title: Clinical assessment of norepinephrine transporter blockade through biochemical and pharmacological profiles.
abstract: BACKGROUND
  To assess the sensitivity of biochemical, physiological, and pharmacological markers of peripheral norepinephrine (NE) transporter (NET) function, we chronically antagonized NET by a range of doses of duloxetine [(+)-N-methyl-3-(1-naphthalenyloxy)-2 thiophenepropanamine], which blocks the NE reuptake process.
  
  
  RESULTS
  Duloxetine was administered in a randomized, placebo-controlled study in 15 healthy volunteers. Plasma from duloxetine-treated subjects (ex vivo effect) dose-dependently decreased radioligand binding to human NET (maximum inhibition was 60%) (P=0.02). The dose of intravenous tyramine required to raise systolic blood pressure by 30 mm Hg (PD30) increased dose-dependently with duloxetine and was significant at the end of the 120-mg/d dosage (P<0.001). The plasma dihydoxyphenylglycol to NE (DHPG/NE) ratio was reduced significantly at 2 weeks of treatment with 80 mg/d duloxetine (11.3 at baseline, 3.4 at 240 mg/d, P<0.001). Plasma NE was significantly increased starting at 120 mg/d duloxetine. Urine results (corrected for 24-hour creatinine excretion) showed a dose-dependent change from the baseline urinary excretion for NE, DHPG, and the DHPG/NE ratio. The most sensitive measure, the DHPG/NE ratio, was significant at the 80-mg dose. Urinary NE excretion was significantly raised after 2 weeks of treatment with 80 mg/d duloxetine (P<0.001), the lowest dose used in the study.
  
  
  CONCLUSIONS
  These findings suggest that the degree of NET blockade can be assessed with the plasma or urine DHPG/NE ratio and the pressor effect of tyramine. Also, the DHPG/NE ratio is more sensitive at the lower end of NET inhibition, whereas tyramine exhibits a linear relation, with NET inhibition commencing at a higher dose.
authors.affiliation: Autonomic Dysfunction Center, Departments of Medicine, Pharmacology, and Neurology, Vanderbilt University, Nashville, Tenn 37232-2195, USA.
authors.forename: Simi
authors.initials: S
authors.lastname: Vincent
authors.forename: Peter R
authors.initials: PR
authors.lastname: Bieck
authors.forename: Emily M
authors.initials: EM
authors.lastname: Garland
authors.forename: Corina
authors.initials: C
authors.lastname: Loghin
authors.forename: Frank P
authors.initials: FP
authors.lastname: Bymaster
authors.forename: Bonnie K
authors.initials: BK
authors.lastname: Black
authors.forename: Celedon
authors.initials: C
authors.lastname: Gonzales
authors.forename: William Z
authors.initials: WZ
authors.lastname: Potter
authors.forename: David
authors.initials: D
authors.lastname: Robertson
mesh_terms: D000293:Adolescent; D018759:Adrenergic Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000328:Adult; D004305:Dose-Response Relationship, Drug; D000068736:Duloxetine Hydrochloride; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives* / Q000652:urine; D009638:Norepinephrine / Q000097:blood / Q000652:urine; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011187:Posture; D011869:Radioligand Assay; D012680:Sensitivity and Specificity; D027981:Symporters / Q000037:antagonists & inhibitors*; D013599:Systole / Q000187:drug effects; D013876:Thiophenes / Q000008:administration & dosage / Q000494:pharmacology*; D014439:Tyramine / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D018759:Adrenergic Uptake Inhibitors; D050484:Norepinephrine Plasma Membrane Transport Proteins; C493227:SLC6A2 protein, human; D027981:Symporters; D013876:Thiophenes; D008734:Methoxyhydroxyphenylglycol; D000068736:Duloxetine Hydrochloride; C010117:3,4-dihydroxyphenylglycol; D009638:Norepinephrine; D014439:Tyramine