Metabolism of the enantiomers of 2-hydroxy-N-cyclopropylmethylmorphinan in dog and man.

The major metabolic pathway of the (-) enantiomer and the (+) enantiomer of 2-hydroxy-N-cyclopropylmethylmorphinan in dogs was shown to be conjugation with glucuronic acid and/or sulfate. Gas chromatography mass spectrometry, nuclear magnetic resonance spectroscopy and X-ray crystallography were used to identify additional metabolites of the two enantiomers in dog urine after hydrolysis with Glusulase. Metabolites of the (-) enantiomer were identified as 2-hydroxymorphinan and 2,7beta-dihydroxy-N-cyclopropropylmethylmorphinan. The major metabolites of the (+) enantiomer in hydrolyzed dog urine were identified as 2-hydroxymorphinan,2,3-dihydroxy-N-cyclopropylmethylmorphinan and 2-methoxy-3-hydroxy-N-cyclopropylmethylmorphinan. In addition, tentative or partial structures were postulated for three minor metabolites of the (+) enantiomer: 2-methoxy-3-hydroxymorphinan, a metabolite containing a hydroxyl group on either carbon 4, 5, 6 or 7 and a methylated catechol metabolite containing a hydroxyl group on carbon 4, 5, 6 or 7. Thus, the major oxidative pathways of the (-) enantiomer were N-dealkylation and aliphatic hydroxylation, while the (+) enantiomer mainly underwent N-dealkylation and aromatic hydroxylation, followed by phenolic methylation. Analysis of urine from a human subject administered the (-) enantiomer suggested that the metabolism of this isomer by man was similar to its metabolism by dog.