Human Disposition, Metabolism and Excretion of Etamicastat, a Reversible Peripherally Selective Dopamine ß-Hydroxylase Inhibitor.

British journal of clinical pharmacology

PubMedID: 24168152

Loureiro AI, Rocha JF, Fernandes-Lopes C, Nunes T, Wright LC, Almeida L, Soares-da-Silva P. Human Disposition, Metabolism and Excretion of Etamicastat, a Reversible Peripherally Selective Dopamine ß-Hydroxylase Inhibitor. Br J Clin Pharmacol. 2013;.
AIMS
Etamicastat, (R)-5-(2-aminoethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3H)-thione hydrochloride, is a reversible dopamine-ß-hydroxylase (DBH) inhibitor that decreases noradrenaline (NA) levels in sympathetically innervated tissues and slows down sympathetic nervous system drive. In this study the disposition, metabolism and excretion of etamicastat were evaluated following [14C]-etamicastat dosing.

METHODS
Healthy Caucasian males (n=4) were enrolled in this single dose, open-label study. Subjects were administered 600 mg of unlabelled etamicastat and 0.623 mg [14C]-etamicastat containing 98 µCi weighing. Blood samples, urine and faeces were taken to characterize the disposition, excretion and metabolites of etamicastat.

RESULTS
Eleven days after administration, 94.0% of the administered radioactivity had been excreted: 33.3% and 58.5% of the administered dose was found in the faeces and urine, respectively. Renal excretion of unchanged etamicastat and its N-acetylated metabolite (BIA 5-961), accounted for 20.0% and 10.7% of the dose, respectively. Etamicastat and BIA 5-961 accounted for most of the circulating radioactivity with a BIA 5-961/etamicastat ratio highly variable both for Cmax (19.68 to 226.28%) and for AUC0-t (15.82% to 281.71%). Alongside with N-acetylation, metabolism of etamicastat also occurs through oxidative deamination of the aminoethyl moiety, alkyl oxidation, desulfation, and glucuronidation.

CONCLUSION
Etamicastat is rapidly absorbed, primarily excreted via urine and its bio-transformation occurs mainly via N-acetylation (NAT2), though glucuronidation, oxidation, oxidative deamination and desulfation also take place.