Clinical doses of atomoxetine significantly occupy both norepinephrine and serotonin transports: Implications on treatment of depression and ADHD

Ding, Yu‐Shin; Naganawa, Mika; Gallezot, Jean‐Dominique; Nabulsi, Nabeel; Lin, Shu-fei; Ropchan, Jim; Weinzimmer, David; McCarthy, Timothy J.; Carson, Richard E.; Huang, Yiyun; Laruelle, Marc

doi:10.1016/j.neuroimage.2013.08.001

Cited by 80 publications

(57 citation statements)

References 39 publications

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“…2006;Robbins and Arnsten 2009). Recently, in vivo investigations utilizing positron emission tomography (PET) imaging assessing clinically relevant doses of atomoxetine in rhesus monkeys, reported the surprising finding that the drug occupied not only the NET (as anticipated), but also the serotonin transporter (Ding et al 2014). These latter results suggest that the mechanism of therapeutic action of atomoxetine may extend beyond what was previously understood.…”

Section: Introductionmentioning

confidence: 85%

Atomoxetine: A Review of Its Pharmacokinetics and Pharmacogenomics Relative to Drug Disposition

Markowitz

2016

Journal of Child and Adolescent Psychopharmacology

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Atomoxetine is a selective norepinephrine (NE) reuptake inhibitor approved for the treatment of attention-deficit/ hyperactivity disorder (ADHD) in children ( ‡6 years of age), adolescents, and adults. Its metabolism and disposition are fairly complex, and primarily governed by cytochrome P450 (CYP) 2D6 (CYP2D6), whose protein expression varies substantially from person to person, and by race and ethnicity because of genetic polymorphism. These differences can be substantial, resulting in 8-10-fold differences in atomoxetine exposure between CYP2D6 poor metabolizers and extensive metabolizers. In this review, we have attempted to revisit and analyze all published clinical pharmacokinetic data on atomoxetine inclusive of public access documents from the new drug application submitted to the United States Food and Drug Administration (FDA). The present review focuses on atomoxetine metabolism, disposition, and genetic polymorphisms of CYP2D6 as they specifically relate to atomoxetine, and provides an in-depth discussion of the fundamental pharmacokinetics of the drug including its absorption, distribution, metabolism, and excretion in pediatric and adult populations. Further, a summary of relationships between genetic variants of CYP2D6 and to some degree, CYP2C19, are provided with respect to atomoxetine plasma concentrations, central nervous system (CNS) pharmacokinetics, and associated clinical implications for pharmacotherapy. Lastly, dosage adjustments based on pharmacokinetic principles are discussed.

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Section: Introductionmentioning

confidence: 85%

Atomoxetine: A Review of Its Pharmacokinetics and Pharmacogenomics Relative to Drug Disposition

Markowitz

2016

Journal of Child and Adolescent Psychopharmacology

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“…Moreover, we did not measure norepinephrine transporter (NET) and serotonin transporter (SERT) binding after ATX treatment. A recent study on monkeys showed that ATX, at clinically relevant dose, displays a dose-dependent occupancy on both NET and SERT, with a higher occupancy on NET (Ding et al, 2014). Thus, we cannot rule out a possible serotonergic effect of ATX on the observed changes in marble burying behaviour.…”

Section: Discussionmentioning

confidence: 76%

Atomoxetine for Hoarding Disorder: A Preclinical and Clinical Investigation

Grassi

Micheli

Mannelli

et al. 2017

European Neuropsychopharmacology

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“…[ 11 C]DASB were used for the determination of transporter occupancy by reuptake inhibitors 12,13,14,15 . Interventions to either elevate or deplete extracellular serotonin, however, did not affect [ 11 C]DASB binding in humans 16 .…”

Section: Pet Radiotracers That Have Enabled Imaging Of Neurotransmmentioning

confidence: 99%

News and views on in-vivo imaging of neurotransmission using PET and MRI

Sander

Hesse

2017

Q J Nucl Med Mol Imaging

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Clinical doses of atomoxetine significantly occupy both norepinephrine and serotonin transports: Implications on treatment of depression and ADHD

Cited by 80 publications

References 39 publications

Atomoxetine: A Review of Its Pharmacokinetics and Pharmacogenomics Relative to Drug Disposition

Atomoxetine: A Review of Its Pharmacokinetics and Pharmacogenomics Relative to Drug Disposition

Atomoxetine for Hoarding Disorder: A Preclinical and Clinical Investigation

News and views on in-vivo imaging of neurotransmission using PET and MRI

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