Differential tramadol and O-desmethyl metabolite levels in brain vs. plasma of mice and rats administered tramadol hydrochloride orally.

Objective: To investigate a possible differential brain uptake of tramadol vs. its major metabolite (O-desmethyl tramadol; M1) in mice and rats.
Methods: An extraction and measurement technique (gas chromatograph equipped with a nitrogen phosphorus detector) was used to measure plasma and brain levels of tramadol and M1 at intervals 10-300 min after oral dosing of tramadol hydrochloride to mice and rats.
Results: For all doses of tramadol administered (5, 10, 20, or 40 mg/kg), tramadol and M1 plasma levels were greatest 10 min after dosing: in mice, peak tramadol plasma levels were 47.75-736.72 ng/mL and peak M1 levels were 75.30-1084.92 ng/mL; in rats, peak tramadol plasma levels were 185.03-455.81 ng/mL and peak M1 levels were 106.74-455.70 ng/mL. Tramadol brain levels were also greatest 10 min after dosing. In mice, peak tramadol brain levels were 226.42-1847.46 ng/g. Peak M1 levels (72.17-572.97 ng/g) occurred 20-60 min after dosing. In rats, peak tramadol brain levels were 258.50-1777.37 ng/g and peak M1 levels were 80.35-289.60 ng/g. In mice, the ratio of tramadol/M1 in plasma was 0.5-1.0 throughout the measurements, whereas the ratio in brain was about 10 at 10 min and about 2 from 20 to 50 min. In rats, the ratio of tramadol/M1 in plasma was 0.5-1.5, whereas the ratio in brain was about 15 at 10 min and about 4-7 thereafter.
Conclusion: In mice and rats, there appears to be preferential brain vs. plasma distribution of tramadol over M1.