Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptors.
The blockade of serotonin (5-HT) and norepinephrine (NE) transporters in vitro and in vivo by the dual 5-HT/NE reuptake inhibitors duloxetine and venlafaxine was compared. Duloxetine inhibited binding to the human NE and 5-HT transporters with K(i) values of 7.5 and 0.8 nM, respectively, and with a K(i) ratio of 9. Venlafaxine inhibited binding to the human NE and 5-HT transporters with K(i) values of 2480 and 82 nM, respectively, and with a K(i) ratio of 30. Duloxetine inhibited ex vivo binding to rat 5-HT transporters and NE transporters with ED(50) values of 0.03 and 0.7 mg/kg, respectively, whereas venlafaxine had ED(50) values of 2 and 54 mg/kg, respectively. The depletion of rat brain 5-HT by p-chloramphetamine and depletion of rat hypothalamic NE by 6-hydroxydopamine was blocked by duloxetine with ED(50) values of 2.3 and 12 mg/kg, respectively. Venlafaxine had ED(50) values of 5.9 and 94 mg/kg for blocking p-chloramphetamine- and 6-hydroxydopamine-induced monoamine depletion, respectively. Thus, duloxetine more potently blocks 5-HT and NE transporters in vitro and in vivo than venlafaxine.
Bymaster
F P
FP
Neuroscience Research Division, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285-0510, USA. fbymaster@lilly.com
Dreshfield-Ahmad
L J
LJ
Threlkeld
P G
PG
Shaw
J L
JL
Thompson
L
L
Nelson
D L
DL
Hemrick-Luecke
S K
SK
Wong
D T
DT
D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D003511:Cyclohexanols / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D000068736:Duloxetine Hydrochloride; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins; D008995:Monoamine Oxidase / Q000378:metabolism; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000187:drug effects*; D050484:Norepinephrine Plasma Membrane Transport Proteins; D016627:Oxidopamine / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects*; D018490:Serotonin Agents / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013565:Sympatholytics / Q000494:pharmacology; D027981:Symporters / Q000378:metabolism*; D013876:Thiophenes / Q000494:pharmacology*; D000069470:Venlafaxine Hydrochloride; D010133:p-Chloroamphetamine / Q000037:antagonists & inhibitors
D015306:Biogenic Monoamines; D002352:Carrier Proteins; D003511:Cyclohexanols; D000068736:Duloxetine Hydrochloride; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008995:Monoamine Oxidase; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D016627:Oxidopamine; D011985:Receptors, Serotonin; D018490:Serotonin Agents; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D013565:Sympatholytics; D027981:Symporters; D013876:Thiophenes; D000069470:Venlafaxine Hydrochloride; D010133:p-Chloroamphetamine; C493227:SLC6A2 protein, human; C493230:SLC6A4 protein, human; C493226:Slc6a2 protein, rat; C493232:Slc6a4 protein, rat