The metabolism and drug–drug interaction potential of the selective prostacyclin receptor agonist selexipag

Abstract

1. The metabolism of selexipag has been studied in vivo in man and the main excreted metabolites were identified. Also, metabolites circulating in human plasma have been structurally identified and quantified.

2. The main metabolic pathway of selexipag in man is the formation of the active metabolite ACT-333679. Other metabolic pathways include oxidation and dealkylation reactions. All primary metabolites undergo subsequent hydrolysis of the sulphonamide moiety to their corresponding acids. ACT-333679 undergoes conjugation with glucuronic acid and aromatic hydroxylation to P10, the main metabolite detected in human faeces.

3. The formation of the active metabolite ACT-333679 is catalysed by carboxylesterases, while the oxidation and dealkylation reactions are metabolized by CYP2C8 and CYP3A4. CYP2C8 is the only P450 isoform catalysing the aromatic hydroxylation to P10. CYP2C8 together with CYP3A4 are also involved in the formation of several minor ACT-333679 metabolites. UGT1A3 and UGT2B7 catalyse the glucuronidation of ACT-333679.

4. The potential of selexipag to inhibit or induce cytochrome P450 enzymes or drug transport proteins was studied in vitro. Selexipag is an inhibitor of CYP2C8 and CYP2C9 and induces CYP3A4 and CYP2C9 in vitro. Also, selexipag inhibits the transporters OATP1B1, OATP1B3, OAT1, OAT3, and BCRP. However, due to its low dose and relatively low unbound exposure, selexipag has a low potential for causing drug–drug interactions.

Keywords:

• Cytochrome P450
• drug interaction
• drug transporter
• metabolism in man
• prostacyclin receptor agonist
• selexipagl

Acknowledgments

The authors would like to thank Noura Akel, Julia Friedrich, Joëlle Pichot, Ervan Hauy and Ali Selimi for their dedication and experimental contributions and Hashem Salloukh and Alexey Veligodskiy for their assistance in the preparation of this manuscript.

Declaration of interest

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

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