Labelling studies for structure elucidation of a new hydroxymetabolite of tramadol

Tramadol, racemic 1-(3-methoxyphenyl)-2-(dimethylamino methyl)cyclohexane-1 -ol, is an effective analgesic drug. Metabolites of tramadol described so f ar originate from O- and N-demethylation and are excreted in urine directly or after conjugation. A further metabolite was found in human liver micros ome incubations and in the urine of volunteers after ingestion of tramadol. To elucidate the structure of the new metabolite, seven deuterated isotopo mers of tramadol have been synthesized and ingested by volunteers. The mass spectra of the metabolites derived showed (i) that it was a hydroxy metabo lite, (ii) that the hydroxy group was not located on the aromatic ring, the side chain, or the positions 2 and 6 of the cyclohexane ring, (iii) that t he hydroxy-group was introduced to one of the the positions 3, 4 or 5 of th e cyclohexane ring. The hydroxy metabolite was formed preferentially from t he (-)-enantiomer, (1S,2S)-tramadol.