(3)H]Alvimopan binding to the micro opioid receptor: comparative binding kinetics of opioid antagonists

Alvimopan is a novel peripheral μ opioid antagonist in clinical development for the management of post-operative ileus and opioid-induced bowel dysfunction. We hypothesized that the long duration of action of alvimopan might be related to a slower dissociation rate from the μ opioid receptor compared to other shorter acting antagonists. The dissociation rate of alvimopan from the μ opioid receptor (t_1/2 = 30–44 min) was comparable to that of the long acting partial agonist buprenorphine (t_1/2 = 44 min), but was slower than those of the antagonists naloxone (t_1/2 = 0.82 min) and N-methylnaltrexone (t_1/2 = 0.46 min). Also, increases in the apparent affinities and potencies of buprenorphine and alvimopan, but not of naloxone and methylnaltrexone, were observed upon preincubation with the μ opioid receptor. Consistent with its long duration of action, alvimopan has a slow dissociation rate from the μ opioid receptor compared to other shorter acting antagonists and may be more potent if administered prior to dosing with exogenous opioids.