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.
| Original language | English |
|---|---|
| Pages (from-to) | 9-16 |
| Number of pages | 8 |
| Journal | Journal of Clinical Psychopharmacology |
| Volume | 34 |
| Issue number | 1 |
| DOIs | |
| State | Published - Feb 1 2014 |
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Keywords
- 5-HIAA
- CSF
- DHPG
- Duloxetine
- Norepinephrine
- Serotonin
ASJC Scopus subject areas
- Psychiatry and Mental health
- Pharmacology (medical)
Cite this
Effects of duloxetine on norepinephrine and serotonin transporter activity in healthy subjects. / Chappell, Jill C.; Eisenhofer, Graeme; Owens, Michael J.; Haber, Harry; Lachno, D. Richard; Dean, Robert A.; Knadler, Mary Pat; Nemeroff, Charles; Mitchell, Malcolm I.; Detke, Michael J.; Iyengar, Smriti; Pangallo, Beth; Lobo, Evelyn D.
In: Journal of Clinical Psychopharmacology, Vol. 34, No. 1, 01.02.2014, p. 9-16.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Effects of duloxetine on norepinephrine and serotonin transporter activity in healthy subjects
AU - Chappell, Jill C.
AU - Eisenhofer, Graeme
AU - Owens, Michael J.
AU - Haber, Harry
AU - Lachno, D. Richard
AU - Dean, Robert A.
AU - Knadler, Mary Pat
AU - Nemeroff, Charles
AU - Mitchell, Malcolm I.
AU - Detke, Michael J.
AU - Iyengar, Smriti
AU - Pangallo, Beth
AU - Lobo, Evelyn D.
PY - 2014/2/1
Y1 - 2014/2/1
N2 - 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.
AB - 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.
KW - 5-HIAA
KW - CSF
KW - DHPG
KW - Duloxetine
KW - Norepinephrine
KW - Serotonin
UR - http://www.scopus.com/inward/record.url?scp=84891738871&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84891738871&partnerID=8YFLogxK
U2 - 10.1097/JCP.0000000000000061
DO - 10.1097/JCP.0000000000000061
M3 - Article
C2 - 24346757
AN - SCOPUS:84891738871
VL - 34
SP - 9
EP - 16
JO - Journal of Clinical Psychopharmacology
JF - Journal of Clinical Psychopharmacology
SN - 0271-0749
IS - 1
ER -