Absorption, distribution, metabolism, and excretion of [¹⁴ C]-dasotraline in humans

Abstract

Dasotraline is a dopamine and norepinephrine reuptake inhibitor, and the early clinical trials show a slow absorption and long elimination half‐life. To investigate the absorption, distribution, metabolism, and excretion of dasotraline in humans, a single dose of [14C]‐dasotraline was administered to eight healthy male adult volunteers. At 35 days, 90.7% of the dosed radioactivity was recovered in the urine (68.3%) and feces (22.4%). The major metabolic pathways involved were: (1) amine oxidation to form oxime M41 and sequential sulfation to form M42 or glucuronidation to form M43; (2) N‐hydroxylation and sequential glucuronidation to form M35; (3) oxidative deamination to form (S)‐tetralone; (4) mono‐oxidation of (S)‐tetralone and sequential glucuronidation to form M31A and M32; and (5) N‐acetylation to form (1R,4S)‐acetamide M102. A total of 8 metabolites were detected and structurally elucidated with 4 in plasma (M41, M42, M43, and M35), 7 in urine (M41, M42, M43, M31A, M32, M35, and (S)‐tetralone), and 3 in feces (M41, (S)‐tetralone, and (1R,4S)‐acetamide). The 2 most abundant circulating metabolites were sulfate (M42) and glucuronide (M43) conjugates of the oxime of dasotraline, accounting for 60.1% and 15.0% of the total plasma radioactivity, respectively; unchanged dasotraline accounted for 8.59%. The oxime M41 accounted for only 0.62% of the total plasma radioactivity and was detected only at early time points. M35 was a minor glucuronide metabolite, undetectable by radioactivity but identified by mass spectrometry. The results demonstrate that dasotraline was slowly absorbed, and extensively metabolized by oxidation and subsequent phase II conjugations. The findings from this study also demonstrated that metabolism of dasotraline by humans did not produce metabolites that may cause a safety concern.

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“…Dasotraline is absorbed slowly and has a long elimination half-life resulting in stable plasma concentrations over 24 h with once-daily dosing. 76 Dasotraline carries a low potential for abuse. 77 Data are available in poster form from two 12-week randomized, double-blind, placebo-controlled studies that have been completed in adults with moderate to severe BED, one using flexible doses of dasotraline 4-8 mg/day, 78,79 and the second using fixed doses of dasotraline 4 and 6 mg/day.…”

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“…Dasotraline [(1R,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetra-hydronaphthalen-1-amine] is a potent catecholamine reuptake inhibitor (DAT: IC 50 = 3 nM and NET: IC 50 = 4 nM) with weaker effects on the 5-HT transporter (SERT: IC 50 = 15 nM) ( Koblan et al, 2016 ). Dasotraline is slowly absorbed after oral administration in humans with a t max of 10–12 h and a very long t 1/2 (terminal elimination half-life) of 47–77 h ( Chen et al, 2016 ; Hopkins et al, 2016 ; Koblan et al, 2015 ). It takes 2 weeks of daily dosing to reach steady state plasma concentrations ( Chen et al, 2016 ; Koblan et al, 2015 ).…”

“…Dasotraline is slowly absorbed after oral administration in humans with a t max of 10–12 h and a very long t 1/2 (terminal elimination half-life) of 47–77 h ( Chen et al, 2016 ; Hopkins et al, 2016 ; Koblan et al, 2015 ). It takes 2 weeks of daily dosing to reach steady state plasma concentrations ( Chen et al, 2016 ; Koblan et al, 2015 ). Microdialysis measurements of ACB dopamine efflux were consistent with human PK ( Heal et al, 2017 ; Rowley et al, 2017 ), that is small, dose-dependent increases that were slow in onset and sustained for many hours ( Figure 5 ).…”