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 6b-naltrexol from naltrexone in human liver cytosol, and to investigate the role of potential inhibitors. Methods The kinetics of the formation of 6b-naltrexol from naltrexone were examined in eight human liver cytosol preparations using h.p.l.c. to quantify 6b-naltrexol and, the extent of inhibition of 6b-naltrexol formation was determined using chemical inhibitors. The formation of 6b-naltrexol and the back reaction of 6b-naltrexol to naltrexone were also examined in a microsomal preparation. Results The V max , K m and CL int values for the formation of 6b-naltrexol from naltrexone were in the ranges of 16±45 nmol mg x1 protein h x1 , 17±53 mM and 0.3±2.2 ml h x1 mg x1 protein, respectively. The steroid hormones testosterone (K i =0.3t0.1 mM) and dihydrotestosterone (K i =0.7t0.4 mM) were the most potent competitive inhibitors of 6b-naltrexol formation, with naloxone, menadione and corticosterone also producing >50% inhibition at a concentration of 100 mM. The opioid agonists morphine, oxycodone, oxymorphone and hydromorphone, and a range of benzodiazepines showed <20% inhibition at 100 mM. In the microsomal preparation, there was no formation of naltrexone from 6b-naltrexol nor any formation of 6b-naltrexol from naltrexone.Conclusions The intersubject variability in the kinetic parameters of 6b-naltrexol formation could play a role in the ef®cacy 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 6b-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 signi®cance of the latter ®nding remains to be established.

Irinotecan eluting embolization beads (DEBIRI) are currently being evaluated in the clinic for the treatment of colorectal cancer metastases to the liver. The aim of this study was to determine the safety and pharmacokinetics associated with two cycles of hepatic embolization using DEBIRI followed by intravenous administration of irinotecan. Pigs were embolized with DEBIRI (100–300 μm, 100 mg dose, n = 6) and blood samples taken over 24 h to determine plasma levels of irinotecan and SN-38 metabolite and for haematology and biochemistry. At 24 h an IV infusion of 250 mg/m2 of irinotecan was administered and the plasma levels taken again. This cycle was repeated 3 weeks later. A single animal was subjected to a more aggressive regimen of embolization with 200 mg bead dose and IV of 350 mg/m2 for two cycles. Three animals were sacrificed at 6 weeks and the remaining four (n = 3 standard dose, n = 1 high dose) animals at 12 weeks and detailed histopathology performed. All animals tolerated the treatments well, with only minor changes in haematological and biochemical parameters. There was no overlap in drug plasma levels observed from the bead and IV treatments when given 24 h apart and no difference between the pharmacokinetic profiles of the two cycles separated by 3 weeks. Irinotecan plasma AUC values were similar in both the embolization and IV arms of the study. Cmax values obtained during the IV arms of the study are approximately double that of the embolization arms whilst Tmax times are shorter in the IV arms, supporting extended release of drug from the beads. Bioavailability for bead-based delivery was double that for IV administration, which was attributed to reduced clearance of the drug when delivered by this route. No additive toxicity was observed as a consequence of the combined treatments. The combination of irinotecan delivery via drug eluting bead and IV was well-tolerated with no significant clinical effects. Pharmacokinetic analyses suggest the bioavailability from bead-based delivery of drug is double that of IV infusion, attributable to reduced drug clearance for the former.