1. The metabolism of the prostacyclin receptor agonist selexipag (NS-304; ACT-293987) and its active metabolite MRE-269 (ACT-333679) has been investigated in liver microsomes and hepatocytes of rats, dogs, and monkeys. MRE-269 formation is the main pathway of selexipag metabolism, irrespective of species. Some interspecies differences were evident for both compounds in terms of both metabolic turnover and metabolic profiles. The metabolism of MRE-269 was slower than that of selexipag in all three species.

2. The metabolism of selexipag was also studied in bile-duct-cannulated rats and dogs after a single oral and intravenous dose of [¹⁴C]selexipag. MRE-269 acyl glucuronide was found in both rat and dog bile. Internal acyl migration reactions of MRE-269 glucuronide were identified in an experiment with the synthetic standard MRE-6001.

3. MRE-269 was the major component in the faeces of rats and dogs. In ex vivo study using rat and dog faeces, selexipag hydrolysis to MRE-269 by the intestinal microflora is considered to be a contributory factor in rats and dogs.

4. A taurine conjugate of MRE-269 was identified in rat bile sample. Overall, selexipag was eliminated via multiple routes in animals, including hydrolysis, oxidative metabolism, conjugation, intestinal deconjugation, and gut flora metabolism.

1.已在大鼠，犬和猴子的肝微粒体和肝细胞中研究了前列环素受体激动剂selexipag（NS-304; ACT-293987）及其活性代谢产物MRE-269（ACT-333679）的代谢。MRE-269的形成是selexipag代谢的主要途径，与物种无关。就代谢转换和代谢谱而言，两种化合物之间存在某些种间差异。在这三个物种中，MRE-269的代谢都比selexipag的慢。

2.还对单次口服和静脉内剂量的[ ¹⁴ C] selexipag的胆管插管大鼠和狗进行了selexipag的代谢研究。在大鼠和狗的胆汁中均发现了MRE-269酰基葡糖醛酸苷。使用合成标准品MRE-6001在实验中鉴定了MRE-269葡糖醛酸苷的内部酰基迁移反应。

3. MRE-269是大鼠和狗粪便中的主要成分。在使用大鼠和狗粪便的体内研究中，肠道菌群将selexipag水解为MRE-269被认为是大鼠和狗中的一个促成因素。

4.在大鼠胆汁样品中鉴定出MRE-269的牛磺酸缀合物。总体而言，selexipag在动物中通过多种途径消除，包括水解，氧化代谢，结合，肠道去结合和肠道菌群代谢。