Narcotic Antagonist Activity of Several Metabolites of Naloxone and Naltrexone Tested in Morphine Dependent Mice 1

Abstract

Summary

A rabbit liver enzyme system was used to produce the 6β-OH reduced metabolites of naloxone and naltrexone. GC analysis indicated the presence of some 6α-0H metabolite in these samples. The narcotic antagonist activity of these 6β-OH metabolite samples were compared to nalox-one, naltrexone and standard 6α-OH nalox-one (EN 2265A) and 6α-OH naltrexone (EN 2260A) using the jumping response of morphine pellet implanted mice. For the nal-oxone series, the potencies were: Naloxone > EN 2265A > 6β-OH naloxone. For the naltrexone series: Naltrexone > EN 2260A > 6β-OH naltrexone. The low potency of the reduced metabolites and the rapid onset of action of the parent compounds militate against the formation of these metabolites contributing substantially to the overall narcotic antagonist action of the parent compounds.

The authors wish to acknowledge the excellent technical assistance of Miss Ann Klecker. Dr. Harold Blumberg of Endo Laboratories generously provided the naloxone, naltrexone, EN 2265 and EN 2260.