Absorption, metabolism and excretion of opicapone in human healthy volunteers

AIMS: The absorption, metabolism and excretion of opicapone (2,5‐dichloro‐3‐(5‐[3,4‐dihydroxy‐5‐nitrophenyl]‐1,2,4‐oxadiazol‐3‐yl)‐4,6‐dimethylpyridine 1‐oxide), a selective catechol‐O‐methyltransferase inhibitor, were investigated. METHODS: Plasma, urine and faeces were collected from healthy male subjects following a single oral dose of 100 mg [(14)C]‐opicapone. The mass balance of [(14)C]‐opicapone and metabolic profile were evaluated. RESULTS: The recovery of total administered radioactivity averaged >90% after 144 hours. Faeces were the major route of elimination, representing 70% of the administered dose; 5% and 20% were excreted in urine and expired air, respectively. The C (max) of total radioactivity matched that of unchanged opicapone, whereas the total radioactivity remained quantifiable for a longer period, attributed to the contribution of opicapone metabolites, involving primarily 3‐O‐sulfate conjugation (58.6% of total circulating radioactivity) at the nitrocatechol ring. Other circulating metabolites, accounting for <10% of the radioactivity exposure, were formed by glucuronidation, methylation, N‐oxide reduction and gluthatione conjugation. Additionally, various other metabolites resulting from combinations with the opicapone N‐oxide reduced form at the 2,5‐dichloro‐4,6‐dimethylpyridine 1‐oxide moiety, including nitro reduction and N‐acetylation, reductive opening and cleavage of the 1,2,4‐oxadiazole ring and the subsequent hydrolysis products were identified, but only in faeces, suggesting the involvement of gut bacteria. CONCLUSION: [(14)C]‐opicapone was fully excreted through multiple metabolic pathways. The main route of excretion was in faeces, where opicapone may be further metabolized via reductive metabolism involving the 1,2,4‐oxadiazole ring‐opening and subsequent hydrolysis.