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Clinical doses of atomoxetine significantly occupy both norepinephrine and serotonin transports: Implications on treatment of depression and ADHD.
- Source :
-
NeuroImage [Neuroimage] 2014 Feb 01; Vol. 86, pp. 164-71. Date of Electronic Publication: 2013 Aug 09. - Publication Year :
- 2014
-
Abstract
- Background: Atomoxetine (ATX), a drug for treatment of depression and ADHD, has a high affinity for the norepinephrine transporter (NET); however, our previous study showed it had a blocking effect similar to fluoxetine on binding of [(11)C]DASB, a selective serotonin transporter (SERT) ligand. Whether the therapeutic effects of ATX are due to inhibition of either or both transporters is not known. Here we report our comparative PET imaging studies with [(11)C]MRB (a NET ligand) and [(11)C]AFM (a SERT ligand) to evaluate in vivo IC50 values of ATX in monkeys.<br />Methods: Rhesus monkeys were scanned up to four times with each tracer with up to four doses of ATX. ATX or saline (placebo) infusion began 2h before each PET scan, lasting until the end of the 2-h scan. The final infusion rates were 0.01-0.12mg/kg/h and 0.045-1.054mg/kg/h for the NET and SERT studies, respectively. ATX plasma levels and metabolite-corrected arterial input functions were measured. Distribution volumes (VT) and IC50 values were estimated.<br />Results: ATX displayed dose-dependent occupancy on both NET and SERT, with a higher occupancy on NET: IC50 of 31±10 and 99±21ng/mL plasma for NET and SERT, respectively. At a clinically relevant dose (1.0-1.8mg/kg, approx. 300-600ng/mL plasma), ATX would occupy >90% of NET and >85% of SERT. This extrapolation assumes comparable free fraction of ATX in humans and non-human primates.<br />Conclusion: Our data suggests that ATX at clinically relevant doses greatly occupies both NET and SERT. Thus, therapeutic modes of ATX action for treatment of depression and ADHD may be more complex than selective blockade of NET.<br /> (© 2013.)
- Subjects :
- Adrenergic Uptake Inhibitors administration & dosage
Adrenergic Uptake Inhibitors pharmacokinetics
Animals
Atomoxetine Hydrochloride
Attention Deficit Disorder with Hyperactivity drug therapy
Attention Deficit Disorder with Hyperactivity metabolism
Brain drug effects
Depression drug therapy
Depression metabolism
Dose-Response Relationship, Drug
Macaca mulatta
Positron-Emission Tomography methods
Tissue Distribution
Brain metabolism
Norepinephrine Plasma Membrane Transport Proteins metabolism
Propylamines administration & dosage
Propylamines pharmacokinetics
Serotonin Plasma Membrane Transport Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1095-9572
- Volume :
- 86
- Database :
- MEDLINE
- Journal :
- NeuroImage
- Publication Type :
- Academic Journal
- Accession number :
- 23933039
- Full Text :
- https://doi.org/10.1016/j.neuroimage.2013.08.001