Clinical assessment of norepinephrine transporter blockade through biochemical and pharmacological profiles.
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.
Vincent
Simi
S
Autonomic Dysfunction Center, Departments of Medicine, Pharmacology, and Neurology, Vanderbilt University, Nashville, Tenn 37232-2195, USA.
Bieck
Peter R
PR
Garland
Emily M
EM
Loghin
Corina
C
Bymaster
Frank P
FP
Black
Bonnie K
BK
Gonzales
Celedon
C
Potter
William Z
WZ
Robertson
David
D
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
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