Atomoxetine (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?
First, 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?
Paroxetine 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 

The 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

References:

1. Atomoxetine (Strattera) product package insert.  Eli Lilly and Company. Indianapolis, IN.  September 2008. 
2. Barkley RA.  International consensus statement on ADHD. January 2002.  Clin Child Fam Psychol Rev  2002;5:89-111.      
   
3. Paroxetine (Paxil CR) product package insert.  GalxoSmithKline. Research Triangle Park, NC.  January 2009.
4. Sauer 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.       
   
5. Ring BJ, Gillespie JS, Eckstein JA et al.  Identification of the human cytochromes P450 responsible for atomoxetine metabolism.  Drug Metab Dispos  2002;30:319-23.      
   
6. Bertelesen 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.        
   
7. Wu D, Otton SV, Inaba T et al.  Interactions of amphetamine analogs with human liver CYP2D6.  Biochem Pharmacol  1997;53:1605-12.

SSRI, Paxil CR, Paroxetine, Paxil, Atomoxetine, Strattera