Atomoxetine Pharmacokinetics in Children and Adolescents with Attention Deficit Hyperactivity Disorder

Witcher, Jennifer; Long, Amanda; Smith, Brian P.; Sauer, John‐Michael; Heilgenstein, John; Wilens, Timothy E.; Spencer, Thomas; Biederman, Joseph

doi:10.1089/104454603321666199

Cited by 104 publications

(96 citation statements)

References 13 publications

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“…Further studies using mammalian cells, including neurons and cardiac myocytes, at physiological temperature may be useful for advancing our understanding of the effects of NRIs on GIRK channels. Atomoxetine is predominantly metabolized by the genetically polymorphic cytochrome P450 2D6 (CYP2D6) pathway, and its pharmacokinetics and metabolism are characterized by two distinct activities of CYP2D6: active or poor metabolic capability (Witcher et al, 2003;Simpson and Plosker, 2004). The maximum plasma concentrations during treatment with atomoxetine at therapeutic doses ranged from B0.7-4.8 mM in CYP2D6 active metabolizers (Witcher et al, 2003), whereas those in CYP2D6 poor metabolizers (B7% of the Caucasian population) were six-fold higher than those in CYP2D6 active metabolizers (Simpson and Plosker, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…Atomoxetine is predominantly metabolized by the genetically polymorphic cytochrome P450 2D6 (CYP2D6) pathway, and its pharmacokinetics and metabolism are characterized by two distinct activities of CYP2D6: active or poor metabolic capability (Witcher et al, 2003;Simpson and Plosker, 2004). The maximum plasma concentrations during treatment with atomoxetine at therapeutic doses ranged from B0.7-4.8 mM in CYP2D6 active metabolizers (Witcher et al, 2003), whereas those in CYP2D6 poor metabolizers (B7% of the Caucasian population) were six-fold higher than those in CYP2D6 active metabolizers (Simpson and Plosker, 2004). Additionally, co-administration of the SSRI paroxetine, a potent inhibitor of CYP2D6, increased the plasma concentrations of atomoxetine by 3.5-fold, with a pharmacokinetic profile similar to CYP2D6 poor metabolizers (Belle et al, 2002), suggesting a significant increase in atomoxetine concentrations with concomitant treatment with CYP2D6 inhibitors.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of G-Protein-Activated Inwardly Rectifying K+ Channels by the Selective Norepinephrine Reuptake Inhibitors Atomoxetine and Reboxetine

Kobayashi

Washiyama

Ikeda

2010

Neuropsychopharmacol

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Atomoxetine and reboxetine are commonly used as selective norepinephrine reuptake inhibitors (NRIs) for the treatment of attentiondeficit/hyperactivity disorder and depression, respectively. Furthermore, recent studies have suggested that NRIs may be useful for the treatment of several other psychiatric disorders. However, the molecular mechanisms underlying the various effects of NRIs have not yet been sufficiently clarified. G-protein-activated inwardly rectifying K + (GIRK or Kir3) channels have an important function in regulating neuronal excitability and heart rate, and GIRK channel modulation has been suggested to be a potential treatment for several neuropsychiatric disorders and cardiac arrhythmias. In this study, we investigated the effects of atomoxetine and reboxetine on GIRK channels using the Xenopus oocyte expression assay. In oocytes injected with mRNA for GIRK1/GIRK2, GIRK2, or GIRK1/GIRK4 subunits, extracellular application of atomoxetine or reboxetine reversibly reduced GIRK currents. The inhibitory effects were concentrationdependent, but voltage-independent, and time-independent during each voltage pulse. However, Kir1.1 and Kir2.1 channels were insensitive to atomoxetine and reboxetine. Atomoxetine and reboxetine also inhibited GIRK currents induced by activation of cloned A 1 adenosine receptors or by intracellularly applied GTPgS, a nonhydrolyzable GTP analogue. Furthermore, the GIRK currents induced by ethanol were concentration-dependently inhibited by extracellularly applied atomoxetine but not by intracellularly applied atomoxetine. The present results suggest that atomoxetine and reboxetine inhibit brain-and cardiac-type GIRK channels, revealing a novel characteristic of clinically used NRIs. GIRK channel inhibition may contribute to some of the therapeutic effects of NRIs and adverse side effects related to nervous system and heart function.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inhibition of G-Protein-Activated Inwardly Rectifying K+ Channels by the Selective Norepinephrine Reuptake Inhibitors Atomoxetine and Reboxetine

Kobayashi

Washiyama

Ikeda

2010

Neuropsychopharmacol

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“…PTMS was performed, blinded to clinical ratings, twice at each visit -before and 90 minutes after (Witcher et al, 2003) ATX administration. All subjects were studied awake in a comfortable chair in the TMS laboratory at CCHMC, using two Magstim 200® stimulators (Magstim Co., New York, NY, USA) connected through a Bistim® module to a 90 mm circular coil.…”

