Cross-species comparison of the metabolism and excretion of selexipag

Abstract

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.

Keywords:

• Prostacyclin receptor agonist
• selexipag
• metabolism
• species difference
• rat
• dog
• monkey

Acknowledgements

We thank Dr. Gerald E. Smyth, Discovery Research Laboratories, Nippon Shinyaku Co., Ltd, for his help with the manuscript.

Disclosure statement

The authors report no declarations of interest. All experiments described in this report have been conducted in the research facilities of Nippon Shinyaku and Actelion Pharmaceuticals Ltd. During manuscript preparation review, Actelion Pharmaceuticals Ltd was acquired by Johnson & Johnson, and its drug discovery and early development activities were subsequently transferred to a newly created company, Idorsia Pharmaceuticals Ltd. With the exception of Tomohiko Ichikawa, Tetsuhiro Yamada and Kiyoko Nonaka, all authors of this report were employees of Idorsia Pharmaceuticals Ltd at the time of manuscript publication.

Additional information

Funding

This work was funded by Nippon Shinyaku Co, Ltd, Kyoto, Japan, and Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.