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

• Published in: Journal of clinical psychopharmacology Vol. 34; no. 1; p. 9
• Main Authors: Chappell, Jill C, Eisenhofer, Graeme, Owens, Michael J, Haber, Harry, Lachno, D Richard, Dean, Robert A, Knadler, Mary Pat, Nemeroff, Charles B, Mitchell, Malcolm I, Detke, Michael J, Iyengar, Smriti, Pangallo, Beth, Lobo, Evelyn D
• Format: Journal Article
• Language: English
• Published: United States 01.02.2014
• Subjects: Adrenergic Uptake Inhibitors - adverse effects; Adrenergic Uptake Inhibitors - blood; Adrenergic Uptake Inhibitors - pharmacokinetics; Adrenergic Uptake Inhibitors - pharmacology; Adult; Aged; California; Central Nervous System - drug effects; 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 - antagonists & inhibitors; Norepinephrine Plasma Membrane Transport Proteins - metabolism; Serotonin Plasma Membrane Transport Proteins - drug effects; Serotonin Plasma Membrane Transport Proteins - metabolism; Serotonin Uptake Inhibitors - adverse effects; Serotonin Uptake Inhibitors - blood; Serotonin Uptake Inhibitors - pharmacokinetics; Serotonin Uptake Inhibitors - pharmacology; Texas; Thiophenes - adverse effects; Thiophenes - blood; Thiophenes - pharmacokinetics; Thiophenes - pharmacology; Young Adult
• ISSN: 1533-712X
• DOI: 10.1097/JCP.0000000000000061

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.