(Strattera) is a selective norepinephrine reuptake inhibitor that is commonly
used in the treatment of attention-deficit/hyperactivity disorder (ADHD) in
both pediatric and adult patients. It has the advantage of being a
non-stimulant agent and therefore has less diversion potential.
Unfortunately, 20-30% of ADHD patients also suffer from depression that often
requires additional treatment with antidepressants, a scenario in which
selective serotonin reuptake inhibitors (SSRIs) are likely to be prescribed
first-line.2 Of the SSRI's that may be used in clinical practice,
paroxetine (Paxil; Paxil CR) is popular for a number of reasons, these include
its generic status, broad spectrum of activity and the number of FDA approved
indications it holds for various psychiatric conditions.3 As such, a
situation involving the coadministration of atomoxetine and paroxetine in
patients with both ADHD and depression is quite possible. The problem
with this particular combination is that paroxetine has been shown to increase
atomoxetine exposure 6 to 8 fold.1,4
How does paroxetine
cause such significant increases in atomoxetine concentrations?
it is important to understand the basic mechanism of action and the normal
metabolic processes for atomoxetine. Atomoxetine is a selective inhibitor
of norepinephrine reuptake in the synaptic cleft of the neuron, thus aiding in
central noradrenergic transmission and improvement in ADHD symptoms.1
Atomoxetine's primary mode of oxidative metabolism is through the enzyme CYP2D6
resulting in the formation of 4-hydroxyatomoxetine, which has equipotent
inhibition of the reuptake of norepinephrine in the synaptic cleft (this will
be important later on in the consideration of potential side effects).1,4,5
Other CYP450 enzymes aiding in the phase I oxidative metabolism of atomoxetine
include CYP1A2, 1A6, 2C19, 2E1, and 3A4, but these are involved to a lesser
extent.4 These other minor pathways are known to form
4-hydroxyatomoxetine as well as N-desmethylatomoxetine and 2-hydroxymethylatomoxetine
(this becomes important later on).4 Therefore, anything that inhibits the
activity of CYP2D6 will decrease the primary pathway for atomoxetine metabolism
but will allow the minor CYP450 pathways to remain active. As a result,
atomoxetine would still be removed from the body, just at a slower rate.
What role does paroxetine play in this drug interaction?
is a known substrate of CYP2D6; metabolism through this pathway leads to the
formation of the methylenedioxy metabolite and then eventually the catechol
metabolite.3,6,7 The generation of these metabolic products of paroxetine
metabolism form what is known as a "mechanism-based inactivation
complex" against CYP2D6 enzyme activity.6 Simply stated, paroxetine
requires CYP2D6 for its metabolism; however, the paroxetine metabolites
generated in the process can then inhibit CYP2D6 activity by acting as a
competitive, reversible inhibitor.6 Therefore, paroxetine mechanism-based
inactivation complexes will inhibit the primary metabolic pathway of
atomoxetine.6 In fact, drug interaction studies show that the
combination of these two medications results in atomoxetine exposure similar to
exposures seen in individuals known to be "poor metabolizers" or have
the genetic polymorphism to CYP2D6.1,4 In this situation, atomoxetine's
excretion rate is decreased from the standard 24 hours to 72 hours.4 This
results in an accumulation of atomoxetine and some of its metabolites and
causes blood concentration to increase by 6 to 8 fold.1
greatest concern with this degree of accumulation of atomoxetine and
4-hydroxyatomoxetine is their ability to inhibit the reuptake of norepinephrine
in the central nervous system. This increase in norepinephrine could
negatively impact cardiovascular processes under sympathetic control, such as
blood pressure and heart rate.1 To our knowledge, there is no definitive
data evaluating the negative impact of this drug interaction on important
patient outcomes, but does warrant consideration in patients - especially those
with a history of cardiovascular or cerebrovascular disease (CVD). This
is also important given the increased use of this drug combination in the
treatment of adult ADHD where CVD has a higher incidence. Regardless, the
manufacturer of atomoxetine does recommend a dose reduction in patients with
hepatic impairment, those on a known CYP2D6 inhibitor or those known to be a
"2D6 poor metabolizer".1
- Atomoxetine (Strattera) product package insert. Eli Lilly and Company. Indianapolis, IN. September 2008.
- Barkley RA. International consensus statement on ADHD. January 2002. Clin Child Fam Psychol Rev 2002;5:89-111.
- Paroxetine (Paxil CR) product package insert. GalxoSmithKline. Research Triangle Park, NC. January 2009.
JM, Ponsler GD, Mattiuz EL et al. Disposition and metabolic fate of
atomoxetine hydrochloride: the role of CYP2D6 in human disposition and
metabolism. Drug Metab Dispos 2003;31:98-107.
BJ, Gillespie JS, Eckstein JA et al. Identification of the human
cytochromes P450 responsible for atomoxetine metabolism. Drug Metab
KM, Venkatakrishnan K, Von Moltke LL et al. Apparent mechanism-based
inhibition of human CYP2D6 in vitro by paroxetine: comparison with
fluoxetine and quinidine. Drug Metab Dispos 2003;31:289-93.
D, Otton SV, Inaba T et al. Interactions of amphetamine analogs with
human liver CYP2D6. Biochem Pharmacol 1997;53:1605-12.