Evaluation of probe drugs and pharmacokinetic metrics for CYP2D6 phenotyping

Introduction Cytochrome P450 2D6 (CYP2D6) is one of the most important enzymes catalyzing biotransformation of xenobiotics in the human liver. This enzyme's activity shows a high degree of interindividual variability caused in part by its genetic polymorphism, the so-called debrisoquine/sparteine polymorphism. The genetic component influencing CYP2D6 activity can be determined by genotyping. However, genotyping alone is not sufficient to accurately predict an individual's actual CYP2D6 activity, as this is also influenced by other factors. For the determination of the exact actual enzymatic activity (phenotyping), adequate probe drugs have to be administered prior to measurements of these compounds and/or their metabolites in body fluids. Probe drugs Debrisoquine, sparteine, metoprolol or dextromethorphan represent well-established probe drugs while tramadol has been recently investigated for this purpose. The enzymatic activity is reflected by various pharmacokinetic metrics such as the partial clearance of a parent compound to the respective CYP2D6-mediated metabolite or metabolic ratios. Appropriate metrics need to fulfill pre-defined validation criteria. Methods In this review, we have compiled a list of such criteria useful to select the best metrics to reflect CYP2D6 activity. A comprehensive Medline search for reports on CYP2D6 phenotyping trials with the above mentioned probe drugs was carried out. Conclusion Application of the validation criteria suggests that dextromethorphan and debrisoquine are the best CYP2D6 phenotyping drugs, with debrisoquine having the problem of very limited availability as a therapeutic drug. However, the assessment of the best dextromethorphan CYP2D6 phenotyping metric/procedure is still ongoing.