Potential interactions of methylphenidate and atomoxetine with dextromethorphan.
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.


METHODS
In vitro and ex vivo analysis of changes in metabolism of study drugs.


METHODS
Laboratory.


METHODS
Not applicable.


METHODS
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 0.1x, 1x, and 10x 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.


METHODS
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.


CONCLUSIONS
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.
Ciccone
Patrick E
PE
McNeil Pediatrics, Division of McNeil-PPC, Inc.-Medical Affairs, 7050 Camp Hill Rd. Fort Washington, PA 19034-2299, USA. pciccon@mccus.jnj.com
Ramabadran
Kris
K
Jessen
Lois M
LM
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000996:Antitussive Agents / Q000493:pharmacokinetics*; D000069445:Atomoxetine Hydrochloride; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy; D001711:Biotransformation; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D003915:Dextromethorphan / Q000493:pharmacokinetics*; D003917:Dextrorphan / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D008774:Methylphenidate / Q000494:pharmacology* / Q000627:therapeutic use; D008862:Microsomes, Liver / Q000378:metabolism; D017374:Paroxetine / Q000494:pharmacology; D011437:Propylamines / Q000494:pharmacology* / Q000627:therapeutic use
D018759:Adrenergic Uptake Inhibitors; D000996:Antitussive Agents; D007527:Isoenzymes; D011437:Propylamines; D003917:Dextrorphan; D008774:Methylphenidate; D017374:Paroxetine; D000069445:Atomoxetine Hydrochloride; D003915:Dextromethorphan; D019389:Cytochrome P-450 CYP2D6