Section: Motor Cortex Physiologymentioning

confidence: 99%

Atomoxetine treatment of ADHD in Tourette Syndrome: Reduction in motor cortex inhibition correlates with clinical improvement

Gilbert

Zhang

Lipps

et al. 2007

Clinical Neurophysiology

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Objective: In children with Attention Deficit Hyperactivity Disorder (ADHD), clinical responses to the selective norepinephrine reuptake inhibitor atomoxetine (ATX) vary. We sought to determine in children with Tourette Syndrome (TS) whether clinical responses correlate with changes in short interval cortical inhibition (SICI). Methods:Fourteen children, ages 8 to 16, with ADHD and TS were treated open-label with ATX for one month. ADHD rating scale scores and SICI, measured with paired-pulse Transcranial Magnetic Stimulation (pTMS), were assessed blindly and independently at treatment onset and one month later.Results: Eleven children, mean ADHD Rating Scale scores 31.8 (SD 8.2) at onset completed the study. After one month, ADHDRS changes ranged from an increase of 4 points to a decrease (improvement) of 24 points (mean change -9.6, SD 9.1). The changes in ADHDRS scores correlated with reduction in SICI (r = .74, p = .010). Conclusions:In children with TS, one month of atomoxetine treatment appears to induce correlated improvements in ADHD and, paradoxically, further reductions in cortical inhibition.Significance: PTMS-evoked SICI in ADHD with TS may be a biomarker of both deficiency and compensatory changes within cortical interneuronal systems. Effective atomoxetine treatment may augment compensatory processes and thereby reduce SICI.

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“…Subjects and investigators were blinded to the order of treatment assignment throughout the study. The 1-week interval was based on published pharmacokinetic data for single doses of ATX (Witcher et al, 2003) and MPH (Kimko et al, 1999;Shader et al, 1999).…”

Section: Study Design and Drug Administrationmentioning

confidence: 99%

“…After baseline TMS testing, subjects were administered study medication and all measurements were repeated, beginning 90 min later, consistent with expected peak serum drug levels (Swanson and Volkow, 2003;Witcher et al, 2003). Each TMS session took approximately 30 min.…”

Section: Neurophysiologymentioning

confidence: 99%

Comparison of the Inhibitory and Excitatory Effects of ADHD Medications Methylphenidate and Atomoxetine on Motor Cortex

Gilbert

Ridel

Sallee

et al. 2005

Neuropsychopharmacol

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Stimulant and norepinephrine (NE) reuptake inhibitor medications have different effects at the neuronal level, but both reduce symptoms of attention deficit hyperactivity disorder (ADHD). To understand their common physiologic effects and thereby gain insight into the neurobiology of ADHD treatment, we compared the effects of the stimulant methylphenidate (MPH) and NE uptake inhibitor atomoxetine (ATX) on inhibitory and excitatory processes in human cortex. Nine healthy, right-handed adults were given a single, oral dose of 30 mg MPH and 60 mg ATX at visits separated by 1 week in a randomized, double-blind crossover trial. We used paired and single transcranial magnetic stimulation (TMS) of motor cortex to measure conditioned and unconditioned motor-evoked potential amplitudes at inhibitory (3 ms) and facilitatory (10 ms) interstimulus intervals (ISI) before and after drug administration. Data were analyzed with repeated measures, mixed model regression. We also analyzed our findings and the published literature with meta-analysis software to estimate treatment effects of stimulants and NE reuptake inhibitors on these TMS measures. There were no significant pretreatment differences or effects of treatment order. Both agents produced a significant increase in facilitation and a decrease in inhibition. Effects of ATX and MPH did not differ significantly. Pooled estimates from published studies show similar results for stimulants and NE reuptake inhibitors. In conclusion, in healthy adults, both stimulant and nonstimulant medications for ADHD decrease cortical inhibition and increase cortical facilitation. Cortical inhibition, shown previously to be abnormal in ADHD, may play a key role producing behavioral pathology.

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Atomoxetine Pharmacokinetics in Children and Adolescents with Attention Deficit Hyperactivity Disorder

Abstract: The pharmacokinetics of atomoxetine in extensive metabolizer patients were well characterized over a wide range of doses in this study. Atomoxetine pharmacokinetics in pediatric patients and adult subjects were similar after adjustment for body weight.

Cited by 104 publications

References 13 publications

Inhibition of G-Protein-Activated Inwardly Rectifying K+ Channels by the Selective Norepinephrine Reuptake Inhibitors Atomoxetine and Reboxetine

Inhibition of G-Protein-Activated Inwardly Rectifying K+ Channels by the Selective Norepinephrine Reuptake Inhibitors Atomoxetine and Reboxetine

Atomoxetine treatment of ADHD in Tourette Syndrome: Reduction in motor cortex inhibition correlates with clinical improvement

Comparison of the Inhibitory and Excitatory Effects of ADHD Medications Methylphenidate and Atomoxetine on Motor Cortex

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