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 ED50 values of 0.03 and 0.7 mg/kg, respectively, whereas venlafaxine had ED50 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 ED50 values of 2.3 and 12 mg/kg, respectively. Venlafaxine had ED50 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. [Neuropsychopharmacology 25:871-880, 2001] (C) 2001 American College of Neuropsychopharmacology. Published by Elsevier Science Inc.