Polymorphic CYP2D6 mediates O-demethylation of the opioid analgesic tramadol

Objective: This study was designed to investi gate whether the in vivo metabolism of tramadol was influenced by CYP2D6 polymorphism. Methods: The extent of tramadol 0- and N-demethylation was calculated by determining the amounts of tramadol and 0- and N-desmethyltramadol in 24 h urine after ingestion of a test dose of tramadol. The 0- and N-demethylation rates were calculated by dividing the 24-h urinary excretion amount of tramadol by that of O-and N-desmethyltramadol. Volunteers were phenotyped for CYP2D6 polymorphism using sparteine as an in vivo probe. Results and conclusion: High correlation was found between tramadol-O-demethylation and sparteine oxidation in 71 extensive metabolizers of sparteine (r(s) = 0.544). The mean metabolic ratio of tramadol O-demethylation was significantly higher in poor metabolizers of sparteine than in extensive metabolizers (4.4 vs 0.8). These in vivo results confirm that tramadol O-demethylation is carried out to a large extent by the polymorphic CYP2D6.