYP enzymes. In extensive metabolisers, potent and
selective CYP2D6 inhibitors reduce atomoxetine clearance; however, administra-
tion of CYP inhibitors to poor metabolisers has no effect on the steady-state
plasma concentrations of atomoxetine.

1. Overview of Pharmacological Agents ing oppositional defiant disorder, conduct disorder,

Used for the Treatment of
Attention-Deficit Hyperactivity Disorder
Attention-deficit hyperactivity disorder (ADHD)
is the most common neurobehavioural disorder of
childhood. The incidence of ADHD is 5–10% in
children and the symptoms are known to persist into
adulthood in 10–60% of cases.[1-5] Behavioural fea-
tures of ADHD include inattention, hyperactivity
and impulsivity, which may lead to academic under-
achievement, poor interpersonal relationships and
low self esteem.[6] Additionally, comorbid medical
conditions are often associated with ADHD, includ-
depression, anxiety disorders and tic disorders.[7,8]
The exact aetiology of ADHD is unknown, al-
though neurotransmitter deficits, genetic traits and
prenatal complications have been implicated.[9]
Symptoms of ADHD respond to treatment with psy-
chostimulants. These drugs have been demonstrated
to increase the availability of extracellular dopamine
by blocking dopamine transporters[10] and in some
cases enhancing dopamine release.[11] Psychostimu-
lants are the most common pharmacological inter-
vention used in the treatment of ADHD.[12] A detri-
mental attribute associated with the drugs in this

© 2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (6)
Clinical Pharmacokinetics of Atomoxetine
class (pemoline, methylphenidate and amphet-
amines) is their potential for abuse.[13] These effects
place the psychostimulant drugs as Schedule II or IV
(pemoline), putting them under close monitoring by
regulators. As these drugs were developed many
years ago, contemporary clinical metabolism and
drug interaction studies are lacking or have only
recently received description. Markowitz and Pat-
rick[14] provide an authoritative review on the
pharmacokinetic and pharmacodynamic interactions
of psychostimulants with other drugs.
Among the psychostimulants, methylphenidate
in a variety of formulations (Ritalin® 1, Ritalin LA®,
Novartis Pharmaceuticals Corporation, East Hano-
ver, NJ, USA; Concerta®, Alza Corporation, Moun-
tain View, CA, USA) is the most widely pre-
scribed medication for the treatment of ADHD.
Methylphenidate, a dopamine transporter inhibitor,
does not appear to be a substrate for transport into
the neuron and it elicits little presynaptic dopamine
release. Methylphenidate is a racemic mixture of
threo-(R,R)-(+)- and threo-(S,S)-(–)-isomers, but
some marketed forms only include a single enanti-
omer [threo-(R,R)-(+)-isomer]. Methylphenidate is
rapidly cleared from the systemic circulation and
has a half-life of 2.5 hours. Recently, several modi-
fied-release products (Concerta®, Ritalin LA®)
have been introduced into the market to extend the
apparent plasma half-life of methylphenidate by al-
tering its absorption kinetics.[15,16]
Dexamfetamine, the (S)-(+)-isomer of amfe-
tamine, as well as mixed isomers (81% [–] and 19%
[+]) of amfetamine salts have been demonstrated to
be an effective treatment of ADHD. Amfetamine is
cleared from the systemic circulation by oxidative
metabolism and has a half-life of approximately 12
hours. Recently, a longer acting formulation, Adder-
all XR® (Shire Laboratories, Inc., Wayne, PA,
USA), was introduced into the market. Adderall
XR® alters the pharmacokinetics of the mixed am-
phetamine salts by prolonging the absorption kinet-
ics.[17] Aromatic oxidation catalysed by cytochrome
P450 (CYP) 2D6 is the primary means of systemic
1 The use of trade names is for product identification purposes only and does not imply endorsement.
© 2005 Adis Data Information BV. All rights reserved.
573
clearance for the amphetamines.[18] Definitive
clinical drug interaction studies with CYP2D6 in-
hibitors or substrates have not been reported for
amfetamine. Likewise, the effect of the polymorphic
expression of CYP2D6 on the metabolism of
amfetamine has not been reported.
Pemoline (Cylert®, Abbott Laboratories, Abbott
Park, IL, USA), unlike the other psychostimulants,
is not a phenethylamine derivative. The risk of
hepatotoxicity has significantly limited the clinical
usage of pemoline.[19] The half-life of pemoline is
approximately 12 hours and it is typically adminis-
tered once daily. The isoforms of CYP responsible
for oxidative metabolism of pemoline are unknown.
Additionally, there are no published reports on the
interaction of pemoline with other drugs.
Several other pharmacological interventions in-
cluding tricyclic antidepressants and selective sero-
tonin reuptake inhibitors have been used to treat
ADHD.[20] However, until the recent introduction of
atomoxetine (Strattera®; Eli Lilly and Company,
Indianapolis, IN, USA), a potent and selective
norepinephrine reuptake inhibitor,[21] no new medi-
cations have been developed for the treatment of this
disease over the last 3 decades. Atomoxetine in-
creases both dopamine and norepinephrine in the
prefrontal cortex.[22] This is markedly different from
the actions of psychostimulants like methylpheni-
date, which increases dopamine in the prefrontal
cortex, as well as the striatum and nucleus accum-
bens.[22] Neurotransmitter changes in the striatum
and nucleus accumbens are postulated to be respon-
sible for the abuse potential associated with psy-
chostimulants.[13]
With a favourable safety profile and novel mech-
anism of action, atomoxetine represents an advance
for the treatment of ADHD in children, adolescents
and adults.[23-27] In 2003, atomoxetine was launched
in the US and is currently marketed under the brand
name Strattera®. Atomoxetine is the first nonstimu-
lant treatment approved by the US FDA for ADHD
and has the advantage of not being a scheduled drug.
Clin Pharmacokinet 2005; 44 (6)
574
2. Physicochemical Properties
Atomoxetine hydrochloride is known chemically
as (–)-N-methyl-3-phenyl-3-(o-tolyloxy)-propy-
lamine hydrochloride, or (–)-N-methyl-γ-(2-
methylphenoxy) benzenepropanamine hydrochlo-
ride (figure 1). Atomoxetine is marketed as the R(–)
isomer (apparent inhibition constant [Ki] = 1.9
nmol/L), which is approximately 9-fold more potent
as an inhibitor of the norepinephrine transporter than
the S(+) isomer (Ki = 16.8 nmol/L).[21] Compared to
its effect on the norepinephrine transporter, atomox-
etine (R(–) isomer) has very little affinity for the
dopamine (Ki = 1800 nmol/L) or serotonin (Ki = 750
nmol/L) transporters.[21] Atomoxetine hydrochloride
(C17H21NO • HCl) has a molecular weight of 291.8
and a free base molecular weight of 255.4. Atomox-
etine hydrochloride is a white to practically white
solid. Its solubility is 27.8 mg/mL in water and its
dissociation constant (pKa) is 10.13.
3. Pharmacokinetics
3.1 Overview
Following oral administration, atomoxetine is
well absorbed. It is primarily cleared from the body
via oxidative metabolism and is subsequently elimi-
nated into the urine as conjugated metabolites.[28]
Similar to many compounds, the biotransformation
of atomoxetine governs its overall disposition in
humans. As a result of the central role of CYP2D6 in
the metabolism of atomoxetine, the activity of this
enzyme plays a significant role in its pharmacoki-
netics.[28-30]
The enzymatic activity of CYP2D6 is determined
by a genetic polymorphism resulting in two primary
populations of individuals with either extensive or
poor metabolic capabilities for substrates of this
H uals, the absorption is rapid and the maximum plas-
H3C N ma concentration (Cmax) of atomoxetine is 533
O 1 mg/kg dose and occurs at a median time of 1–2
CH3
Fig. 1. Chemical structure of atomoxetine, a selective nore-
pinephrine transporter inhibitor.
© 2005 Adis Data Information BV. All rights reserved.
Sauer et al.
enzyme (table I and figure 2).[31] The majority of
people (>90%), who metabolise atomoxetine and
other CYP2D6 substrates relatively rapidly, are des-
ignated as CYP2D6 extensive metabolisers. These
individuals possess a range of activities considered
to be normal CYP2D6 activity. Mutations or dele-
tion of the CYP2D6 gene results in a minority of
people (up to 7%) who are known as poor
metabolisers of CYP2D6 substrates and metabolise
atomoxetine relatively slowly. As the clearance of
atomoxetine is influenced by its metabolism, it is not
surprising that its clearance across patients results in
a bimodal distribution indicative of a genetic poly-
morphism (figure 3).
The extensive metaboliser population can be sub-
divided into three groups based on the number of
available wild-type alleles, homozygous, heterozy-
gous and ultra-rapid metabolisers. Ultra-rapid
metabolisers of CYP2D6 substrates result from gene
duplication of functional CYP2D6 alleles.[32] The
ultra-rapid metabolisers genotype accounts for ap-
proximately 3–7% of the population.[33] The ultra-
rapid metaboliser population appears to be compara-
ble to the upper end of the extensive metaboliser
range, with a great deal of overlap of apparent
plasma clearance (CL/F) values between ultra-rapid
metaboliser and extensive metaboliser patients (fig-
ure 3). The extensive metaboliser subpopulations
are not distinguishable from each other on an indi-
vidual patient basis. Therefore, genotype is more
useful for differentiating extensive and poor
metabolisers, rather than predicting an individual’s
precise clearance within the extensive metaboliser
range of clearances.
The plasma pharmacokinetic parameters of ato-
moxetine in extensive and poor metaboliser subjects
have been reported in a number of publications
(table II).[28-30,34-37] In extensive metaboliser individ-
ng/mL (coefficient of variance [CV] 32%) after a
hours following oral administration.[36] The mean
half-life is 5.2 hours (range 3.7–7.5 hours) with a
mean CL/F of 0.35 L/h/kg (intersubject CV
Clin Pharmacokinet 2005; 44 (6)
Clinical Pharmacokinetics of Atomoxetine 575

