title: Human disposition, metabolism and excretion of etamicastat, a reversible, peripherally selective dopamine β-hydroxylase inhibitor.
abstract: OBJECTIVE
  Etamicastat is a reversible dopamine-β-hydroxylase inhibitor that decreases noradrenaline 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 [(14)C]-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 98 µCi weighing 0.623 mg [(14)C]-etamicastat. Blood samples, urine and faeces were collected 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 that was highly variable both for the maximal plasma concentration (19.68-226.28%) and for the area under the plasma concentration-time curve from time zero to the last sampling time at which the concentration was above the limit of quantification (15.82- 281.71%). Alongside N-acetylation, metabolism of etamicastat also occurs through oxidative deamination of the aminoethyl moiety, alkyl oxidation, desulfation and glucuronidation.
  
  
  CONCLUSIONS
  Etamicastat is rapidly absorbed, primarily excreted via urine, and its biotransformation occurs mainly via N-acetylation (N-acetyltransferase type 2), although glucuronidation, oxidation, oxidative deamination and desulfation also take place.
authors.affiliation: Department of Research and Development, BIAL - Portela & Cª. S.A., S. Mamede do Coronado, Portugal.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Loureiro
authors.forename: Jose F
authors.initials: JF
authors.lastname: Rocha
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernandes-Lopes
authors.forename: Teresa
authors.initials: T
authors.lastname: Nunes
authors.forename: Lyndon C
authors.initials: LC
authors.lastname: Wright
authors.forename: Luis
authors.initials: L
authors.lastname: Almeida
authors.forename: Patricio
authors.initials: P
authors.lastname: Soares-da-Silva
mesh_terms: D000328:Adult; D001191:Arylamine N-Acetyltransferase / Q000235:genetics; D001578:Benzopyrans / Q000378:metabolism*; D002250:Carbon Radioisotopes; D004299:Dopamine beta-Hydroxylase / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000378:metabolism*; D005243:Feces / Q000737:chemistry; D005838:Genotype; D006801:Humans; D007093:Imidazoles / Q000378:metabolism*; D007527:Isoenzymes / Q000235:genetics; D008297:Male; D008875:Middle Aged
chemical_list: D001578:Benzopyrans; D002250:Carbon Radioisotopes; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007527:Isoenzymes; C509002:etamicastat; D004299:Dopamine beta-Hydroxylase; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1; C478900:NAT2 protein, human
keywords: N-acetylation; dopamine β-hydroxylase; etamicastat; excretion; metabolism; pharmacokinetics