Tramadol as a New Probe for Cytochrome P450 2D6 Phenotyping: A Population Study

Background and Objective Polymorphic cytochrome P450 (CYP) 2D6 activity has been shown to be a determinant of the pharmacokinetics and pharmacodynamics of tramadol via hepatic phase I O ‐demethylation of (+)‐tramadol to (+)‐ O ‐desmethyltramadol. Our objective was to investigate whether tramadol can be used as a probe for CYP2D6 phenotyping by determining the concordance between the 8‐hour tramadol and 12‐hour sparteine metabolic urinary ratios. Methods Sparteine phenotyping test was carried out in 278 healthy, white subjects. At a minimum of 2 weeks later, each subject took 50 mg tramadol hydrochloride followed by 8‐hour urine collection, and a venous blood sample was drawn from 276 subjects. Urine and plasma concentrations of (+/−)‐tramadol and (+/−)‐ O ‐desmethyltramadol were determined. CYP2D6 genotyping was performed with regard to *3 , *4 , *6 , and *9 alleles. Results There were 28 poor metabolizers of sparteine (10.1% [confidence interval, 6.8%‐14.2%]). Very low recoveries of (+)‐M1 were found in poor metabolizers (0.53% [range, 0.1%‐1.1%]) compared with extensive metabolizers (8.7% [range, 1.7%‐23.2%]). A bimodal distribution of the metabolic ratio of (−)‐M1/(+)‐M1 was found. The visual antimode was 2.0. This new phenotype test had only 1 misclassified subject compared with sparteine phenotyping (sensitivity and negative predictive value, 100% specificity, 99.6% positive predictive value, 96.6%). Of the 28 sparteine poor metabolizers, 26 were found to be genotypically poor metabolizers with regard to the inactivating mutations *3 , *4 , and *6 . Conclusion Fifty milligrams of tramadol is an alternative CYP2D6 phenotype probe by use of the 8‐hour urinary ratio of (−)‐M1/(+)‐M1. The poor metabolizers have a metabolic ratio of 2.0 or higher. Clinical Pharmacology & Therapeutics (2005) 77 , 458–467; doi: 10.1016/j.clpt.2005.01.014