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

• Published in: Xenobiotica 2006-06, Vol.36 (6), p.551-565
• Main Authors: Wu, W. N., McKown, L. A., Codd, E. E., Raffa, R. B.
• Format: Article
• Language: English
• Subjects: analgesic agents; Analgesics, Opioid - administration & dosage; Analgesics, Opioid - pharmacokinetics; Animals; Biotransformation; Male; metabolism; metabolite identification; Mice; Species Specificity; specific pathogen-free and axenic mice; Specific Pathogen-Free Organisms; Spectrometry, Mass, Electrospray Ionization; tramadol; Tramadol - administration & dosage; Tramadol - analogs & derivatives; Tramadol - pharmacokinetics; Tramadol-N-oxide
• ISSN: 0049-8254; 1366-5928
• DOI: 10.1080/00498250600653372

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.