Table I. Noncompartmental pharmacokinetic parameters for atomoxetine and its metabolites in cytochrome P450 (CYP) 2D6 extensive and
poor metabolisers following oral administration of atomoxetine 20mg twice daily (≈0.5 mg/kg/day)[28]
Parameter Arithmetic mean (CV %)
atomoxetine 4-hydroxyatomoxetine N-desmethylatomoxetine 4-hydroxyatomoxetine-
O-glucuronide
CYP2D6 extensive metabolisers
Cmax,ss (ng/mL) 159.70 (51.9) 2.03 (17.5) 7.02 (71.5) 413.88 (35.5)
Cmin,ss (ng/mL) 36.05 (115.8) 0.52 (115.6) 3.12 (113.6) 104.36 (19.3)
Cav,ss (ng/mL) 89.64 (64.3) 5.15 (86.4) 228.70 (13.6)
tmaxa (h) 2.00 (1.00–3.00) 2.50 (2.00–4.00) 3.50 (2.00–6.00) 2.00 (2.00–4.00)
t1/2b (h) 5.34 (3.67–9.09) 8.97 (2.11–21.9) 6.74 (5.90–8.30)
AUCτ (μg • h/mL) 1.08 (64.3) 0.0618 (86.4) 2.74 (13.6)
CLss/F (L/h/kg) 0.373 (75.1)
Vz/F (L/kg) 2.33 (51.0)

CYP2D6 poor metabolisers

Cmax,ss (ng/mL) 914.72 (30.5) 259.22 (39.6) 88.00 (16.9)
Cmin,ss (ng/mL) 502.84 (29.2) 193.09 (40.6) 69.27 (16.4)
Cav,ss (ng/mL) 703.63 (26.9) 234.89 (41.2) 77.88 (17.0)
tmaxa (h) 2.00 (2.00–3.00) 6.00 (3.00–6.00) 4.00 (2.00–6.00)
t1/2b (h) 20.0 (16.8–25.2) 33.3 (27.7–42.7) 19.0 (15.2–22.8)
AUCτ (μg • h/mL) 8.44 (26.9) 2.82 (41.2) 0.935 (17.0)
CLss/F (L/h/kg) 0.0357 (26.2)
Vz/F (L/kg) 1.06 (42.9)
a Median (range).
b Mean (range).
AUCτ = area under the plasma concentration-time curve during a dosage interval (τ) at steady state; CLss/F = apparent plasma clearance at
steady-state; Cav,ss = average steady-state drug concentration in plasma; Cmax,ss = maximum (peak) steady-state drug concentration in the
plasma; Cmin,ss = minimum (trough) steady-state drug concentration in the plasma; CV = coefficient of variance; t1/2 = half-life; tmax = time to
maximum plasma concentration; Vz/F = apparent volume of distribution during terminal phase.

56%).[37] The volume of distribution is 0.85 L/kg
(CV 16%) after an intravenous dose, indicating that
atomoxetine is distributed in total body water in
both extensive and poor metabolisers.[37] With a
short half-life and rapid clearance, accumulation
after twice-daily administration is minimal (mean
9%, range 5–15%) with a mean plasma fluctuation
of 273%.[36] The mean maximum steady-state plas-
ma concentration (Cmax,ss) is 584 ng/mL (CV 46%)
after 1 mg/kg twice-daily administration and, when
compared with Cmax following a single dose, indi-
cates minimal accumulation.[36]
The poor metaboliser trait, inherited as an autoso-
mal recessive characteristic, is an important source
of intersubject variability in metabolism for a num-
ber of drugs metabolised through CYP2D6.[38,39]
Although the inability to metabolise CYP2D6 sub-
strates is principally mediated by the genetic poly-
morphism associated with CYP2D6, the phenotypic
manifestation of this condition can result from expo-
sure to potent inhibitors of this metabolic pathway.
In individuals lacking CYP2D6 activity, oxidative
metabolism is still the primary route of atomoxetine
clearance, albeit at a much slower rate than that
observed in extensive metabolisers. In poor
metabolisers, the mean Cmax after a single 1 mg/kg
dose is approximately 2-fold higher than Cmax for
extensive metabolisers. The mean half-life in poor
metabolisers is considerably longer than in exten-
sive metabolisers (21.6 hours, range 14.1–26.8
hours) and the CL/F (0.03 L/h/kg, intersubject CV
19%) is about one-tenth of the extensive metabolis-
ers’ value.[37] The mean apparent volume of distribu-
tion (1.06 L/kg, CV 43%) is about half the extensive
metabolisers’ value, likely due to differences in first
pass metabolism.[28] The average steady-state plas-

© 2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (6)
576 Sauer et al.

