The slow and long-lasting blockade of dopamine transporters in human brain induced by the new antidepressant drug radafaxine predict poor reinforcing effects.
BACKGROUND
(2S,3S)-2-(3-Chlorophenyl)-3,5,5,-trimethyl-2-morpholinol hydrochloride (radafaxine) is a new antidepressant that blocks dopamine transporters (DAT). A concern with drugs that block (DAT) is their potential reinforcing effects and abuse liability. Using positron emission tomography (PET) we have shown that for DAT-blocking drugs to produce reinforcing effects they must induce >50% DAT blockade and the blockade has to be fast (within 15 minutes). This study measures the potency and kinetics for DAT blockade by radafaxine in human brain.


METHODS
PET and [11C]cocaine were used to estimate DAT blockade at 1, 4, 8, and 24 hours after radafaxine (40 mg p.o.) in 8 controls. Plasma pharmacokinetics and behavioral and cardiovascular effects were measured in parallel.


RESULTS
DAT blockade by radafaxine was slow, and at 1 hour, it was 11%. Peak blockade occurred at about 4 hours and was 22%. Blockade was long lasting: at 8 hours 17%, and at 24 hours 15%. Peak plasma concentration occurred about 4 to 8 hours. No behavioral or cardiovascular effects were observed.


CONCLUSIONS
The relatively low potency of radafaxine in blocking DAT and its slow blockade suggests that it is unlikely to have reinforcing effects. This is consistent with preclinical studies showing no self-administration. This is the first utilization of PET to predict abuse liability of a new antidepressant in humans based on DAT occupancy and pharmacokinetics.
Volkow
Nora D
ND
Brookhaven National Laboratory, Upton, NY 11973, USA. volkow@bnl.gov
Wang
Gene-Jack
GJ
Fowler
Joanna S
JS
Learned-Coughlin
Susan
S
Yang
Julia
J
Logan
Jean
J
Schlyer
David
D
Gatley
John S
JS
Wong
Christopher
C
Zhu
Wei
W
Pappas
Naomi
N
Schueller
Michael
M
Jayne
Millard
M
Carter
Pauline
P
Warner
Donald
D
Ding
Yu-Shin
YS
Shea
Colleen
C
Xu
Youwen
Y
D000328:Adult; D000928:Antidepressive Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000033:anatomy & histology / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000503:physiopathology; D001931:Brain Mapping; D016642:Bupropion / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D003042:Cocaine / Q000493:pharmacokinetics*; D050483:Dopamine Plasma Membrane Transport Proteins; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods; D012054:Reinforcement, Psychology; D018709:Statistics, Nonparametric; D013997:Time Factors; D014316:Tritium / Q000493:pharmacokinetics
D000928:Antidepressive Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493214:SLC6A3 protein, human; D016642:Bupropion; D014316:Tritium; D003042:Cocaine; C496215:radafaxine