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Distribution, metabolism and elimination of opicapone in the rats and non‐human primates
Author(s) -
Loureiro Ana,
FernandesLopes Carlos,
SoaresdaSilva Patrício
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.712.9
Subject(s) - pharmacokinetics , urine , dosing , oral administration , pharmacology , medicine
Objectives Pharmacokinetic evaluation of opicapone in Cynomolgus monkey and Wistar rat. Methods Opicapone disposition was evaluated in the Cynomolgus monkey and Wistar rat after intravenous (1 mg/kg) and oral administration (10 mg/kg) of [14C]‐opicapone. Results Five to seven days after administration of [14C]‐opicapone, more than 89.0% and more than 68% of opicapone related radioactivity has been excreted in rats and in monkeys, respectively. The radioactivity peaked in plasma at 4 and 0.25 h post‐dosing in rats and monkeys, respectively, followed by a quick decline and a very slow terminal phase. Opicapone related radioactivity were mainly recovered via the biliary route with a very low levels (less than 10%) excreted in urine in both species, rat and monkey. Whole body autoradiography studies in rat following single oral administration of [14C]‐opicapone (10 mg/kg), indicate that radioactivity was rapidly absorbed and distributed throughout the body. The high tissue to blood ratio of total radioactivity observed in liver and kidney at 48h post‐dosing suggests a slower elimination of opicapone related radioactivity from this tissues. Following oral administration of 1000 mg/kg opicapone, opicapone 3‐O‐sulfate, glucuronidation 3‐O‐glucuronide and the N‐oxide reduced form of opicapone were quantified in rat and monkey. With exception of N‐oxide reduced form for which the AUC0‐t was 13‐fold higher in monkeys, the exposure to opicapone and quantified metabolites were higher in rat. Conclusions Opicapone was found to be rapidly absorbed and primarily excreted via feaces in the Cynomolgus monkey and the Wistar rat. Differences in opicapone and metabolites exposure were noticed between species.