Atomoxetine
N-desmethylatomoxetine
4-Hydroxyatomoxetine
4-Hydroxyatomoxetine-O-glucuronide

a b

1000

800

600

400
Plasma concentration (μg/L)

200

1000

100

10

0.1
−12 0 12 24 36 48 60 72 0 24 48 72 96 120 144 168 192 216
Time (h)
Fig. 2. Mean plasma concentration-time profiles (cartesian [upper panel] and semi-log [lower panel]) for cytochrome P450 2D6 extensive
metabolisers (a) and poor metabolisers (b). Multiple 20mg doses of atomoxetine were administered twice daily for 6 days.

ma concentration (Cav,ss) is about 10-fold higher
than observed in extensive metabolisers and is readi-
ly predictable from half-life and dosing interval.
Although Cav,ss is approximately 10-fold higher in
poor metabolisers compared with extensive
metabolisers, at the Cmax,ss the difference is only
about 5-fold.[37] For example, following 6 days of
20mg twice-daily administration of atomoxetine
(≈0.5 mg/kg/day) the mean Cav,ss was 90 ng/mL
(CV 64%) in extensive metabolisers and 704 ng/mL
(CV 27%) in poor metabolisers.[28] The mean
Cmax,ss was 160 ng/mL (CV 52%) in extensive
metabolisers and 915 ng/mL (CV 31%) in poor
metabolisers.[28] The dissimilarities observed be-
tween extensive and poor metabolisers are princi-
pally mediated by differences in first-pass metabo-
lism and clearance rather than being driven by dif-
ferences in absorption of atomoxetine.
3.2 Absorption and Bioavailability
As a result of its high water solubility, as well as
its favourable dissolution and intestinal permeability
characteristics, atomoxetine is rapidly absorbed fol-
lowing oral administration.[28] The absolute oral
bioavailability of atomoxetine is 94% (90% CI 0.88,
0.99) in poor metabolisers and 63% (90% CI 0.59,
0.67) in extensive metabolisers, indicating nearly
complete absorption with higher first-pass metabo-

© 2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (6)
Clinical Pharmacokinetics of Atomoxetine
lism in extensive metabolisers.[40] Food does not
affect the extent of atomoxetine absorption but does
decrease Cmax (37% with a standard high-fat break-
fast and 9% with a more typical meal) and delays
time to reach maximum plasma concentration (tmax)
by 3 hours.[37,40]
3.3 Distribution and Protein Binding
The tissue and organ distribution of atomoxetine
was evaluated in rats following an oral dose (50
mg/kg) of radiolabelled atomoxetine.[41] Peak con-
centrations of radiocarbon occurred at 1 hour after
administration in nearly all tissues. By 8 hours after
administration, radiocarbon associated with most
tissues, including the brain, had declined to either
low or background levels.
In humans, regardless of CYP2D6 status, atom-
oxetine is well distributed and its volume of distri-
bution is equivalent to total body water at 0.85
L/kg.[37] Atomoxetine and its metabolites undergo
only limited partitioning into human red blood
cells.[28] In plasma, atomoxetine is highly protein-
bound (98.7% bound in plasma) primarily to albu-
min.[28] The plasma protein binding of N-desmethy-
latomoxetine (99.1% bound) is similar to atomoxe-
tine, while the binding of 4-hydroxyatomoxetine to
plasma protein (66.6% bound) is substantially less
than atomoxetine.[28] In vitro drug-displacement
studies demonstrated that atomoxetine did not affect
the binding of warfarin, aspirin (acetylsalicylic ac-
id), phenytoin and diazepam to human albumin.[37]
Similarly, these compounds did not affect the bind-
ing of atomoxetine to human albumin.
The ability of atomoxetine and its metabolites to
cross the placenta was examined in gravid rats fol-
lowing an oral dose (50 mg/kg) of radiolabelled
atomoxetine on gestational day 18.[42] Atomoxetine
and/or its metabolites crossed the placenta. None-
theless, fetal tissue exposure was substantially less
than that observed in maternal tissues. The distribu-
tion of radioactivity in milk was investigated in
lactating rats. Only a small amount of atomoxetine
and/or its metabolites were present in rat milk (<1%
of the dose).
© 2005 Adis Data Information BV. All rights reserved.
577
3.4 Metabolism and Excretion
As with many compounds, the rate of metabolism
of atomoxetine governs its overall pharmacokinetic
profile in humans.[28] Atomoxetine is primarily
cleared from the body by oxidative metabolism and
nearly all of its metabolites are eliminated by excre-
tion into urine. Three primary biotransformation
reactions direct the overall metabolism of atomoxe-
tine: aromatic ring-hydroxylation, benzylic hydrox-
ylation and N-demethylation. For most of the prima-
ry metabolites, secondary aromatic oxidation is also
observed. Conjugation of hydroxylated metabolites
by uridine diphosphate glucuronosyltransferase is
the only conjugation (phase II) metabolic pathway
to participate in the biotransformation of atomoxe-
tine. Figure 4 illustrates the overall biotransforma-
tion of atomoxetine in humans.
Aromatic ring-hydroxylation forms the primary
oxidative metabolite of atomoxetine, 4-hydroxyato-
moxetine. This metabolite is subsequently glu-
curonidated and excreted in urine.[28] Biotrans-
formation of atomoxetine to 4-hydroxyatomoxetine
is primarily mediated by CYP2D6.[43] Therefore, the
overall pharmacokinetic parameters of atomoxetine
are influenced by polymorphic expression of this
enzyme. In individuals lacking CYP2D6 activity, 4-
hydroxyatomoxetine is still the major oxidative me-
tabolite. This fact demonstrates that the metabolite
can also be formed by several isoforms of CYP,
albeit at a much lower efficiency than CYP2D6. The
80 PM
EM
UM
60
No. of patients
40
20
0
0 1 2 3 4 5
Ln (CL/F) [L/h/kg]
Fig. 3. Frequency distribution of individual atomoxetine clearance
values based on cytochrome P450 2D6 genotype. EM = extensive
metaboliser; Ln (CL/F) = log transformed apparent plasma clear-
ance; PM = poor metaboliser; UM = ultra-rapid metaboliser.
Clin Pharmacokinet 2005; 44 (6)
 Table II. Summary of atomoxetine pharmacokinetic parametersa

Dosage No. of subjects Age group tmax Cmax or Cmax,ss t1/2 CL/F Vz/F Reference
578
(h) (ng/mL) (h) (L/h/kg) (L/kg)
Healthy CYP2D6 extensive metabolisers (single dose)

10mg PO 7 Paediatric 2 144 3.1 0.46 2.0 36

20mg PO 10 Adult 1 142 4.3 0.51 2.7 34

Healthy CYP2D6 extensive metabolisers (multiple dose)

20mg PO, bid 4 Adult 2 160 5.3 0.37 2.3 35

20mg PO, bid 21 Adult 1 184 4.0 0.40 2.2 30

20–45mg PO, bid 16 Paediatric 1.7 537 3.3 0.48 2.3 36

© 2005 Adis Data Information BV. All rights reserved.

40mg PO, bid 6 Adult 1 552 4.0 0.33 1.5 35

60mg PO, bid 15 Adult 1 591 3.4 0.40 1.8 35

Healthy CYP2D6 poor metabolisers (multiple dose)

20mg PO, bid 3 Adult 2 915 20 0.04 1.1 28

60mg PO, bid 6 Adult 4 2610 0.04 35

Healthy CYP2D6 extensive metabolisers (multiple dose) with CYP2D6 inhibitor

20mg PO, bid 14 Adult 1.5 690 11 0.06 0.8 30

CYP2D6 extensive metabolisers with hepatic impairment (single dose)

20mg POb 6 Adult 3 116 11 0.21 3.3 34

20mg POc 4 Adult 6 126 16 0.16 2.7 34

a The study by Farid et al.[29] contains compartmental analysis for atomoxetine in extensive and poor metabolisers, which is not shown in this table as different parameters
were calculated.

b Child-Pugh B.

c Child-Pugh C.

bid = twice daily; CL/F = apparent plasma clearance; Cmax = maximum observed plasma concentration; Cmax,ss = maximum (peak) steady-state drug concentration in the plasma;
CYP = cytochrome P450; PO = oral; t1/2 = half-life; tmax = time to reach Cmax; Vz/F = apparent volume of distribution during terminal phase.

