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.