Clinical Assessment of Norepinephrine Transporter Blockade Through Biochemical and Pharmacological Profiles

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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. Methods and 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 (PD 30 ) increased dose-dependently with duloxetine and was significant at the end of the 120-mg/d dosage ( P P P 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.

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