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(Circulation. 2004;109:3202-3207.)
© 2004 American Heart Association, Inc.

Clinical Investigation and Reports

Clinical Assessment of Norepinephrine Transporter Blockade Through Biochemical and Pharmacological Profiles

Simi Vincent, MD, PhD; Peter R. Bieck, MD, PhD; Emily M. Garland, PhD; Corina Loghin, MD; Frank P. Bymaster, MS; Bonnie K. Black, RN, NP; Celedon Gonzales, MS; William Z. Potter, MD, PhD; David Robertson, MD

From the Autonomic Dysfunction Center, Departments of Medicine, Pharmacology, and Neurology, Vanderbilt University, Nashville, Tenn (S.V., E.M.G., B.K.B., D.R.); and Lilly Research Laboratories, Indianapolis, Ind (P.R.B., C.L., F.P.B., C.G., W.Z.P.).

Correspondence to Dr D. Robertson, Autonomic Dysfunction Center, AA3228 MCN, 1161 21st Ave South, Nashville, TN 37232-2195. E-mail david.robertson{at}vanderbilt.edu

Received June 23, 2003; de novo received November 3, 2003; revision received March 9, 2004; accepted March 16, 2004.

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 (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.

Key Words: norepinephrine • blood pressure • plasma • drugs • catecholamines

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