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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.

Aims: To determine the kinetics of the formation of 6beta-naltrexol from naltrexone in human liver cytosol, and to investigate the role of potential inhibitors., Methods: The kinetics of the formation of 6 beta-naltrexol from naltrexone were examined in eight human liver cytosol preparations using h.p.l.c. to quantify 6 beta-naltrexol and, the extent of inhibition of 6 beta-naltrexol formation was determined using chemical inhibitors. The formation of 6 beta-naltrexol and the back reaction of 6 beta-naltrexol to naltrexone were also examined in a microsomal preparation., Results: The Vmax, Km and CLint values for the formation of 6 beta-naltrexol from naltrexone were in the ranges of 16-45 nmol mg-1 protein h-1, 17-53 microM and 0.3-2.2 ml h-1 mg-1 protein, respectively. The steroid hormones testosterone (Ki = 0.3 +/- 0.1 microM) and dihydrotestosterone (Ki = 0.7 +/- 0.4 microM) were the most potent competitive inhibitors of 6 beta-naltrexol formation, with naloxone, menadione and corticosterone also producing > 50% inhibition at a concentration of 100 microM. The opioid agonists morphine, oxycodone, oxymorphone and hydromorphone, and a range of benzodiazepines showed < 20% inhibition at 100 microM. In the microsomal preparation, there was no formation of naltrexone from 6beta-naltrexol nor any formation of 6beta-naltrexol from naltrexone., Conclusions: The intersubject variability in the kinetic parameters of 6beta-naltrexol formation could play a role in the efficacy of and patient compliance with naltrexone treatment. This variability could be due in part to a genetic polymorphism of the dihydrodiol dehydrogenase DD4, one of the enzymes reported to be responsible for the formation of 6beta-naltrexol from naltrexone. DD4 also has hydroxysteroid dehydrogenase activity which could account for the potent inhibition by the steroid hormones testosterone and dihydrotestosterone. The clinical significance of the latter finding remains to be established.