Metabolism of the analgesic drug, tramadol hydrochloride, in rat and dog

1. Metabolism of the analgesic agent, tramadol hydrochloride, was investiga ted after a single oral administration of C-14-tramadol to four rats (50 mg kg(-1)) and two dogs (20 mg kg(-1)). 2. Recovery of total radioactivity in rat and dog urine samples over 24 h w as 73 and 65% of the radioactive dose, respectively. 3. Unchanged tramadol and a total of 24 metabolites, consisting of 16 Phase I metabolites and eight conjugates (seven glucuronides, one sulphate), wer e isolated and tentatively identified, which accounted for > 52% of the dos e in urine of both species. 4. Of the metabolites, five (M1-5) were previously identified. 5. The metabolites were formed via the following six metabolic pathways: O- demethylation, N-demethylation, cyclohexyl oxidation, oxidative N-dealkylat ion, dehydration and conjugation. 6. Pathways 1-3 appear to be major steps, forming seven O-desmethyl/N-desme thyl and hydroxy-cyclohexyl metabolites in major quantities. 7. Pathways 1-3 in conjunction with pathway 6 produced four glucuronides al ong with four minor conjugates. 8. In addition, the in vitro metabolism of tramadol was conducted using rat hepatic S9 fraction in the presence of an NADPH-generating system. Unchang ed tramadol (30% of the sample) plus nine metabolites, M1-7, tramadol-N-oxi de (M31) and OH-cyclohexyl-M1 (M32), were profiled and tentatively identifi ed based on MS and MS/MS data.