title: Effects of duloxetine on norepinephrine and serotonin transporter activity in healthy subjects.
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.
authors.affiliation: From *Eli Lilly and Company, Indianapolis, IN; †Institute of Clinical Chemistry and Laboratory Medicine; ‡Department of Medicine, University of Dresden, Dresden, Germany; §Laboratory of Neuropsychopharmacology, Department of Psychiatry & Behavioral Sciences, Emory University, Atlanta, GA; ∥MMS Holdings, Inc, Canton, MI; ¶Eli Lilly and Company, Windlesham, Surrey, UK; #Department of Psychiatry & Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL; **Detke Biopharma Consulting, LLC; and ††Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Jill C
authors.initials: JC
authors.lastname: Chappell
authors.forename: Graeme
authors.initials: G
authors.lastname: Eisenhofer
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Owens
authors.forename: Harry
authors.initials: H
authors.lastname: Haber
authors.forename: D Richard
authors.initials: DR
authors.lastname: Lachno
authors.forename: Robert A
authors.initials: RA
authors.lastname: Dean
authors.forename: Mary Pat
authors.initials: MP
authors.lastname: Knadler
authors.forename: Charles B
authors.initials: CB
authors.lastname: Nemeroff
authors.forename: Malcolm I
authors.initials: MI
authors.lastname: Mitchell
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Detke
authors.forename: Smriti
authors.initials: S
authors.lastname: Iyengar
authors.forename: Beth
authors.initials: B
authors.lastname: Pangallo
authors.forename: Evelyn D
authors.initials: ED
authors.lastname: Lobo
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D000328:Adult; D000368:Aged; D002140:California; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism; D015283:Citalopram / Q000494:pharmacology; D018592:Cross-Over Studies; D000068736:Duloxetine Hydrochloride; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000134:cerebrospinal fluid; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000097:blood / Q000134:cerebrospinal fluid / Q000652:urine; D008875:Middle Aged; D009638:Norepinephrine / Q000097:blood / Q000134:cerebrospinal fluid / Q000652:urine; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000187:drug effects* / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D013781:Texas; D013876:Thiophenes / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D018759:Adrenergic Uptake Inhibitors; D015283:Citalopram; D000068736:Duloxetine Hydrochloride; D006897:Hydroxyindoleacetic Acid; D008734:Methoxyhydroxyphenylglycol; D009638:Norepinephrine; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D013876:Thiophenes; C493227:SLC6A2 protein, human; C493230:SLC6A4 protein, human; C010117:3,4-dihydroxyphenylglycol