title: Distribution and pharmacokinetics of etamicastat and its N-acetylated metabolite (BIA 5-961) in dog and monkey.
abstract: 1. The disposition etamicastat was evaluated in the Cynomolgus monkey after intravenous and oral administration of [(14)C]-etamicastat. The pharmacokinetics of etamicastat and its N-acetylated metabolite BIA 5-961 were also evaluated in monkeys and dogs. 2. In the monkey, 7 days after intravenous and oral administration of [(14)C]-etamicastat, 76.6-91.1% of the etamicastat-related radioactivity had been excreted mainly in urine. The radioactivity peaked in plasma between 4- and 8-h post-dosing followed by a quick decline and a slow terminal phase (half-life of 68.7 h). The calculated oral bioavailability for etamicastat was 46.1%. Etamicastat was quickly absorbed in monkeys and dogs with a half-life ranging from 5.2 to 9.9 h in monkeys and 6.9 to 11.4 h in dogs over. 3. The N-acetylated metabolite of etamicastat, represented 4-7% of the extent of exposure of etamicastat in the monkey, but was not found detectable in dogs. Gender did not influence etamicastat exposure and the concentration versus time curves fitted a dose-dependent pharmacokinetics in the dog, but not in the monkey. 4. In conclusion, etamicastat is rapidly absorbed and primarily excreted via urine in monkeys. Similarly, to humans, monkeys, unlike dogs, N-acetylate etamicastat and evidence that etamicastat pharmacokinetics is less than dose proportional.
authors: a Department of Research and Development , BIAL - Portela & Ca. S.A., S Mamede do Coronado , Portugal and.
authors: A I
authors: AI
authors: Loureiro
authors: P
authors: P
authors: Soares-da-Silva
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000818:Animals; D001578:Benzopyrans / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002250:Carbon Radioisotopes / Q000008:administration & dosage / Q000493:pharmacokinetics; D004285:Dogs; D005243:Feces; D005260:Female; D006207:Half-Life; D007093:Imidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008252:Macaca fascicularis; D008297:Male; D014018:Tissue Distribution
chemical_list: C561745:BIA 5-961; D001578:Benzopyrans; D002250:Carbon Radioisotopes; D007093:Imidazoles; C509002:etamicastat
keywords: Etamicastat; N-acetyltransferase; metabolism; monkey; pharmacokinetics