Pharmacological characterization of naloxegol: In vitro and in vivo studies.

Abstract

Opioid-induced constipation is the most prevalent adverse effect of opioid drugs. Peripherally acting mu opioid receptor antagonists (PAMORAs), including naloxegol, are indicated for the treatment of opioid-induced constipation. The aim of this study was the in vitro and in vivo pharmacological characterization of naloxegol in comparison with naloxone. In vitro experiments were performed to measure calcium mobilization in cells coexpressing opioid receptors and chimeric G proteins and mu receptor interaction with G protein and β-arrestin 2 using bioluminescence resonance energy transfer. In vivo experiments were performed in mice to measure pain threshold using the tail withdrawal assay and colonic transit using the bead expulsion assay. In vitro, naloxegol behaved as a selective and competitive mu receptor antagonist similarly to naloxone, being 3-10-fold less potent. In vivo, naloxone was effective in blocking fentanyl actions when given subcutaneously (sc), but not per os (po). In contrast, naloxegol elicited very similar effects with sc or po administration counteracting in a dose dependent manner the constipating effects of fentanyl without interfering with the fentanyl mediated analgesia. Thus, a useful PAMORA action could be obtained with naloxegol both after po and sc administration.

• Authors: Anna Costanzini, Chiara Ruzza, Joaquim Azevedo Neto, Chiara Sturaro, Davide Malfacini, Catia Sternini, Roberto De Giorgio, Girolamo Calò
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 903 Pg. 174132 (Jul 15 2021) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 33933466 (Publication Type: Comparative Study, Journal Article)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• Analgesics, Opioid
• Morphinans
• Narcotic Antagonists
• Receptors, Opioid, mu
• Naloxone
• Polyethylene Glycols
• naloxegol
• Morphine
• Calcium
• Fentanyl

Topics

• Administration, Oral
• Analgesics, Opioid (administration & dosage, adverse effects, pharmacology)
• Animals
• Behavior, Animal (drug effects)
• CHO Cells
• Calcium (metabolism)
• Constipation (chemically induced, drug therapy)
• Cricetulus
• Fentanyl (administration & dosage, adverse effects, pharmacology)
• Injections, Subcutaneous
• Male
• Mice
• Morphinans (administration & dosage, pharmacology)
• Morphine (pharmacology)
• Naloxone (administration & dosage, pharmacology)
• Narcotic Antagonists (administration & dosage, pharmacology)
• Pain (drug therapy)
• Polyethylene Glycols (administration & dosage, pharmacology)
• Receptors, Opioid, mu (antagonists & inhibitors, drug effects)