Plasma levels of tramadol and O-des- methyltramadol enantiomers in patients with different CYP2D6 genotypes

Objective: The influence of the number of active CYP2D6 alleles on enantiomeric plasma levels of tramadol (T) and its M1 metabolite O-desmethyltramadol (ODT) and the response to postoperative tramadol analgesia was investigated. Methods: After abdominal surgery the plasma levels of T and ODT enantiomers were measured after an intravenous bolus application of tramadol of 3 mg/kg body weight. Subsequent postoperative analgesia over 48 hours was performed by patient controlled analgesia. Blood samples were drawn 30, 90 and 180 min after initial infusion of T. Concentrations of the T enantiomers (+)-T, (-)-T, and metabolites (+)-ODT and (-)-ODT were analyzed by liquid chromatography–tandem mass spectrometry. Genotyping was performed for CYP2D6 polymorphisms and the gene duplication by PCR and real-time PCR. Concentration of T and ODT enantiomers between patients with no, one, two, or at least three functionally active CYP2D6 alleles as well as response to T medication were compared. Results: Demographic and surgery related data were comparable between the four different genotypes. Number of active alleles was correlated to metabolic capacity of CYP2D6. Patients with no active CYP2D6 allele showed the highest levels for T and negligible plasma levels for +ODT. Non response rates to pharmacologic treatment in patients with no active allele were more than doubled compared to patients with at least one wild type allele (p<0.001). Conclusions: CYP2D6 genetic variations determine plasma levels of T and ODT enantiomers and influence efficacy of T treatment.