Pharmacokinetics of the selective prostacyclin receptor agonist selexipag in rats, dogs and monkeys

  title={Pharmacokinetics of the selective prostacyclin receptor agonist selexipag in rats, dogs and monkeys},
  author={Tomohiko Ichikawa and Tetsuhiro Yamada and Alexander Treiber and Carmela Gnerre and Kiyoko Nonaka},
  pages={186 - 196}
Abstract 1. This study examined the pharmacokinetics, distribution, metabolism and excretion of the selective prostacyclin receptor agonist selexipag (NS-304; ACT-293987) and its active metabolite MRE-269 (ACT-33679). The compounds were investigated following oral and/or intravenous administration to intact rats, dogs and monkeys, and bile-duct-cannulated rats and dogs. 2. After oral administration of [14C]selexipag, selexipag was well absorbed in rats and dogs with total recoveries of over 90… 
Cross-species comparison of the metabolism and excretion of selexipag
Overall, selexipag was eliminated via multiple routes in animals, including hydrolysis, oxidative metabolism, conjugation, intestinal deconjugation, and gut flora metabolism.
Simultaneous quantification and pharmacokinetic investigation of selexipag and its main metabolite ACT-333679 in rat plasma by UPLC-MS/MS method.
The newly developed UPLC-MS/MS assay was forward successfully used to describe the pharmacokinetic profiles of selexipag and ACT-333679 in rats after oral treatment with 6.0 mg/kg selexIPag.


The metabolism of the dual endothelin receptor antagonist macitentan in rat and dog
Metabolism was a prerequisite for macitentan excretion as relevant amounts of parent drug were neither detected in bile nor urine, and all metabolic pathways were present in rat and dog.
Selexipag: An Oral and Selective IP Prostacyclin Receptor Agonist for the Treatment of Pulmonary Arterial Hypertension.
A medicinal chemistry program searched for novel nonprostanoid prostacyclin receptor agonists not subject to these limitations and synthesized a compound with a diphenylpyrazine structural core that was developed for the treatment of pulmonary arterial hypertension and shown to reduce the risk of the composite morbidity/mortality end point in a phase 3 event-driven clinical trial.
Selexipag: First Global Approval
Oral selexipag reduced the risk of the primary composite endpoint of death or a complication related to PAH (whichever occurred first) by 40 % compared with placebo in patients with PAH, leading to this first approval for PAH.
Synthesis and evaluation of N-acylsulfonamide and N-acylsulfonylurea prodrugs of a prostacyclin receptor agonist.
N-Acylsulfonamide and N-acylsulfonylurea derivatives of the carboxylic acid prostacyclin receptor agonist 1 were synthesized and some of the compounds were shown to yield sustained plasma concentrations of 1 when they were orally administered to monkeys.
Butyrylcholinesterase, paraoxonase, and albumin esterase, but not carboxylesterase, are present in human plasma.
It is demonstrated that mice, unlike humans, have substantial amounts of soluble AChE as well as BChE in their plasma, in contrast to mouse, rat, rabbit, horse, cat, and tiger that have high amounts of plasma carboxylesterase.
2-{4-[(5,6-Diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide (NS-304), an Orally Available and Long-Acting Prostacyclin Receptor Agonist Prodrug
The findings indicate that NS-304 acts as a long-acting IP receptor agonist in vivo and is a promising drug candidate for various vascular diseases, especially pulmonary arterial hypertension and arteriosclerosis obliterans.
Selexipag: first global approval. Drugs 76:413–8
  • 2016