{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T20:49:43Z","timestamp":1764276583371,"version":"3.38.0"},"reference-count":31,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2013,3,7]],"date-time":"2013-03-07T00:00:00Z","timestamp":1362614400000},"content-version":"vor","delay-in-days":400,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2012,2]]},"abstract":"<jats:p>The safety, tolerability, pharmacokinetics, and pharmacodynamics of etamicastat (BIA 5\u2013453), a novel dopamine \u03b2\u2010hydroxylase (D\u03b2H) inhibitor, were investigated in 10 sequential groups of 8 healthy male subjects under a double\u2010blind, randomized, placebo\u2010controlled design. In each group, 6 subjects received a single dose of etamicastat (2, 10, 20, 50, 100, 200, 400, 600, 900, or 1200 mg) and 2 subjects received placebo. Etamicastat was well tolerated at all dose levels tested. Maximum plasma etamicastat concentrations occurred at 1 to 3 hours postdose. Elimination was biphasic, characterized by a first short early elimination half\u2010life followed by a longer elimination phase of 16 to 20 hours for etamicastat doses of 100 mg and above. A high interindividual variability of pharmacokinetic parameters of etamicastat and its acetylated metabolite was observed. Pharmacogenomic data showed that N\u2010acetyltransferase type 2 (NAT2) phenotype (rapid or slow N\u2010acetylating ability) was a major source of variability. In NAT2 poor acetylators, the area under the plasma concentration\u2010time curve from time zero to the last sampling time at which concentrations were at or above the limit of quantification (AUC<jats:sub>0\u2010t<\/jats:sub>) of etamicastat was twice that observed in rapid acetylators. Consistent with that finding, AUC<jats:sub>0\u2010t<\/jats:sub>of the acetylated metabolite was markedly higher in NAT2 rapid acetylators compared with poor acetylators. Inhibition of D\u03b2H activity was observed, reaching statistical significance for etamicastat doses of 100 mg and above.<\/jats:p>","DOI":"10.1177\/0091270010390805","type":"journal-article","created":{"date-parts":[[2011,2,23]],"date-time":"2011-02-23T03:37:25Z","timestamp":1298432245000},"page":"156-170","source":"Crossref","is-referenced-by-count":20,"title":["Single\u2010Dose Tolerability, Pharmacokinetics, and Pharmacodynamics of Etamicastat (BIA 5\u2013453), a New Dopamine \u03b2\u2010Hydroxylase Inhibitor, in Healthy Subjects"],"prefix":"10.1002","volume":"52","author":[{"given":"Jos\u00e9 Francisco","family":"Rocha","sequence":"first","affiliation":[]},{"given":"Manuel","family":"Vaz\u2010Da\u2010Silva","sequence":"additional","affiliation":[]},{"given":"Teresa","family":"Nunes","sequence":"additional","affiliation":[]},{"given":"Bruno","family":"Igreja","sequence":"additional","affiliation":[]},{"given":"Ana 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