Abstract

The metabolic fate of levallorphan was studied in the rat, mouse, guinea pig, rabbit and dog as well as in surviving liver slices from these species.

In both in vivo and in vitro studies the formation of two metabolites of levallorphan was demonstrated. These were designated Metabolite I and Metabolite II. Crystalline Metabolite I was isolated from rat urine and from rat liver incubation mixtures. Some chemical and physical properties of this metabolite are described but its structure remains unknown. Crystalline Metabolite II, isolated from rat urine, was identified as 3-hydroxymorphinan.

Quantitative aspects of the metabolic fate of levallorphan in the rat were studied. Urine collected during the first 24 hours after a single subcutaneous injection of levallorphan tartrate (250 mg per kg) was found to contain levallorphan, Metabolite I and 3-hydroxymorphinan in the following equivalent percentages of injected drug: 5.1, 6.9 and 1.5, respectively. Levallorphan and its metabolites were found to be excreted during this period largely in conjugated form (levallorphan, 75, Metabolite I, 48, and 3-hydroxymorphinan, 80% conjugated). About 1% of the administered drug was recovered as parent compound and metabolites during the second 24-hour urine collection. Only a trace (about 1%) of levallorphan and its metabolites was found in the feces collected during the 48 hours following injection. Thus, the combined recovery of unaltered drug, Metabolite I and 3-hydroxymorphinan in the excreta leaves about 85% of the administered drug unaccounted for.

When incubated with rat liver slices, levallorphan disappears rapidly. After 3 hours of incubation only about 18% of the drug was recovered as levallorphan, Metabolite I and 3-hydroxymorphinan (3.0, 12.0 and 3.4%, respectively). Most of the drug disappears during the first hour of incubation.

Evidence is presented to show that all of the species studied form 3-hydroxymorphinan. The guinea pig and the dog do not appear to form Metabolite I. Chromatographic data indicate that Metabolite I is produced by the mouse. In addition to 3-hydroxymorphinan, the rabbit makes a metabolite which differs from Metabolite I in its chromatographic behavior.