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Metabolism of two analgesic agents, tramadol-n-oxide and tramadol, in specific pathogen-free and axenic mice
1Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Spring House, PA 19477, USA.
Abstract:
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.
Insights
Tramadol and tramadol-N-oxide undergo extensive metabolism in mice, forming numerous metabolites via O/N-demethylation and oxidation. Differences in metabolism between specific pathogen-free and axenic mice were minimal.
Area of Science:
- Pharmacology
- Drug Metabolism
- Toxicology
Background:
- Tramadol is a widely used analgesic.
- Understanding its metabolic pathways is crucial for optimizing therapeutic use and identifying potential drug interactions.
- Tramadol-N-oxide (TNO) is a known metabolite of tramadol.
Purpose of the Study:
- To investigate and compare the in vivo metabolism of tramadol and TNO in mice.
- To identify and characterize novel metabolites.
- To explore potential differences in metabolism between specific pathogen-free and axenic mice.
Main Methods:
- Oral administration of tramadol and TNO to specific pathogen-free and axenic mice.
- Urine sample collection over 0-24 hours post-dose.
- Profiling, quantification, and tentative identification of metabolites using atmospheric pressure ionization mass spectrometry (API-MS) and tandem mass spectrometry (MS/MS).
Main Results:
- Both tramadol and TNO were extensively metabolized, with unchanged TNO and tramadol representing <=42% and <=15% of the dose, respectively.
- 23 metabolites from TNO and 20 from tramadol were identified, including six novel metabolites (M18-23).
- Major metabolic pathways included N-oxide reduction, O/N-demethylation, cyclohexyloxidation, and glucuronidation. Minimal qualitative and quantitative differences were observed between mouse groups, except for higher unchanged TNO in axenic mice.
Conclusions:
- Tramadol and TNO are extensively metabolized in mice through various pathways.
- Several novel metabolites were identified, expanding the understanding of tramadol's metabolic profile.
- The gut microbiota does not appear to play a significant role in the overall metabolism of tramadol and TNO in mice.
