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Effects of duloxetine on norepinephrine and serotonin transporter activity in healthy subjects.
- 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.
- Subjects :
- Adrenergic Uptake Inhibitors adverse effects
Adrenergic Uptake Inhibitors blood
Adrenergic Uptake Inhibitors pharmacokinetics
Adult
Aged
California
Central Nervous System metabolism
Citalopram pharmacology
Cross-Over Studies
Duloxetine Hydrochloride
Female
Healthy Volunteers
Humans
Hydroxyindoleacetic Acid cerebrospinal fluid
Male
Methoxyhydroxyphenylglycol analogs & derivatives
Methoxyhydroxyphenylglycol blood
Methoxyhydroxyphenylglycol cerebrospinal fluid
Methoxyhydroxyphenylglycol urine
Middle Aged
Norepinephrine blood
Norepinephrine cerebrospinal fluid
Norepinephrine urine
Norepinephrine Plasma Membrane Transport Proteins metabolism
Serotonin Plasma Membrane Transport Proteins metabolism
Selective Serotonin Reuptake Inhibitors adverse effects
Selective Serotonin Reuptake Inhibitors blood
Selective Serotonin Reuptake Inhibitors pharmacokinetics
Texas
Thiophenes adverse effects
Thiophenes blood
Thiophenes pharmacokinetics
Young Adult
Adrenergic Uptake Inhibitors pharmacology
Central Nervous System drug effects
Norepinephrine Plasma Membrane Transport Proteins antagonists & inhibitors
Serotonin Plasma Membrane Transport Proteins drug effects
Selective Serotonin Reuptake Inhibitors pharmacology
Thiophenes pharmacology
Subjects
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