Potential Interactions of ADHD Medications With Dextromethorphan

Abstract and Introduction

Abstract

Objective: To examine the potential for drug-drug interactions to influence drug metabolism between the attention-deficit/hyperactivity disorder (ADHD) dl-methylphenidate and atomoxetine with dextromethorphan, a probe for interactions involving cytochrome P450 (CYP) 2D6 isoenzyme
Design: In vitro and ex vivo analysis of changes in metabolism of study drugs.
Setting: Laboratory.
Patients: Not applicable.
Interventions: Pooled human liver microsomal fractions prepared at CEDRA Corporation (now CellzDirect, Austin, Tex.) by the standard differential centrifugation method (lot 821-1). Human liver microsomes were pooled from 15 donors. Recombinant CYP 2D6-containing microsomes (Supersomes; lots 20 and 24 BD Gentest; Woburn, Mass.) were prepared from a baculovirus-infected insect cell line that expressed only the human CYP 2D6 isoform. Dextromethorphan, with and without effector, was incubated with pooled human liver and recombinant CYP 2D6-containing microsomes. Atomoxetine and dl-methylphenidate were tested at 0.1×, 1×, and 10×their reported therapeutic concentrations. Paroxetine, a known inhibitor of CYP 2D6, was used as a reference agent, and quinidine was used as a positive control inhibitor of CYP 2D6.
Main Outcome Measures: Changes in substrate metabolism indicative of CYP 2D6-mediated interactions.
Results: Atomoxetine and paroxetine inhibited the formation of dextrorphan by about 50% in human liver microsomes and by more than 80% in recombinant microsomes; the profiles of atomoxetine and the known 2D6 inhibitor paroxetine were similar. High concentrations of dextromethorphan reversed the inhibition of its metabolism, indicating a competitive mechanism of the interaction. Conversely, dextromethorphan and dextrorphan only modestly inhibited atomoxetine and paroxetine metabolism. dl-Methylphenidate did not inhibit dextrorphan formation in either microsome preparation, and dl-methylphenidate metabolism was unaffected by dextromethorphan or dextrorphan.
Conclusion: These results demonstrate the potential for in vivo interactions between dextromethorphan and atomoxetine in patients with ADHD. However, they do not support the plausibility of an in vivo interaction between dextromethorphan and dl-methylphenidate.Introduction

Attention-deficiency/hyperactivity disorder (ADHD) is a common chronic condition that typically requires long-term pharmacotherapy during childhood and often into adulthood. The estimated prevalence of ADHD is 8% to 10% of all children,[1] and 50% to 60% of patients require treatment as adults.[2]

The most common treatments for ADHD are stimulant medications,[3] including methylphenidate and amphetamines. The non-stimulant atomoxetine (Strattera—Lilly) has also been approved by the U.S. Food and Drug Administration for the treatment of ADHD.[4]

Patients with ADHD develop common acute or chronic somatic illnesses, such as upper respiratory infections, common colds, or asthma.[5] Moreover, ADHD often coexists with other mental health conditions, including learning and language disorders, oppositional defiant and conduct disorders, anxiety, depression, and bipolar disorder, as well as posttraumatic stress, tic disorders, and adjustment disorders.[6] These comorbid conditions may require pharmacotherapy, and patients with ADHD may receive multiple medications for comorbidities for brief or sustained periods, placing them at an risk for potential drug-drug interactions.[5]

The human cytochrome P450 2D6 (CYP 2D6) enzymatic pathway is responsible for the metabolism of approximately 30% to 40% of pharmaceutical agents[7,8]; therefore, drug-drug interactions may occur when medications metabolized by this pathway are given concomitantly.[5,9,10] The general population is polymorphic for the CYP 2D6 genetic loci. As a result, some people are extensive metabolizers while others are poor metabolizers.[11,12] Poor metabolizers, including an estimated 7% of whites and less than 1% of the Asian population, may thus experience increased levels of agents metabolized by CYP 2D6.[11,12]

Methylphenidate, the most common pharmacologic treatment for ADHD, is metabolized primarily by desterification.[13] It has a well-established efficacy and safety profile with a low potential for drug-drug interactions.[14-17] Atomoxetine is a selective norepinephrine reuptake inhibitor[4,18] approved for the treatment of ADHD. Limited data are available on the use of atomoxetine and the incidence of interactions between atomoxetine and other drugs.[19] Atomoxetine is primarily metabolized by the cytochrome P450 enzymatic pathway, specifically, the CYP 2D6 isozyme, which raises the possibility that it may be prone to interaction with other drugs metabolized by this pathway.[20]

This study was an in vitro analysis of potential drug interactions between (1) dl-methylphenidate, atomoxetine, and dextromethorphan (a common antitussive ingredient in cough medicine and a frequently used probe for measurement of P450 enzymatic activity)[21,22] and (2) dl-methylphenidate, atomoxetine, and dextrorphan (the primary and CYP 2D6-specific metabolite of dextromethorphan).[21,23]  Printer- Friendly Email This

J Am Pharm Assoc.  2006;46(4):472-478.  ©2006 American Pharmacists Association
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