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 [¹⁴C]-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 [¹⁴C]-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.

• Etamicastat
• metabolism
• monkey
• N-acetyltransferase
• pharmacokinetics

Declaration of interest

A.I.L. and P.S.S. have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and A.I.L. and P.S.S. were employees of BIAL – Portela & C^a, S.A. in the previous 3 years. BIAL – Portela & C^a, S.A. supported this study.