In vivo and in vitro potency studies of 6beta-naltrexol, the major human metabolite of naltrexone.

Naltrexone, a mu opioid receptor antagonist, is used in the treatment of opioid and alcohol dependence. Naltrexone's longer duration of action compared to naloxone has been considered to be due partly to its major human metabolite, 6beta-naltrexol. To date, no studies have examined the in vitro or in vivo potency of 6beta-naltrexol compared to naltrexone and naloxone. In the electrically-stimulated guinea pig ileum, 6beta-naltrexol was more potent (K(i) = 94 +/- 25 pM), than naloxone (420 +/- 150 pM), and naltrexone (265 +/- 101 pM). In vivo comparative potencies were assessed using the mouse hotplate test and morphine (agonist), with doses of the antagonists from 0.001 to 30 mg/kg. The order of potency was naltrexone (ID(50) 7 microg/kg), naloxone (ID(50) 16 microg/kg) and 6beta-naltrexol (ID(50) 1300 microg/kg). Antagonist ID(50) doses were then administered at 45, 90, 120, 180 and 1080 minutes prior to morphine administration. The duration of antagonist activity to decrease by 50% was 80, 125 and 340 minutes for naltrexone, naloxone and 6beta-naltrexol, respectively. 6beta-naltrexol is highly potent in the guinea pig ileum, but much less so in vivo after an acute dose. However, the potency of 6beta-naltrexol in vivo is time-dependent, and it has a longer duration of action than naloxone and naltrexone, consistent with a pharmacokinetic longer terminal half-life. Therefore, 6beta-naltrexol is likely to contribute to the efficacy of naltrexone in humans.