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

Pharmacological characterization of naloxegol: In vitro and in vivo studies

  • Eur J Pharmacol. 2021 Jul 15;903:174132. doi: 10.1016/j.ejphar.2021.174132.
Anna Costanzini 1 Chiara Ruzza 2 Joaquim Azevedo Neto 3 Chiara Sturaro 3 Davide Malfacini 4 Catia Sternini 5 Roberto De Giorgio 1 Girolamo Calò 4
Affiliations

Affiliations

  • 1 Department Translational Medicine, St. Anna University Hospital, University of Ferrara, Ferrara, Italy.
  • 2 Department of Neuroscience and Rehabilitation, Section of Pharmacology, University of Ferrara, Ferrara, Italy; LTTA Laboratory for Advanced Therapies, Technopole of Ferrara, Ferrara, Italy. Electronic address: chiara.ruzza@unife.it.
  • 3 Department of Neuroscience and Rehabilitation, Section of Pharmacology, University of Ferrara, Ferrara, Italy.
  • 4 Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Italy.
  • 5 Digestive Disease Division, Departments of Medicine and Neurobiology, University of California at Los Angeles, Los Angeles, CA, USA.
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.

Keywords

BRET assay; Bead expulsion assay; Calcium mobilization assay; Naloxegol; Naloxone; PAMORA; Tail withdrawal assay.

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