CYP2D6 polymorphism in relation to tramadol metabolism: a study of faroese patients

Several studies have demonstrated the impact of CYP2D6 polymorphism on the pharmacokinetics of tramadol. However, the relationship between the O-demethylation of tramadol and O-desmethyltramadol (M1) and CYP2D6 activity has not previously been investigated with tramadol in multimedicated outpatients under steady-state conditions. Hence, the aim of this study was to determine if the well documented pharmacokinetics of tramadol regarding CYP2D6 could be verified in a study including 88 multimedicated Faroese patients, treated with tramadol at steady-state conditions. Further, the study aimed to investigate whether the previously observed frequency of CYP2D6 poor metabolizers (PMs) in the Faroese, which was shown to be double that of other Europeans, was evident in a patient group medicated with a CYP2D6 substrate. The patients were CYP2D6-phenotyped by the intake of sparteine, followed by urine collection over 12 hours. Sparteine and its metabolites were assayed by gas chromatography. Genotype analyses for the CYP2D6 3, 4, 6, and 9 alleles were performed by polymerase chain reaction and Taqman technology. Plasma and urinary concentrations of (+/-)-tramadol and (+/-)-M1 were determined by high-performance liquid chromatography. With use of CYP2D6 phenotyping, 10 patients (11.5% [95% confidence interval (CI), 5.7-20.1%]) were classified as CYP2D6 PMs, and 8 (9.3% [95% CI, 4.1-17.3%]) of these were genotyped as CYP2D6 PMs. The PM frequency was not statistically significantly higher than that in other European populations (7%-10%). The concentrations of (+)-M1 when corrected for dose (nM/mg) and the (+)-M1/(+)-tramadol ratio were approximately 14-fold higher in the extensive metabolizers (EMs) than in the PMs. In conclusion, the impact of the CYP2D6 polymorphism on the pharmacokinetics of tramadol was clearly demonstrated in a group of multimedicated patients treated with tramadol under steady-state conditions. Further, the frequency of PMs was not higher than that in other European populations, as previously shown in different Faroese groups, possibly because of discontinued tramadol treatment in Faroese patients who were PMs.