Ecopipam, a Dopamine D1 Receptor Antagonist: Pharmacokinetics, Mass Balance, and Metabolism in Healthy Volunteers.

Ecopipam is a dopamine-1 (D1) receptor antagonist in development for Tourette syndrome. In vitro data showed that ecopipam is metabolized to ecopipam glucuronide through uridine diphosphate-glucuronosyltransferase 1A9 and to EBS-101-40853 (previously called N-desmethylecopipam or SCH 40853) through cytochrome P450 3A4. This open-label, non-randomized, mass balance study investigated metabolism and elimination pathways of ecopipam. A single oral dose of ecopipam 179.2 mg containing 88.5 μCi (3.27 MBq) of [14C]-labeled ecopipam was administered to 8 healthy males. Total radioactivity, ecopipam, and ecopipam metabolite concentrations were measured in blood, plasma, urine, and feces periodically until discharge (between Days 8 and 15 postdose). Pooled plasma was used to identify and quantify unknown metabolites. Overall, 83.3% of radioactivity was recovered in urine as metabolites (< 1% as ecopipam), and 8.27% was excreted in feces (6.43% as ecopipam). Ecopipam glucuronide accounted for 80.0% of radioactivity in plasma and 66.9% of radioactivity in urine. EBS-101-40853 accounted for 10.5% of the plasma AUC∞ for ecopipam. Geometric mean half-lives of ecopipam, EBS-101-40853, and total radioactivity in plasma were 17.3, 25.6, and 94.1 h, respectively. Uncharacterized metabolites P3 and P5, 'corrected' for extraction efficiency, had plasma half-lives (97.4 and 122 h, respectively) similar to total radioactivity. Unknown P3, P4, and P5 metabolites accounted for 4.62%, 0.243%, and 6.03%, respectively, of plasma radioactivity. Ecopipam is primarily metabolized to ecopipam glucuronide, with only 10.5% metabolized to EBS-101-40853. The long half-life of plasma radioactivity was attributed to previously uncharacterized metabolites that each accounted for < 10% of radioactivity and were considered not clinically relevant.