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


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.


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.


CONCLUSIONS
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.
Department of Diagnostic Radiology, Yale University, New Haven, CT, USA; Department of Psychiatry and Radiology, New York University, New York, NY, USA. Electronic address: yu-shin.ding@nyumc.org.
Y-S
YS
Ding
Department of Diagnostic Radiology, Yale University, New Haven, CT, USA.
M
M
Naganawa
Department of Diagnostic Radiology, Yale University, New Haven, CT, USA.
J-D
JD
Gallezot
Department of Diagnostic Radiology, Yale University, New Haven, CT, USA.
N
N
Nabulsi
Department of Diagnostic Radiology, Yale University, New Haven, CT, USA.
S-F
SF
Lin
Department of Diagnostic Radiology, Yale University, New Haven, CT, USA.
J
J
Ropchan
Department of Diagnostic Radiology, Yale University, New Haven, CT, USA.
D
D
Weinzimmer
Pfizer Global R&D, Groton, CT, USA.
T J
TJ
McCarthy
Department of Diagnostic Radiology, Yale University, New Haven, CT, USA.
R E
RE
Carson
Department of Diagnostic Radiology, Yale University, New Haven, CT, USA.
Y
Y
Huang
New Medicines, UCB Pharma S.A., Brussels, Belgium.
M
M
Laruelle
D018759:Adrenergic Uptake Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D000818:Animals; D000069445:Atomoxetine Hydrochloride; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D003863:Depression / Q000188:drug therapy / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008253:Macaca mulatta; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods; D011437:Propylamines / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D014018:Tissue Distribution
D018759:Adrenergic Uptake Inhibitors; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011437:Propylamines; D050486:Serotonin Plasma Membrane Transport Proteins; D000069445:Atomoxetine Hydrochloride
Atomoxetine; Attention deficit hyperactivity disorder; Depression; Norepinephrine transporter; Positron emission tomography; Serotonin transporter