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 (< or =42% of the initial drug sample), tramadol, and 23 metabolites from TNO-treated mice and unchanged tramadol (< or =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.
Wu
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WN
Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Spring House, PA 19477, USA.
McKown
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LA
Codd
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EE
Raffa
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RB
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000818:Animals; D001711:Biotransformation; D008297:Male; D051379:Mice; D013045:Species Specificity; D013047:Specific Pathogen-Free Organisms; D021241:Spectrometry, Mass, Electrospray Ionization; D014147:Tramadol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
D000701:Analgesics, Opioid; C101588:tramadol N-oxide; D014147:Tramadol