Loureiro Ana I, Rocha Francisco, Santos Ana T, Singh Nand, Bonifácio Maria João, Pinto Rui, Kiss Laszlo E, Soares-da-Silva Patrício
Department of Research and Development, BIAL - Portela & Cª. S.A., S Mamede do Coronado, Portugal.
Quotient Sciences - Sherwood House Mere Way, Ruddington Fields, Nottingham, UK.
Br J Clin Pharmacol. 2022 Oct;88(10):4540-4551. doi: 10.1111/bcp.15383. Epub 2022 May 20.
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.
Plasma, urine and faeces were collected from healthy male subjects following a single oral dose of 100 mg [ C]-opicapone. The mass balance of [ C]-opicapone and metabolic profile were evaluated.
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 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.
[ 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.
研究选择性儿茶酚-O-甲基转移酶抑制剂奥匹卡朋（2,5-二氯-3-(5-[3,4-二羟基-5-硝基苯基]-1,2,4-恶二唑-3-基)-4,6-二甲基吡啶1-氧化物）的吸收、代谢及排泄情况。
健康男性受试者单次口服100mg[C] -奥匹卡朋后，收集其血浆、尿液和粪便。评估[C] -奥匹卡朋的质量平衡及代谢谱。
144小时后，总给药放射性回收率平均>90%。粪便为主要排泄途径，占给药剂量的70%；5%和20%分别经尿液和呼出气体排泄。总放射性的曲线下面积与未变化的奥匹卡朋的曲线下面积匹配，而总放射性在更长时间内仍可定量，这归因于奥匹卡朋代谢产物的作用，主要是硝基儿茶酚环上的3-O-硫酸盐结合（占总循环放射性的58.6%）。其他循环代谢产物占放射性暴露的比例<10%，通过葡萄糖醛酸化、甲基化、N-氧化物还原和谷胱甘肽结合形成。此外，在2,5-二氯-4,6-二甲基吡啶1-氧化物部分与奥匹卡朋N-氧化物还原形式结合产生的各种其他代谢产物，包括硝基还原和N-乙酰化、1,2,4-恶二唑环的还原开环和裂解以及随后的水解产物均被鉴定出来，但仅在粪便中出现，提示肠道细菌参与其中。
[C] -奥匹卡朋通过多种代谢途径完全排泄。主要排泄途径是粪便，在粪便中奥匹卡朋可能通过涉及1,2,4-恶二唑环开环及随后水解的还原代谢进一步代谢。