Clin Pharmacokinet 2005; 44 (6)

Sauer et al.
Clinical Pharmacokinetics of Atomoxetine 579

average Michaelis-Menten constant (Km) for 4-
hydroxyatomoxetine formation in human liver mi-
crosomes containing a full complement of CYP was
2.3 μmol/L, and in CYP2D6-deficient microsomes
was 149 μmol/L. In addition, the estimated intrinsic
clearance (CLint) for 4-hydroxyatomoxetine forma-
tion was 200-fold higher for the microsomes with a
full complement of CYPs than that calculated for the
CYP2D6-deficient microsomes (103 versus 0.2 μL/
min/mg, respectively).[43]
Atomoxetine undergoes the same biotransforma-
tion regardless of CYP2D6 activity, with no pheno-
type-specific metabolites being formed in extensive
H2N
CYP2C19
O O
CH3
N-desmethylatomoxetine
and poor metabolisers.[28] Although the overall me-
tabolism of atomoxetine is similar regardless of
CYP2D6 status, quantitative amounts of metabolites
formed and the rate of their formation are different
between extensive and poor metabolisers. Radio-
labelled atomoxetine has been given to extensive
and poor metabolisers. The mean Cmax of radioac-
tivity is essentially the same in both extensive and
poor metabolisers, but the area under the plasma
concentration-time curve from zero to infinity
(AUC∞) was larger in poor metabolisers because of
the slower metabolism and elimination. The mean
half-life of atomoxetine-derived radioequivalents is
HO2C
H2N O
(CYP2D6) OH UGT H2N OH
O OH
HO
O
CH3
CH3
N-desmethyl-4-hydroxyatomoxetine N-desmethyl-4-hydroxyatomoxetine-O-glucuronide

HO2C
H H
H3C N H3 C N H O
CYP2D6 UGT H3C N OH
OH
O OH
HO
O O
O
CH3 CH3
CH3
Atomoxetine 4-Hydroxyatomoxetine 4-Hydroxyatomoxetine-O-glucuronide

H
H H3C N
H3 C N
UGT HO2C
O O
O OH
C O OH
CH2OH H2 HO
2-Hydroxymethylatomoxetine 2-Hydroxymethylatomoxetine-O-glucuronide

H H H
H3C N H3C N H3C N HO2C
OH OH
UGT O
OH
OH
O O O HO
COOH COOH COOH
2-Carboxyatomoxetine Hydroxy-2-carboxyatomoxetine Hydroxy-2-carboxyatomoxetine-O-glucuronide

H H HO2C
H3C N H3C N
OH OH O
UGT OH
OH
O O HO
CH2OH CH2OH
Dihydroxyatomoxetine Dihydroxyatomoxetine-O-glucuronide

Fig. 4. Metabolic biotransformation of atomoxetine. For hydroxy-2-carboxyatomoxetine, dihydroxyatomoxetine and their respective glucuro-
nide conjugates, multiple sites of aromatic hydroxylation were observed. Although only cytochrome P450 (CYP) 2D6 and CYP2C19 are
shown for the formation of 4-hydroxyatomoxetine and N-desmethylatomoxetine, respectively, several other isoforms of CYP (with reduced
affinity) can form these metabolites. UGT = uridine diphosphate glucuronosyltransferase.

