Metabolism of two analgesic agents, tramadol-n-oxide and tramadol, in specific pathogen-free and axenic mice

The in vivo metabolism of both tramadol-N-oxide ( TNO) and tramadol was investigated in urine pools obtained from 0 - 24 h after a single 300 mg kg - 1 oral dose administration of each compound to specific pathogen-free and axenic mice. Unchanged TNO ( <= 42% of the initial drug sample), tramadol, and 23 metabolites from TNO-treated mice and unchanged tramadol ( <= 15% of the sample) plus 20 metabolites from tramadol-treated mice were profiled, quantified and tentatively identified on the basis of atmospheric pressure ionization mass spectrometry ( API-MS) and tandem mass spectrometry ( MS/MS) data. Of the tramadol metabolites, five ( M1-5) have been previously identified in mice. Of the tramadol and TNO metabolites, six ( M18-23) are new metabolites. The tramadol and TNO metabolites were formed via the following seven metabolic pathways: N-oxide reduction ( TNO), O/N-demethylation, cyclohexyloxidation, oxidative N-dealkylation, dehydration ( TNO), N-oxidation ( tramadol), and glucuronidation. Pathways 1 - 3 appear to be predominant steps forming four major O/N-desmethyl and hydroxycyclohexyl metabolites, and in conjunction with pathway 7, formed six minor glucuronides. Both tramadol-N-oxide and tramadol are extensively metabolized in mice, and no significant qualitative or quantitative differences in metabolism were observed between specific pathogen-free and axenic mice with the exception of a greater amount of unchanged TNO in axenic mice than in specific pathogen-free mice, more M2 in specific pathogen-free mice than in axenic mice in the TNO-dosed mice, and visa versa for M2 of tramadol-dosed mice.