The metabolism of (-)-3-phenoxy-N-methylmorphinan in dogs

The disposition of radioactive (-)-3-phenoxy-N-methyl[2-3H]morphinan in dogs after oral administration has been investigated. Unchanged drug was not found in bile, urine, or feces. Excretion of total radioactivity in feces ranged from 67 to 78% of an oral dose. Two unconjugated metabolites were isolated from feces and identified by NMR and GC/MS. Both were substituted on the phenoxy group; they were found to be the p-hydroxy (pOH-PMM) and the m-methoxy-p-hydroxy (mOCH3-pOH-PMM) metabolites. Further, levorphanol and norlevorphanol were identified in feces both as free and conjugated metabolites, as well as a small amount of levomethorphan. Urine contained mostly unknown metabolites and conjugated levorphanol and pOH-PMM. Although the glucuronide of mOCH3-pOH-PMM was the major metabolite in bile, smaller amounts of the glucuronide and sulfate conjugated of both levorphanol and pOH-PMM were also found. Estimates for the total urinary and fecal excretion (as percentages of the dose) by two dogs for the five known metabolites were as follows: levorphanol, 18.8-21.5%; pOH-PMM, 14.4-20.6%; mOCH3-pOH-PMM, 14.9%; norlevorphanol, 2.8-6.1%; levomethorphan, 0.5%. Two of these metabolites, pOH-PMM and levorphanol, are potent analgesics.