Publication Cover
Xenobiotica
the fate of foreign compounds in biological systems
Volume 48, 2018 - Issue 7
617
Views
13
CrossRef citations to date
0
Altmetric
Clinical Pharmacokinetics and Metabolism

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

, , , , , , , , & show all
Pages 704-719 | Received 29 May 2017, Accepted 15 Jul 2017, Published online: 30 Aug 2017
 

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.

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.

Log in via your institution

Log in to Taylor & Francis Online

PDF download + Online access

  • 48 hours access to article PDF & online version
  • Article PDF can be downloaded
  • Article PDF can be printed
USD 65.00 Add to cart

Issue Purchase

  • 30 days online access to complete issue
  • Article PDFs can be downloaded
  • Article PDFs can be printed
USD 897.00 Add to cart

* Local tax will be added as applicable

Related Research

People also read lists articles that other readers of this article have read.

Recommended articles lists articles that we recommend and is powered by our AI driven recommendation engine.

Cited by lists all citing articles based on Crossref citations.
Articles with the Crossref icon will open in a new tab.