• Eike Floettmann, Khanh Bui, Mark Sostek, Kemal Payza, and Michael Eldon.
• AstraZeneca UK Ltd., Cambridge, United Kingdom (E.F.); AstraZeneca Pharmaceuticals LP, Wilmington, Delaware (K.B.); AstraZeneca Pharmaceuticals LP, Gaithersburg, Maryland (M.S.); AstraZeneca Canada, Montreal, Quebec, Canada (K.P.); and Nektar Therapeutics, San Francisco, California, Primary laboratory of origin: AstraZeneca Pharmaceuticals LP, Wilmington, Delaware (M.E.).
• J. Pharmacol. Exp. Ther. 2017 May 1; 361 (2): 280-291.

AbstractOpioid-induced constipation (OIC) is a common side effect of opioid pharmacotherapy for the management of pain because opioid agonists bind to µ-opioid receptors in the enteric nervous system (ENS). Naloxegol, a polyethylene glycol derivative of naloxol, which is a derivative of naloxone and a peripherally acting µ-opioid receptor antagonist, targets the physiologic mechanisms that cause OIC. Pharmacologic measures of opioid activity and pharmacokinetic measures of central nervous system (CNS) penetration were employed to characterize the mechanism of action of naloxegol. At the human µ-opioid receptor in vitro, naloxegol was a potent inhibitor of binding (Ki = 7.42 nM) and a neutral competitive antagonist (pA2 - 7.95); agonist effects were <10% up to 30 μM and identical to those of naloxone. The oral doses achieving 50% of the maximal effect in the rat for antagonism of morphine-induced inhibition of gastrointestinal transit and morphine-induced antinociception in the hot plate assay were 23.1 and 55.4 mg/kg for naloxegol and 0.69 and 1.14 mg/kg by for naloxone, respectively. In the human colon adenocarcinoma cell transport assay, naloxegol was a substrate for the P-glycoprotein transporter, with low apparent permeability in the apical to basolateral direction, and penetrated the CNS 15-fold slower than naloxone in a rat brain perfusion model. Naloxegol-derived radioactivity was poorly distributed throughout the rat CNS and was eliminated from most tissues within 24 hours. These findings corroborate phase 3 clinical studies demonstrating that naloxegol relieves OIC-associated symptoms in patients with chronic noncancer pain by antagonizing the µ-opioid receptor in the ENS while preserving CNS-mediated analgesia.Copyright © 2017 The Author(s).

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