© 2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (6)
580
18 hours in extensive metabolisers and 62 hours in
poor metabolisers.
In extensive metabolisers, the majority of the
radioactive dose is excreted within the first 24 hours
with >96% of the dose excreted in the urine.[28]
Excretion rate is slower in poor metabolisers and the
majority of the radioactive dose is excreted within
72 hours. Only 80% of total radioactivity is excreted
in the urine of poor metabolisers and the remaining
20% is excreted in faeces. The difference between
the amount of metabolites formed in the extensive
and poor metaboliser patient populations is reflected
by the relative formation of 4-hydroxyatomoxetine.
The fraction of the dose excreted in the urine and
faeces as 4-hydroxyatomoxetine and 4-hydroxy-
atomoxetine-O-glucuronide is greater in the exten-
sive metabolisers (approximately 86%) than the
poor metabolisers (approximately 40%). Although
only 40% of the excreted dose is 4-hydroxyatomox-
etine-O-glucuronide in poor metabolisers, this prod-
uct represents the most abundant metabolite. In poor
metabolisers, less prominent routes of biotrans-
formation such as N-desmethylatomoxetine- and 2-
hydroxymethylatomoxetine-derived metabolites are
increased. Regardless of CYP2D6 metabolic status,
very little atomoxetine (<3%) was excreted into the
urine unchanged, indicating a relatively minor role
for direct renal elimination.
Atomoxetine and 4-hydroxyatomoxetine-O-
glucuronide are the principle circulating species in
the plasma of extensive metabolisers, while atomox-
etine and N-desmethylatomoxetine are the principle
circulating species in poor metabolisers (figure
2).[28] Although N-desmethylatomoxetine is a major
circulating metabolite in poor metabolisers, the con-
tribution of the metabolic pathway to the overall
metabolism of atomoxetine is relatively minor (ap-
proximately 6% of the total dose). Extensive
metabolisers have relatively low plasma concentra-
tions of N-desmethylatomoxetine; nonetheless, the
formation amounts of this metabolite are only slight-
ly smaller than the amount formed in poor
metabolisers. Human microsomal studies provide an
average apparent Km value of 83 μmol/L for the
formation of N-desmethylatomoxetine regardless of
© 2005 Adis Data Information BV. All rights reserved.
Sauer et al.
microsomal CYP2D6 content.[43] These studies indi-
cated that CYP2C19 is the primary enzyme respon-
sible for N-desmethylatomoxetine formation. How-
ever, because of its minor role in atomoxetine clear-
ance it was predicted that perturbations in this route
of metabolism would not influence the overall clear-
ance of atomoxetine. Thus, the higher plasma con-
centrations of N-desmethylatomoxetine in poor
metabolisers are not due to enhanced formation of
N-desmethylatomoxetine, but rather due to a parallel
decrease in the systemic clearance of this metabo-
lite. Elimination of N-desmethylatomoxetine re-
quires secondary oxidation (aromatic hydroxyl-
ation) that appears to be primarily mediated by
CYP2D6. Because this enzyme is functionally ab-
sent in poor metabolisers, similar to atomoxetine,
there is an accumulation of N-desmethylatomoxe-
tine to higher steady-state concentrations.
Thus, differences in atomoxetine concentrations
between extensive and poor metabolisers are attrib-
uted to a decrease in the rate of formation of 4-
hydroxyatomoxetine, and subsequent 4-hydroxy-
atomoxetine-O-glucuronide. These differences re-
sult in a reduction in the overall rate of elimination
of atomoxetine in poor metabolisers.
In vitro enzyme studies of the potential for
atomoxetine and its two primary oxidative metabo-
lites, N-desmethylatomoxetine and 4-hydroxy-
atomoxetine, to inhibit CYP1A2, CYP2C9,
CYP2D6 and CYP3A were conducted in human
hepatic microsomes.[35] These compounds exhibit
very little inhibition of CYP2C9 (diclofenac 4′-
hydroxylation) or CYP1A2 (phenacetin O-deethyla-
tion) enzymatic activity. Although apparent Ki val-
ues could not be determined for atomoxetine or 4-
hydroxyatomoxetine, the formation of 4′-hydroxy
diclofenac was inhibited by approximately 37% by
atomoxetine at concentrations of 800 μmol/L, and
34% by 4-hydroxyatomoxetine at concentrations of
500 μmol/L. The formation of paracetamol (ac-
etaminophen) was inhibited by approximately 30%
by atomoxetine at concentrations of 800 μmol/L and
10% by 4-hydroxyatomoxetine at concentrations of
500 μmol/L. For reference, the estimated maximum
plasma concentrations of atomoxetine and its me-
Clin Pharmacokinet 2005; 44 (6)
Clinical Pharmacokinetics of Atomoxetine
tabolites following 1.0 mg/kg twice-daily doses
(2.0 mg/kg/day) of atomoxetine hydrochloride are
12.9 μmol/L for atomoxetine, 6.3 μmol/L for N-
desmethylatomoxetine and 0.03 μmol/L for 4-hy-
droxyatomoxetine. N-desmethylatomoxetine inhib-
its CYP2C9 and CYP1A2 enzymatic activity at high
concentrations with Ki values of 53 μmol/L and
271 μmol/L, respectively. Thus, the likelihood of in
vivo inhibition of CYP2C9 and CYP1A2 is very
low.
Both atomoxetine and N-desmethylatomoxetine
inhibit CYP3A (midazolam 1′-hydroxylation) en-
zyme activity and yield Ki values of 34 μmol/L and
16 μmol/L, respectively. In addition, atomoxetine,
N-desmethylatomoxetine and 4-hydroxyatomoxe-
tine significantly inhibit CYP2D6 (bufuralol 1′-hy-
droxylation) enzyme activity and yield Ki values of
3.6 μmol/L, 5.3 μmol/L and 17 μmol/L, respective-
ly.
These in vitro data predict the possible effect of
atomoxetine on the clearance of coadministered
drugs. The relationship (I/[I + Ki]) • 100, where I is
inhibitor concentration, can be used to calculate an
estimate of expected percent inhibition.[44] Differ-
ences in accumulation and overall exposure profiles
between extensive and poor metaboliser populations
were considered in the interpretation of the in vitro
findings. A conservative approach was used to esti-
mate inhibitor concentration in these calculations,
which assumes that all of the drug measured in the
plasma is potentially an inhibitor. As such, the cal-
culations did not take into account the high plasma
protein binding of either atomoxetine or N-
desmethylatomoxetine. Significant enzyme inhibi-
tion was predicted for CYP3A (56% predicted inhi-
bition in poor metaboliser patients) and CYP2D6
(60% predicted inhibition in extensive metaboliser
patients) for typical therapeutic plasma concentra-
tions. On the basis of these in vitro findings, drug
interaction studies in healthy subjects were conduct-
ed using probe substrates for CYP2D6 (de-
sipramine) in CYP2D6 extensive metaboliser sub-
jects and CYP3A (midazolam) in CYP2D6 poor
metaboliser subjects (see sections 5.3 and 5.4).
© 2005 Adis Data Information BV. All rights reserved.
581
The ability of atomoxetine to induce catalytic
activities associated with CYP1A2 and CYP3A was
studied in primary cultures of human hepatocytes.
Atomoxetine had no effect on the catalytic activities
of 7-ethoxyresorufin O-deethylation (CYP1A2) or
midazolam 1′-hydroxylation (CYP3A).[35]
4. Overview of
Pharmacodynamic Properties
4.1 Mechanism of Action
Atomoxetine is a potent inhibitor of the presy-
naptic norepinephrine transporter with minimal af-
finity for other monoamine transporters or recep-
tors.[21,45-47] Furthermore, as a result of its novel
mechanism of action, atomoxetine does not share
the abuse potential associated with psychostimulant
drugs.[48]
4.2 In Vitro and In Vivo Activity
In vitro studies demonstrate that atomoxetine has
potent nanomolar to subnanomolar affinity for the
rat and human norepinephrine transporters and min-
imal affinity for serotonin and dopamine transport-
ers, as well as other receptors and ion channels.[21]
The human transporter affinities of the primary oxi-
dative metabolites of atomoxetine, 4-hydroxy-
atomoxetine and N-desmethylatomoxetine have
been assessed. 4-Hydroxyatomoxetine has similar
affinity for the norepinephrine transporter (Ki = 12.5
μmol/L) to that of atomoxetine (Ki = 8.5 μmol/L),
and little affinity for the dopamine transporter (Ki
>1000 μmol/L). Unlike atomoxetine (Ki >1000
μmol/L), 4-hydroxyatomoxetine (Ki = 11.3 μmol/L)
has relatively high affinity for the human serotonin
transporter. N-desmethylatomoxetine, on the other
hand, had less affinity for the monoamine transport-
er system compared with atomoxetine and 4-hy-
droxyatomoxetine. As with atomoxetine, these me-
tabolites do not have affinity for other neuronal
receptors or ion channels.[49]
A number of preclinical in vivo studies defined
the central and peripheral potency of atomoxetine as
an inhibitor of norepinephrine reuptake sites.[45,46,50]
In rats, orally administered atomoxetine inhibits
Clin Pharmacokinet 2005; 44 (6)
582
radioligand binding to the norepinephrine transport-
er with a dose that produces 50% response (ED50) of
2.4 mg/kg, while a small amount (30%) of inhibition
