Disposition and metabolism of setipiprant, a selective oral CRTH2 antagonist, in humans.

Abstract

BACKGROUND:

Setipiprant, a tetrahydropyridoindole derivative, is a CRTH2 (chemoattractant receptor-homologous molecule expressed on T-helper [Th]-2 cells) antagonist that has the potential to be effective in the treatment of patients with diseases with an allergic etiology, such as allergic rhinitis and asthma.

OBJECTIVES:

This study investigated the disposition, metabolism, and elimination of setipiprant.

STUDY DESIGN:

In this open-label study, a single oral dose of 1,000 mg (14)C-labeled setipiprant was administered.

PARTICIPANTS:

Six healthy male subjects were enrolled in this study.

RESULTS:

The radioactive dose was almost completely recovered in feces (88.2 %) and to a smaller extent in urine (11.7 %). The main recovery route for unchanged setipiprant was feces (50 % of the radioactive dose). The recovered amount of unchanged setipiprant in urine accounted for 3.7 %. The two main metabolites were M7 and M9 with the intact tetrahydropyridoindole core of setipiprant. M7 and M9 are supposedly two distinct dihydroxy-dihydronaphthalene isomers assumed to be formed by intermediate epoxidation of the naphthyl ring followed by a hydrolytic epoxide ring-opening. M7 and M9 accounted for 20.0 and 15.3 % of the administered radioactive dose. Both metabolites were mainly excreted via feces and to a lesser extent via urine. M7 was the only metabolite quantifiable in plasma, but at concentrations consistently below 10 % of those of the parent drug.

CONCLUSION:

Setipiprant is mainly excreted in feces in the form of the parent drug and in smaller amounts as its metabolites M7 and M9.

• Authors: Matthias Hoch, Janine Wank, Ina Kluge, Winfried Wagner-Redeker, Jasper Dingemanse
• Journal: Drugs in R&D (Drugs R D) Vol. 13 Issue 4 Pg. 253-69 (Dec 2013) ISSN: 1179-6901 [Electronic] New Zealand
• PMID: 24214422 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-(2-(1-naphthoyl)-8-fluoro-3,4-dihydro-1H-pyrido(4,3-b)indol-5(2H)-yl)acetic acid
• Carbon Radioisotopes
• Indoles
• Naphthalenes
• Receptors, Immunologic
• Receptors, Prostaglandin
• prostaglandin D2 receptor

Topics

• Administration, Oral
• Aged
• Carbon Radioisotopes
• Feces (chemistry)
• Humans
• Indoles (administration & dosage, pharmacokinetics)
• Male
• Middle Aged
• Naphthalenes (administration & dosage, pharmacokinetics)
• Receptors, Immunologic (antagonists & inhibitors)
• Receptors, Prostaglandin (antagonists & inhibitors)