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Effects of duloxetine on norepinephrine and serotonin transporter activity in healthy subjects.

Authors :
Chappell JC
Eisenhofer G
Owens MJ
Haber H
Lachno DR
Dean RA
Knadler MP
Nemeroff CB
Mitchell MI
Detke MJ
Iyengar S
Pangallo B
Lobo ED
Source :
Journal of clinical psychopharmacology [J Clin Psychopharmacol] 2014 Feb; Vol. 34 (1), pp. 9-16.
Publication Year :
2014

Abstract

Duloxetine selectively inhibits the serotonin (5-HT) and norepinephrine (NE) transporters (5-HTT and NET, respectively), as demonstrated in vitro and in preclinical studies; however, transporter inhibition has not been fully assessed in vivo at the approved dose of 60 mg/d. Here, the in vivo effects of dosing with duloxetine 60 mg once daily for 11 days in healthy subjects were assessed in 2 studies: (1) centrally (n = 11), by measuring concentrations of 5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylglycol (DHPG), and NE in cerebrospinal fluid, and (2) versus escitalopram 20 mg/d (n = 32) in a 2-period crossover study by assessing the ΔDHPG/ΔNE ratio in plasma during orthostatic testing and by pharmacokinetic/pharmacodynamic modeling of reuptake inhibition using subjects' serum in cell lines expressing cloned human 5-HTT or NET. At steady state, duloxetine significantly reduced concentrations of DHPG and 5-hydroxyindoleacetic acid (P < 0.05), but not NE, in cerebrospinal fluid; DHPG was also decreased in plasma and urine. The ΔDHPG/ΔNE ratio in plasma decreased significantly more with duloxetine than escitalopram (65% and 21%, respectively; P < 0.0001). Ex vivo reuptake inhibition of 5-HTT was comparable (EC50 = 44.5 nM) for duloxetine and escitalopram, but duloxetine inhibited NET more potently (EC50 = 116 nM and 1044 nM, respectively). Maximal predicted reuptake inhibition for 5-HTT was 84% for duloxetine and 80% for escitalopram, and that for NET was 67% and 14%, respectively. In summary, duloxetine significantly affected 5-HT and NE turnover in the central nervous system and periphery; these effects presumably occurred via inhibition of reuptake by the 5-HTT and NET, as indicated by effects on functional reuptake inhibition ex vivo.

Details

Language :
English
ISSN :
1533-712X
Volume :
34
Issue :
1
Database :
MEDLINE
Journal :
Journal of clinical psychopharmacology
Publication Type :
Academic Journal
Accession number :
24346757
Full Text :
https://doi.org/10.1097/JCP.0000000000000061