of the serotonin transporter is observed at the higher
doses of atomoxetine (60 mg/kg). Norepinephrine
transporter inhibition was maximal 1 hour after ad-
ministration and yet still significant for up to 6 hours
after administration. Interestingly, the half-life of
atomoxetine in rats is approximately 2 hours,[51]
suggesting a difference between the pharmacody-
namic and pharmacokinetic half-lives of atomoxe-
tine.
Microdialysis measurement of brain extracellular
monoamines was utilised to evaluate the central
effects of atomoxetine.[22] In these studies, atomoxe-
tine increased extracellular norepinephrine in the
prefrontal cortex 3-fold, but did not alter serotonin.
Atomoxetine also increased dopamine concentra-
tions in the prefrontal cortex 3-fold, but did not alter
dopamine in striatum or nucleus accumbens. In con-
trast, methylphenidate increased norepinephrine and
dopamine equally in prefrontal cortex, and also in-
creased dopamine in the striatum and nucleus ac-
cumbens. The expression of the neuronal activity
marker Fos was increased 3.7-fold in prefrontal
cortex by atomoxetine administration, but was not
increased in the striatum or nucleus accumbens,
consistent with the regional increases of dopamine.
Bymaster et al.[22] concluded that due to the promis-
cuous transport of dopamine via the norepinephrine
transporter in the prefrontal cortex, atomoxetine se-
lectively increases both dopamine and nore-
pinephrine neurotransmission in a region of the
brain involved in attention and memory. In contrast
to methylphenidate, atomoxetine does not increase
dopamine in striatum or nucleus accumbens, sug-
gesting it would have less potential for motoric or
drug abuse liabilities. This conclusion is supported
by the finding that atomoxetine did not substitute
appreciably for metamfetamine in drug discrimina-
tion studies in monkeys.[52]
4.3 Clinical Pharmacodynamics
The results of prospective, placebo-controlled
and dose-finding studies demonstrate that atomoxe-
© 2005 Adis Data Information BV. All rights reserved.
Sauer et al.
tine is an effective and well tolerated treatment for
paediatric, adolescent and adult patients with
ADHD. In children and adolescents, atomoxetine in
a single or divided daily dose of 1.2 mg/kg has been
shown to be superior to placebo in randomised,
placebo-controlled studies.[25,26] Efficacy was as-
sessed by ADHD Rating Scale-IV-Parent Version:
Investigator Administered and Scored (ADHDRS-
IV-Parent:Inv). Effectiveness of atomoxetine in im-
proving ADHD symptoms is comparable to treat-
ment with methylphenidate.[27]
In adult patients with ADHD, atomoxetine effi-
cacy was initially evaluated in a small, double-blind,
placebo-controlled, crossover study.[23] Atomoxe-
tine, at an average dose of 76 mg/day, was well
tolerated. Improvement in ADHD symptomatology
was significant overall and sufficiently robust to be
detectable in a parallel-group comparison. Eleven of
21 patients showed improvement after receiving
atomoxetine, while only 2 of 21 patients improved
after receiving placebo. These results demonstrated
that atomoxetine was effective in treating adult
ADHD, resulting in clinically and statistically sig-
nificant improvement in ADHD symptoms, and was
well tolerated. A number of additional studies have
been conducted demonstrating the effectiveness of
atomoxetine treatment in adults with ADHD.[24]
The safety, tolerability and efficacy of atomoxe-
tine in children and adolescents with ADHD have
been rigorously characterised in comparison to the
other drugs used to treat this disease.[25,53] The most
common drug-related adverse event reported was
decreased appetite and an initial period of weight
loss followed by an apparently normal rate of weight
gain. There are no effects on the corrected QT
interval, and CYP2D6 phenotype of patients does
not affect the overall safety and tolerability of the
drug. However, tachycardia, as well as increases in
diastolic blood pressure (2–5mm Hg) and systolic
blood pressure (3mm Hg) have been observed fol-
lowing treatment with atomoxetine.[54-56] No serious
adverse events have been associated with atomoxe-
tine administration, and there have been few discon-
tinuations resulting from adverse events. The safety
and tolerability associated with atomoxetine admin-
Clin Pharmacokinet 2005; 44 (6)
Clinical Pharmacokinetics of Atomoxetine
istration in children are similar to those previously
reported for adults.[23,57,58]
Since individuals lacking CYP2D6 activity have
higher atomoxetine plasma concentrations after
multiple doses, it was initially believed that poor
metabolisers would not tolerate higher concentra-
tions. Moreover, there was concern that poor
metaboliser patients would need to be phenotypical-
ly or genotypically identified before the initiation of
treatment with atomoxetine. In early clinical trials,
patients were given doses in accordance with their
genotype and poor metabolisers received lower
doses than extensive metabolisers.[25,55] After dem-
onstrating safety in initial safety and tolerability
studies in poor metabolisers, atomoxetine was ad-
ministered without regard for genotype in later
clinical trials.[59] A comparison of 1290 extensive
metabolisers with 67 poor metabolisers taking at
least 1.2 mg/kg/day of atomoxetine, which is the
initial target dose for efficacy, showed little differ-
ence in discontinuations or reporting rates of ad-
verse events.[53,59] However, poor metabolisers did
develop a slightly higher increase in heart rate (10.6
bpm versus 6.9 bpm) and lost slightly more weight
(–1.2kg versus +0.8kg) than extensive metabolisers.
Thus, with the apparently large therapeutic index,
differential dosing based on genotype is not re-
quired.
5. Pharmacokinetic Interactions
5.1 Interactions with Food
Food does not affect the extent of atomoxetine
absorption. However, ingestion of the atomoxetine
dose with food decreases Cmax by 37% with a stan-
dard high-fat breakfast or by 9% with a more typical
meal. Food also delays tmax by 3 hours.[37,40] The
effect of food on atomoxetine pharmacokinetics is
regarded as not clinically important given the small
decrease in Cmax observed in clinical efficacy stud-
ies. The relative oral bioavailability of atomoxetine
administered in the presence of either Maalox®
(Novartis Consumer Health, Parsippany, NJ, USA)
or omeprazole was approximately 100% and it ap-
© 2005 Adis Data Information BV. All rights reserved.
583
pears that an increase in gastric pH had no substan-
tial effect on the absorption of atomoxetine.[40]
5.2 Interactions with Paroxetine
The role of CYP2D6 in the biotransformation of
atomoxetine[28,29,43] and the potential for interaction
with other drugs[30,35] make it important to assess the
impact of concomitant drug treatment. Although the
systemic clearance of atomoxetine is dependent
upon the polymorphic expression of CYP2D6,
chemical inhibitors of this enzymatic pathway also
alter the pharmacokinetics of atomoxetine. In
humans, coadministration of paroxetine, a potent
inhibitor of CYP2D6-catalysed reactions,[60,61] with
known CYP2D6 substrates (such as metoprolol,
desipramine or perphenazine) result in signifi-
cant pharmacokinetic interactions in extensive
metabolisers.[62-65] Although paroxetine substantial-
ly inhibits CYP2D6, it does not seem to affect
CYP1A2, CYP2C9, CYP2C19 and CYP3A4 en-
zyme activities in vivo at therapeutic dose.[66-71]
Administration of paroxetine (20mg once daily)
for 17 days results in steady-state plasma concentra-
tions that are in the same range as its Ki for CYP2D6
(0.15 μmol/L). Consequently, concomitant adminis-
tration of paroxetine and atomoxetine (20mg twice
daily) led to an increase in the plasma concentra-
tions of atomoxetine and its N-demethylated metab-
olite.[30] Paroxetine increased mean Cmax,ss and
AUC during a dosage interval (τ) at steady state
(AUCτ) values of atomoxetine by about 3.5- and
6.5-fold, respectively, which is in the same order of
magnitude as the reported effects of paroxetine on
other CYP2D6 substrates.[62-64] Correspondingly,
the concentration of 4-hydroxyatomoxetine, the ma-
jor CYP2D6 oxidative metabolite, was lower.
After concomitant treatment with paroxetine,
steady-state pharmacokinetic parameters of atom-
oxetine in extensive metabolisers are similar to
the pharmacokinetic values obtained for poor
metabolisers who were administered atomoxetine
alone.[28,29] For example, the CL/F of atomoxetine
averaged 0.0599 L/h/kg after coadministration with
paroxetine, which is comparable to that observed in
poor metabolisers (CL/F = 0.03 L/h/kg).[37] In-
Clin Pharmacokinet 2005; 44 (6)
584
creases in N-desmethylatomoxetine concentrations
after concomitant treatment with paroxetine are also
consistent with the pharmacokinetics of atomoxe-
tine in poor metabolisers. Thus, coadministration of
paroxetine and atomoxetine results in an inhibition
