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Dihydroxyphenylglycol as a Biomarker of Norepinephrine Transporter Inhibition by Atomoxetine

Human Model to Assess Central and Peripheral Effects of Dosing

Bieck, Peter R. MD, PhD; Leibowitz, Mark MD; Lachno, D. Richard DPhil; Ledent, Edouard MS; Padich, Robert PhD; Jhee, Stan PharmD

Journal of Clinical Psychopharmacology: December 2016 - Volume 36 - Issue 6 - p 675–683
doi: 10.1097/JCP.0000000000000611
Original Contributions

To assess the primary metabolite of norepinephrine, 3,4-dihydroxyphenylglycol (DHPG), as a sensitive biomarker for norepinephrine transporter (NET) function and the relationship of DHPG measured peripherally and centrally, NET was antagonized with 80 mg/d atomoxetine for 18 days. Twelve healthy subjects were treated with atomoxetine in an open-label, multiple-dose exploratory study. Plasma atomoxetine reached steady state by day 6, and the pharmacokinetic results demonstrated availability of atomoxetine to the central nervous system. The cerebrospinal fluid (CSF)/plasma ratios of atomoxetine based on area under concentration-time curve from 0 to 12 hours postdose (AUC0–12), maximum concentration (Cmax), and predose were 0.3%, 0.2%, and 11%, respectively. Plasma from atomoxetine-treated subjects (ex vivo) significantly inhibited radioligand binding to human NET (P < 0.001) only 1 hour after dosing. Plasma DHPG and DHPG/norepinephrine (ratio) during repeated posture tests were reduced significantly (P < 0.001) on day 5 and stayed significantly reduced up to 1 day after treatment. In CSF, both DHPG and the ratio were significantly reduced (P < 0.001) on day 18. Urine results showed significant decreases for both DHPG and the ratio (P = 0.010 to P < 0.001). Brain-derived neurotrophic factor in CSF was lesser than the limits of detection. The findings suggest that NET blockade can be assessed with DHPG concentration or with the ratio in plasma, CSF, and urine. The data suggest that DHPG is a useful biomarker to proactively assess the pharmacological activity of compounds intended to inhibit NET activity within the brain. The study shows that CSF is a medium for early identification and quantification of biomarkers useful in assessing novel neuroscience targets.

From the *Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN; †World Wide Clinical Trials, Beverly Hills; ‡California Clinical Trials, Glendale; §CNS Network, Long Beach, CA; ∥Eli Lilly and Company, Windlesham, United Kingdom; ¶Glaxo Smith Kline, Rixensart, Belgium; and #PAREXEL International Early Phase, Glendale, CA.

Received August 14, 2015; accepted after revision September 6, 2016.

Reprints: Peter R. Bieck, MD, PhD, 1220 S Dr Way, Apartment A, Delray Beach, FL 33445 (e-mail:

This study was supported by Eli Lilly and Company.

Presented in part at the 19th Congress of the European College of Neuropsychopharmacology.

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