Journal: The Journal of Pharmacology and Experimental Therapeutics

Article Title: Pharmacologic Profile of Naloxegol, a Peripherally Acting µ -Opioid Receptor Antagonist, for the Treatment of Opioid-Induced Constipation

doi: 10.1124/jpet.116.239061

Figure Lengend Snippet: Chemical structure of naloxegol, a PEGylated derivative of naloxol, which is derived from naloxone. The box encompasses the low molecular weight polyethylene glycol (PEG) chain that is covalently bound to the morphinan ring-based structure of naloxone.

Article Snippet: 14 C-radiolabeled naloxegol [1.0 mCi/ml; specific activity 49.5 mCi/mmol (2.80 MBq/mg); Isotope Chemistry, AstraZeneca] was stored at –20°C in the dark.

Techniques: Derivative Assay, Molecular Weight

Journal: The Journal of Pharmacology and Experimental Therapeutics

Article Title: Pharmacologic Profile of Naloxegol, a Peripherally Acting µ -Opioid Receptor Antagonist, for the Treatment of Opioid-Induced Constipation

doi: 10.1124/jpet.116.239061

Figure Lengend Snippet: Binding affinity of naloxegol to opioid receptor subtypes Data are mean ± S.E.M. values from 3 independent experiments.

Article Snippet: 14 C-radiolabeled naloxegol [1.0 mCi/ml; specific activity 49.5 mCi/mmol (2.80 MBq/mg); Isotope Chemistry, AstraZeneca] was stored at –20°C in the dark.

Techniques: Binding Assay

Journal: The Journal of Pharmacology and Experimental Therapeutics

Article Title: Pharmacologic Profile of Naloxegol, a Peripherally Acting µ -Opioid Receptor Antagonist, for the Treatment of Opioid-Induced Constipation

doi: 10.1124/jpet.116.239061

Figure Lengend Snippet: Competitive antagonism of naloxegol at the human µ -opioid receptor. The effects of 3 different concentrations of naloxegol (A) and methylnaltrexone (B) on morphine agonist concentration-response curves, as measured by guanosine 5- O -(3-[ 35 S]thio)triphosphate ([ 35 S]GTP γ S binding) (1 of 3 independent experiments) are shown. Each compound elicited a rightward shift in the morphine concentration-response curve with no reduction in E max .

Article Snippet: 14 C-radiolabeled naloxegol [1.0 mCi/ml; specific activity 49.5 mCi/mmol (2.80 MBq/mg); Isotope Chemistry, AstraZeneca] was stored at –20°C in the dark.

Techniques: Concentration Assay, Binding Assay

Journal: The Journal of Pharmacology and Experimental Therapeutics

Article Title: Pharmacologic Profile of Naloxegol, a Peripherally Acting µ -Opioid Receptor Antagonist, for the Treatment of Opioid-Induced Constipation

doi: 10.1124/jpet.116.239061

Figure Lengend Snippet: Naloxegol is a competitive neutral antagonist of morphine at the human µ -opioid receptor. This Schild plot depicts the effects of naloxegol (♦) and methylnaltrexone (▪) on morphine agonist concentration-response curves at the human µ -opioid receptor, as measured by [ 35 S]GTP γ S binding (pooled results of 3 independent experiments for each compound). Note the respective Schild slopes: –1.03 for naloxegol and –0.982 for methylnaltrexone. DR, dose ratio.

Article Snippet: 14 C-radiolabeled naloxegol [1.0 mCi/ml; specific activity 49.5 mCi/mmol (2.80 MBq/mg); Isotope Chemistry, AstraZeneca] was stored at –20°C in the dark.

Techniques: Concentration Assay, Binding Assay

Journal: The Journal of Pharmacology and Experimental Therapeutics

Article Title: Pharmacologic Profile of Naloxegol, a Peripherally Acting µ -Opioid Receptor Antagonist, for the Treatment of Opioid-Induced Constipation

doi: 10.1124/jpet.116.239061

Figure Lengend Snippet: Apparent permeability and efflux of naloxegol in the presence and absence of P-gp inhibitors, demonstrated by the Caco2 transport assay

Article Snippet: 14 C-radiolabeled naloxegol [1.0 mCi/ml; specific activity 49.5 mCi/mmol (2.80 MBq/mg); Isotope Chemistry, AstraZeneca] was stored at –20°C in the dark.

Techniques: Permeability

Journal: The Journal of Pharmacology and Experimental Therapeutics

Article Title: Pharmacologic Profile of Naloxegol, a Peripherally Acting µ -Opioid Receptor Antagonist, for the Treatment of Opioid-Induced Constipation

doi: 10.1124/jpet.116.239061

Figure Lengend Snippet: Comparative brain permeation of naloxegol in the rat Data are mean ± S.D.

Article Snippet: 14 C-radiolabeled naloxegol [1.0 mCi/ml; specific activity 49.5 mCi/mmol (2.80 MBq/mg); Isotope Chemistry, AstraZeneca] was stored at –20°C in the dark.

Techniques:

Journal: The Journal of Pharmacology and Experimental Therapeutics

Article Title: Pharmacologic Profile of Naloxegol, a Peripherally Acting µ -Opioid Receptor Antagonist, for the Treatment of Opioid-Induced Constipation

doi: 10.1124/jpet.116.239061

Figure Lengend Snippet: Quantitative whole body autoradiogram of sections through a male pigmented rat at 1 hour after the administration of a single oral dose of [ 14 C]naloxegol (50 mg/kg). Note the absence of radioactivity in the brain.

Article Snippet: 14 C-radiolabeled naloxegol [1.0 mCi/ml; specific activity 49.5 mCi/mmol (2.80 MBq/mg); Isotope Chemistry, AstraZeneca] was stored at –20°C in the dark.

Techniques: Radioactivity

Journal: The Journal of Pharmacology and Experimental Therapeutics

Article Title: Pharmacologic Profile of Naloxegol, a Peripherally Acting µ -Opioid Receptor Antagonist, for the Treatment of Opioid-Induced Constipation

doi: 10.1124/jpet.116.239061

Figure Lengend Snippet: Concentrations of radioactivity in selected tissues after administration of [ 14 C]naloxegol (50 mg/kg) to adult male and pregnant female rats

Article Snippet: 14 C-radiolabeled naloxegol [1.0 mCi/ml; specific activity 49.5 mCi/mmol (2.80 MBq/mg); Isotope Chemistry, AstraZeneca] was stored at –20°C in the dark.

Techniques: Radioactivity, Concentration Assay

Journal: The Journal of Pharmacology and Experimental Therapeutics

Article Title: Pharmacologic Profile of Naloxegol, a Peripherally Acting µ -Opioid Receptor Antagonist, for the Treatment of Opioid-Induced Constipation

doi: 10.1124/jpet.116.239061

Figure Lengend Snippet: Predicted plasma concentration-time profile for oral naloxegol 25 mg. At this maximum clinically approved dose, naloxegol exposure is predicted to be insufficient to antagonize the δ -opioid receptor. The light blue area represents the 90% confidence interval ( N = 500 simulations from phase 3 studies).

Article Snippet: 14 C-radiolabeled naloxegol [1.0 mCi/ml; specific activity 49.5 mCi/mmol (2.80 MBq/mg); Isotope Chemistry, AstraZeneca] was stored at –20°C in the dark.

Techniques: Clinical Proteomics, Concentration Assay