of CYP2D6-mediated conversion of atomoxetine to
4-hydroxyatomoxetine, and produces an atomoxe-
tine pharmacokinetic profile similar to that found in
poor metabolisers.
5.3 Interactions with Desipramine
In vitro inhibition studies designed to evaluate
the 1′-hydroxylation of bufuralol suggest that atom-
oxetine has the potential to inhibit CYP2D6-mediat-
ed metabolism (see section 3.4).[35] The in vitro
predictions indicate that atomoxetine (54% predict-
ed inhibition) but not its metabolites (5% predicted
inhibition) would be primarily responsible for inhi-
bition. These in vitro findings led to an in vivo study
in healthy CYP2D6 extensive metabolisers evaluat-
ing the coadministration of atomoxetine and de-
sipramine.[35,72] Desipramine is a sensitive and se-
lective probe drug for CYP2D6-dependent metabo-
lism; its biotransformation to 2-hydroxydesipramine
is almost exclusively mediated by CYP2D6 and is
not affected by inhibitors of other isoforms of
CYP.[73] Twice-daily 60mg doses of atomoxetine
ranged from 1.2 to 2.3 mg/kg/day, with a median
dose of 1.6 mg/kg/day. At these doses, Cmax,ss of
atomoxetine ranged from 241 to 1046 ng/mL
(0.9–4.1 μmol/L) and these values are in the range
of and exceed the estimated Ki values of atomoxe-
tine for CYP2D6 (Ki = 3.6 μmol/L [919 ng/
mL]).[35] However, because of the rapid elimination
of atomoxetine, the Cav,ss are below the Ki value
(Cav,ss range 105–569 ng/mL [0.4–2.2 μmol/L]).
Upon the concomitant administration of a single
50mg oral dose of desipramine with atomoxetine, no
change in desipramine pharmacokinetics was ob-
served. Thus, in clinical practice, atomoxetine at
maximum steady-state conditions is not likely to
inhibit the metabolic clearance of drugs metabolised
by CYP2D6.
© 2005 Adis Data Information BV. All rights reserved.
Sauer et al.
Effects of atomoxetine on desipramine metabo-
lism were not studied in poor metabolisers because
of the lack of CYP2D6 activity in this population.
5.4 Interactions with Midazolam
In vitro enzyme inhibition studies suggest that
atomoxetine may impact the pharmacokinetics of
agents metabolised by CYP3A, but only when
atomoxetine and N-desmethylatomoxetine plasma
concentrations are relatively high (see section
3.4).[35] These are potential conditions for poor
metaboliser patients. Therapeutic doses of atomoxe-
tine in poor metabolisers may achieve concentra-
tions that approach the Ki values for inhibition of
CYP3A. The in vitro predictions indicate that both
atomoxetine (28% predicted inhibition) and N-
desmethylatomoxetine (28% predicted inhibition)
could participate in CYP3A inhibition. These find-
ings led to a clinical study evaluating the coadminis-
tration of atomoxetine and midazolam in healthy
CYP2D6 poor metabolisers.[35,74] Midazolam is a
sensitive and selective probe drug for CYP3A-
dependent metabolism.[75] Twice-daily 60mg doses
of atomoxetine ranged from 1.5 to 2.7 mg/kg/day,
with a median dose of 1.7 mg/kg/day. At these
doses, Cmax,ss of atomoxetine ranged from 1456 to
3319 ng/mL (5.6–12.9 μmol/L) and N-desmethy-
latomoxetine ranged from 755 to 2485 ng/mL
(3.2–10.4 μmol/L), well below their respective pre-
dicted Ki values for CYP3A (34 μmol/L [8757 ng/
mL] and 16 μmol/L [3837 ng/mL], respectively).[35]
Following a single 5mg oral dose of midazolam in
healthy CYP2D6 poor metabolisers, the midazolam
Cmax and AUC∞ were about 16% larger when
midazolam was concomitantly administered with
atomoxetine; however, the increase was not statisti-
cally significant or regarded as a change that would
reflect a clinically important inhibition of CYP3A
activity.
Coadministration of the potent CYP3A inhibitor
ketoconazole with midazolam results in a 15-fold
increase in midazolam AUC and a 4-fold increase in
Cmax.[76] Furthermore, midazolam half-life increases
from 2.9 hours to 7.0 hours. Unlike the interaction
observed with ketoconazole, atomoxetine did not
Clin Pharmacokinet 2005; 44 (6)
Clinical Pharmacokinetics of Atomoxetine
alter the half-life of midazolam or increase midazo-
lam exposure statistically.[35] Yuan et al.,[77] demon-
strated that moderate inhibitors of CYP3A, such as
grapefruit juice, cause pharmacokinetic changes in
midazolam (increased Cmax and AUC) that are sub-
stantially greater than those observed for atomoxe-
tine. Because there are only minimal changes in
midazolam pharmacokinetics observed, it is predict-
ed that atomoxetine at maximum recommended
clinical doses will not inhibit the metabolic clear-
ance of drugs metabolised by CYP3A.
6. Implications of Pharmacokinetic
Properties for Therapeutic Use
6.1 Dosages and Therapeutic Range
The relationship between exposure and efficacy
of atomoxetine has been evaluated in a randomised,
double-blind, placebo-controlled study conducted in
children and adolescents with ADHD.[78] Patients
were randomised to a target dose of atomoxetine
(placebo, 0.5 mg/kg/day, 1.2 mg/kg/day, 1.8 mg/kg/
day). Using a population pharmacokinetic model,
the modelled clearance values for each patient pro-
vided estimated AUCτ values as a measure of
atomoxetine exposure. A nonlinear model (maxi-
mum effect [Emax] model) was fit to the observed
AUC and change from baseline in ADHDRS-IV-
Parent:Inv total scores data to explore the relation-
ship between AUC and efficacy. The modelling was
restricted to extensive metaboliser data, as there was
only a sparse amount of poor metaboliser data avail-
able. The relationship between AUCτ and change
from baseline in ADHDRS-IV-Parent:Inv total
score suggests that the expected maximum improve-
ment from baseline is –17.4 (compared with –6.2 for
8 weeks of placebo administration) in ADHDRS-
IV-Parent:Inv total score. The overall maximum
benefit of atomoxetine treatment was –11.2 over
that for placebo. At the median AUC values for
atomoxetine doses of 0.5 mg/kg/day, 1.2 mg/kg/day
or 1.8 mg/kg/day, there was a 62%, 78% and 85%
maximum improvement over baseline, respectively.
Therefore, a relationship between systemic exposure
to atomoxetine and efficacy was apparent and these
© 2005 Adis Data Information BV. All rights reserved.
585
improvements in efficacy are similar to those ob-
served between atomoxetine dose and efficacy.
6.2 Sex and Racial Differences in
Atomoxetine Pharmacokinetics
In general, the plasma pharmacokinetic parame-
ters and biotransformation of atomoxetine are not
affected by sex or race.[37] However, as described
earlier, the disposition of atomoxetine is dependent
upon CYP2D6 activity, a trait that differs among
races. For example, the poor metaboliser trait, inher-
ited as an autosomal recessive characteristic, is most
prevalent in Caucasians; up to 7% of the Caucasian
population can be genetically classified as poor
metabolisers,[31] while this genetic trait is observed
in <1% of the Asian population,[79,80] <2% in Arabi-
an populations[81] and approximately 3% in African
populations.[82] Likewise, mutations (allelic varia-
tions) observed in the extensive metaboliser popula-
tion that have relatively minimal functional conse-
quences for CYP2D6 are also distributed differently
among Caucasian, Asian, Arabian and African
populations.[83]
6.3 Influence of Age and Bodyweight on
Atomoxetine Pharmacokinetics
Witcher et al.,[36] evaluated single-dose and
steady-state pharmacokinetics of atomoxetine in
children and adolescent patients across a wide range
of doses. Identical to the pharmacokinetics in adults,
the paediatric pharmacokinetic parameters of
atomoxetine demonstrated a linear and predictable
pharmacokinetic behaviour. As atomoxetine doses
are increased, proportional increases in plasma ex-
posure (AUC and Cmax) are observed. Furthermore,
repeated administration of atomoxetine results in a
predictable pharmacokinetic profile based on the
single-dose data. Because of the rapid absorption
and elimination of the drug, steady-state profiles are
remarkably similar to single-dose profiles in paedia-
tric extensive metaboliser patients. The ability of
children and adolescents to metabolise atomoxetine
rapidly and similarly to adults suggests CYP2D6
metabolic activity is mature and has reached adult
competency by 7–14 years of age. Phenotype distri-
Clin Pharmacokinet 2005; 44 (6)
586
a b
26.3kg
400
29.6kg
35.3kg
Atomoxetine plasma
concentration (μg/L)
300
43.6kg
200
70.0kg
100
0
0 3 6 9
Fig. 5. Predicted effect of bodyweight on atomoxetine plasma concentrations for (a) a 40mg dose and (b) a 1 mg/kg dose.
bution studies for CYP2D6 in children (mean age of
10.4 ± 3.7 years) and adolescents are a mirror of the
distributions observed in adults.[84,85]
The paediatric pharmacokinetic data reported by
Witcher et al.[36] are similar to data described in
adults after adjustment for bodyweight. This study
provides evidence that it is appropriate to ad-
minister atomoxetine on a bodyweight-adjusted ba-
sis (mg/kg) in paediatric patients. Bodyweight has a
