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