1. Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptors.
- Author
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Bymaster FP, Dreshfield-Ahmad LJ, Threlkeld PG, Shaw JL, Thompson L, Nelson DL, Hemrick-Luecke SK, and Wong DT
- Subjects
- Animals, Biogenic Monoamines metabolism, Cell Line, Dose-Response Relationship, Drug, Duloxetine Hydrochloride, Humans, Male, Monoamine Oxidase metabolism, Norepinephrine Plasma Membrane Transport Proteins, Oxidopamine pharmacology, Radioligand Assay, Rats, Rats, Sprague-Dawley, Serotonin Agents pharmacology, Serotonin Plasma Membrane Transport Proteins, Sympatholytics pharmacology, Venlafaxine Hydrochloride, p-Chloroamphetamine antagonists & inhibitors, Carrier Proteins metabolism, Cyclohexanols pharmacology, Membrane Glycoproteins metabolism, Membrane Transport Proteins, Nerve Tissue Proteins, Neurons drug effects, Receptors, Serotonin drug effects, Selective Serotonin Reuptake Inhibitors pharmacology, Symporters metabolism, Thiophenes pharmacology
- Abstract
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.
- Published
- 2001
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