significant impact on atomoxetine pharmacokinet-
ics, which was demonstrated in a separate analysis
using population pharmacokinetic modelling. As
bodyweight increases, both the clearance and vol-
ume of distribution increase in an essentially propor-
tional manner.[37] Figure 5 shows the predicted ef-
fect of bodyweight on atomoxetine plasma concen-
trations for a fixed 40mg dosing regimen in
comparison to a weight-adjusted dose. The similari-
ty between the profiles for the weight-based dose
administration suggests this is a useful means to
provide comparable exposures between patients of
different bodyweights. This dosing method also
maintains constant exposure to drug as a patient
matures and bodyweight increases.
6.4 Diseases and the Pharmacokinetics
of Atomoxetine
6.4.1 Chronic Impairment of Renal Function
Because atomoxetine is primarily cleared
through oxidative metabolism, it is unlikely that the
© 2005 Adis Data Information BV. All rights reserved.
Sauer et al.
26.3kg
29.6kg
35.3kg
43.6kg
70.0kg
12 15 18 21 24 0 3 6 9 12 15 18 21 24
Time from dose (h)
systemic clearance of atomoxetine is influenced by
renal disease. However, the metabolites of atomoxe-
tine are primarily excreted in urine. Therefore, the
pharmacokinetics of atomoxetine and its primary
metabolites were evaluated in six adults with end-
stage renal disease and compared with age-matched
healthy subjects.[37] Atomoxetine mean plasma con-
centrations with end-stage renal disease patients
were higher than the mean for healthy subjects
(about a 65% increase). However, after adjustment
for bodyweight, the differences between these
groups were minimal. As expected, the plasma con-
centrations of 4-hydroxyatomoxetine-O-glucuro-
nide, a metabolite excreted in urine with no known
pharmacological actions, were substantially higher
in individuals with end-stage renal disease. Pharma-
cokinetics of atomoxetine and its metabolites in
individuals with end-stage renal disease suggest that
no dosage adjustments are necessary.[37]
6.4.2 Hepatic Insufficiency
Since atomoxetine is primarily cleared from the
systemic circulation through oxidative metabolism,
it is reasonable to assume that the disposition of
atomoxetine would be affected by impaired hepatic
function. Recently, Chalon et al.[34] compared the
pharmacokinetic parameters of atomoxetine in ten
adults with hepatic impairment (six moderate, four
severe) and ten age- and sex-matched healthy sub-
jects, all being genotyped as CYP2D6 extensive
metabolisers.
Clin Pharmacokinet 2005; 44 (6)
Clinical Pharmacokinetics of Atomoxetine
Systemic clearance of atomoxetine was signifi-
cantly reduced in patients with hepatic impairment
compared with healthy subjects. There was an in-
crease in overall atomoxetine exposure (AUC∞ 1.58
versus 0.85 μg • h/mL) but no change in Cmax or
peak exposure. Mean 4-hydroxyatomoxetine AUC
from zero to time t (AUCt) and Cmax were increased
approximately 7- and 2-fold, respectively, indicat-
ing a reduced rate of glucuronidation in individuals
with hepatic impairment. For the glucuronide conju-
gate of 4-hydroxyatomoxetine, the mean half-life
was longer and mean AUC∞ and Cmax values were
also lower, similar to the type of differences noted
for individuals lacking CYP2D6 activity.[28] De-
creased atomoxetine clearance in hepatically im-
paired patients was correlated with decreased
CYP2D6 activity (debrisoquine clearance) and de-
creased hepatic blood flow (sorbitol clearance).
Chalon et al.,[34] concluded that for ADHD patients
who have hepatic impairment, a dosage reduction is
recommended. Initial doses of atomoxetine should
be reduced to 25% or 50% of the normal dose for
patients with moderate or severe hepatic impair-
ment, respectively.
7. Conclusions
Atomoxetine is a well-tolerated inhibitor of the
presynaptic norepinephrine transporter, and is a
drug that has shown notable efficacy for the treat-
ment of ADHD in children, adolescents and adults.
The metabolism, pharmacokinetics and absolute
oral bioavailability of atomoxetine are influenced by
the CYP2D6 polymorphism. The mean half-life of
atomoxetine is approximately 5-fold longer (5.2 ver-
sus 21.6 hours) and its mean CL/F is about 10-fold
slower (0.35 versus 0.03 L/h/kg) in poor metabolis-
ers compared with extensive metabolisers. After
single oral dose, the mean atomoxetine Cmax is 2-
fold higher in poor metabolisers compared with
extensive metabolisers. At steady state after twice-
daily dosing, the mean atomoxetine Cmax is approxi-
mately 5-fold higher and the mean plasma concen-
tration is approximately 10-fold higher in poor
metabolisers compared with extensive metabolisers.
© 2005 Adis Data Information BV. All rights reserved.
587
Atomoxetine is rapidly and completely absorbed
after oral administration with a median tmax of 1–2
hours. The presence of food in the gastrointestinal
tract does not affect the extent of atomoxetine ab-
sorption but does decrease Cmax (by 37% with a
standard high-fat breakfast and by 9% with a more
modest meal) and delays tmax by 3 hours. Pharma-
cokinetics of atomoxetine are linear over the range
of doses studied in both extensive and poor
metabolisers. The pharmacokinetics following
once-daily and twice-daily dosage regimens are
readily predictable from single-dose data. Despite
greater systemic exposures experienced by poor
metabolisers versus extensive metabolisers, there
has been no clinical significance related to these
pharmacokinetic differences. The same mean doses
were found to be well tolerated and efficacious for
atomoxetine, and atomoxetine dosage recommenda-
tions are the same regardless of CYP2D6 genotype
or phenotype.
In both extensive and poor metabolisers, the pri-
mary oxidative metabolite of atomoxetine is 4-hy-
droxyatomoxetine. This metabolite undergoes fur-
ther metabolism, resulting in the formation of 4-
hydroxyatomoxetine-O-glucuronide, which is pri-
marily excreted in the urine. As a result of either
genetic polymorphism or pharmacologial inhibition,
individuals may exhibit a poor metaboliser pheno-
type that is characterised by slower metabolic elimi-
nation and higher steady-state plasma concentra-
tions of atomoxetine and N-demethylated metab-
olite compared with those observed in extensive
metabolisers.
Atomoxetine administration does not result in
clinically significant inhibition or induction of
the clearance of other drugs metabolised by
CYP. In extensive metabolisers, selective inhibitors
of CYP2D6 (paroxetine) increased atomoxetine
steady-state plasma concentrations to exposures less
than or similar to those observed in poor metabolis-
ers. In vitro studies indicate that the coadministra-
tion of CYP inhibitors to individuals lacking
CYP2D6 activity is not expected to increase the
plasma concentrations of atomoxetine.
Clin Pharmacokinet 2005; 44 (6)
588
The results of the conventional pharmacokinetic
analyses in adults, as well as conventional and popu-
lation pharmacokinetic analyses in children, demon-
strate that the pharmacokinetics of atomoxetine are
similar between these age groups after adjustment
for bodyweight. Weight-based dosage regimens
(mg/kg) are recommended for paediatric patients.
The pharmacokinetic parameters of atomoxetine
were affected by moderate and severe hepatic insuf-
ficiency, and a dosage reduction is recommended in
patients who have hepatic insufficiency. Pharma-
cokinetics of atomoxetine and its metabolites in
individuals with end-stage renal disease suggest that
no dosage adjustment is necessary.
Overall, the pharmacokinetics and metabolism of
atomoxetine are predictable based on an individu-
al’s CYP2D6 phenotype. Both the efficacy and safe-
ty of atomoxetine have been demonstrated for the
treatment of ADHD in children, adolescents and
adults. As the first FDA-approved, nonstimulant
pharmaceutical treatment for ADHD, atomoxetine
represents a significant advance in the treatment of
this disease. Furthermore, due to its novel mecha-
nism of action, atomoxetine does not share the abuse
potential associated with psychostimulant drugs.
Acknowledgements
The authors wish to thank Dr Richard F. Bergstrom from
Department of Drug Disposition, Lilly Research Laborato-
ries, Eli Lilly and Company, Indianapolis, IN, USA, for his
helpful guidance and insightful scientific comments. The
authors also thank Ms Amanda J. Long for her contributions
to the work presented herein. Finally, the authors thank Mr
Nathan P. Sanburn for his editorial comments. At the time of
preparation of this review all authors were employees of Eli
Lilly and Company, Indianapolis, IN, USA.
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Correspondence and offprints: Dr Jennifer W. Witcher, De-
partment of Drug Disposition, Lilly Research Laboratories,
Eli Lilly and Company, Lilly Corporate Center, Indianapo-
lis, IN 46285, USA.
Clin Pharmacokinet 2005; 44 (6)